Long-term renal survival in patients with IgA nephropathy: a systematic review.

The management strategy for IgA nephropathy (IgAN), has undergone constant improvements since the disease entity was first described 50 years ago. However, it is still unknown how these changes affected the long-term renal survival of IgAN patients. We systematically evaluate changes in IgAN renal survival by searching PubMed, Embase, and the Cochrane Library Database of Systematic Reviews from inception to 19 May 2024. We included a large sample of 103076 IgAN cases from 158 studies. Renal survival rates were 94.16% (95% CI: 94.02% to 94.31%), 88.68% (95% CI: 88.48% to 88.87%), and 78.13% (95% CI: 77.82% to 78.43%) at three, five, and ten-year, respectively. Over the past few decades, there haven't been any sound changes in the 3-year and 5-year renal survival rates. The kidney survival rate in developed countries is higher than in developing countries. Researchers consistently show that while proteinuria < 1.0 g/24 h, renal survival rates increase dramatically. In IgAN, long-term renal survival fluctuated rather than continuously improving over time. Our system review's findings indicate that supportive care-the most important recommendation for managing IgAN has shown promising results. The long-term outcomes of IgAN could be significantly improved by the latest developed treatment options.

Adverse renal outcomes following targeted therapies in renal cell carcinoma: a systematic review and meta-analysis.

Introduction: To clarify the prevalence of adverse renal outcomes following targeted therapies in renal cell carcinoma (RCC). Methods: A systematic search was performed in MEDLINE, EMBASE, and Cochrane Central Library. Studies that had reported adverse renal outcomes following targeted therapies in RCC were eligible. Outcomes included adverse renal outcomes defined as either renal dysfunction as evidenced by elevated serum creatinine levels or the diagnosis of acute kidney injury, or proteinuria as indicated by abnormal urine findings. The risk of bias was assessed according to Cochrane handbook guidelines. Publication bias was assessed using Funnel plot analysis and Egger Test. Results: The occurrences of the examined outcomes, along with their corresponding 95% confidence intervals (CIs), were combined using a random-effects model. In all, 23 studies including 10 RCTs and 13 observational cohort studies were included. The pooled incidence of renal dysfunction and proteinuria following targeted therapies in RCC were 17% (95% CI: 12%-22%; I2 = 88.5%, p < 0.01) and 29% (95% CI: 21%-38%; I2 = 93.2%, p < 0.01), respectively. The pooled incidence of both types of adverse events varied substantially across different regimens. Occurrence is more often in polytherapy compared to monotherapy. The majority of adverse events were rated as CTCAE grades 1 or 2 events. Four studies were assessed as having low risk of bias. Conclusion: Adverse renal outcomes reflected by renal dysfunction and proteinuria following targeted therapies in RCC are not uncommon and are more often observed in polytherapy compared to monotherapy. The majority of the adverse events were of mild severity. Systematic Review Registration: Identifier CRD42023441979.

Hypoxia-inducible factor-prolyl hydroxylase inhibitors for treatment of anemia in chronic kidney disease: a systematic review and network meta-analysis.

Purpose: To review current evidence on the efficacy and safety outcomes of HIF-PHIs in chronic kidney disease (CKD) populations with an emphasize on the safety profile. Methods: A systematic search was conducted in the Medline, Embase, and Cochrane Central databases. Randomized controlled trials that had assessed the efficacy and safety of HIF-PHIs for anemia in CKD were included. The efficacy outcome included change of hemoglobin and the safety outcomes any adverse events, severe adverse events, major adverse cardiovascular events, and mortality. The qualities of studies were assessed using the Cochrane ROB tool. Results: 47 studies encompassing 55 RCTs for the study outcomes were included in this study. All six commercially available HIF-PHIs had direct comparisons to ESA and placebo, yet lacked direct comparisons among each other. The network analysis demonstrated all six HIF-PHIs were able to effectively elevate hemoglobin in the general CKD patients compared to placebo. All HIF-PHIs did not differ among each other in the efficacy of correcting anemia. Roxadustat and daprodustat had the largest number of reports in terms of adverse events. The overall risk of each safety outcome did not increase in comparison to erythropoiesis stimulating agent (ESA) or placebo, and did not differ among different types of HIF-PHIs. Conclusion: HIF-PHIs can effectively elevate hemoglobin without causing higher risk of safety concerns in CKD patients with anemia. Further evidence from long-term studies and the ongoing post-market surveillance is necessary.

The predictive value of systemic immune-inflammation index for vascular access survival in chronic hemodialysis patients.

Objective: To examine the prognostic values of systemic immune-inflammation indices of hemodialysis (HD) vascular access failure and develop a prediction model for vascular access failure based on the most pertinent systemic immune-inflammation index. Study design: A prospective cohort study. Setting & participants: Patients undergoing autogenous HD vascular access surgeries or arteriovenous graft as a permanent hemodialysis access in a tertiary center in southwest China from January 2020 to June 2022. Predictors: Systemic immune-inflammation indices, including NLR, dNLR, AAPR, SIRI, SII, PNI, PLR, and LIPI, and clinical variables. Outcomes: The outcome was defined as survival of the hemodialysis access, with both occluded and stenotic access being considered as instances of access failure. Analytical approach: Cox proportional hazard regression model. Results: 2690 patients were included in the study population, of whom 658 experienced access failure during the follow-up period. The median duration of survival for HD vascular access was 18 months. The increased systemic immune-inflammation indices, including dNLR, NLR, SII, PNI, SIRI, PLR, and LIPI, are predictive of HD access failure, with SII demonstrating the strongest prognostic value. A simple SII-based prediction model for HD access failure was developed, achieving C-indexes of 0.6314 (95% CI: 0.6249 - 0.6589) and 0.6441 (95% CI: 0.6212 - 0.6670) for predicting 6- and 12-month access survival, respectively. Conclusions: Systemic immune-inflammation indices are significantly and negatively associated with HD vascular access survival. A simple SII-based prediction model was developed and anticipates further improvement through larger study cohort and validation from diverse centers.

Clinical Pharmacology Strategies for Bispecific Antibody Development: Learnings from FDA-Approved Bispecific Antibodies in Oncology.

Bispecific antibodies, by enabling the targeting of more than one disease-associated antigen or engaging immune effector cells, have both advantages and challenges compared with a combination of two different biological products. As of December 2023, there are 11 U.S. Food and Drug Administration-approved BsAb products on the market. Among these, 9 have been approved for oncology indications, and 8 of these are CD3 T-cell engagers. Clinical pharmacology strategies, including dose-related strategies, are critical for bispecific antibody development. This analysis reviewed clinical studies of all approved bispecific antibodies in oncology and identified dose-related perspectives to support clinical dose optimization and regulatory approvals, particularly in the context of the Food and Drug Administration's Project Optimus: (1) starting doses and dose ranges in first-in-human studies; (2) dose strategies including step-up doses or full doses for recommended phase 2 doses or dose level(s) used for registrational intent; (3) restarting therapy after dose delay; (4) considerations for the introduction of subcutaneous doses; (5) body weight vs. flat dosing strategy; and (6) management of immunogenicity. The learnings arising from this review are intended to inform successful strategies for future bispecific antibody development.

Blasting profile evaluation of sand-mud interbedded surrounding rock during the large-span tunnel construction.

The sand-mud interbedded surrounding rock contains discontinuities, such as horizontal bedding, joints, weak planes and weak interlayers. Drilling and blasting construction in this kind of surrounding rock is very likely to cause very serious over-/under-excavation phenomenon and excessive damage to surrounding rock, and the contour flatness after smooth blasting of the tunnel is also difficult to be guaranteed, which increases subsequent construction procedures and reduces production efficiency. In order to effectively evaluate the smooth blasting effect of the sand-mud interbedded surrounding rock tunnel, taking a tunnel project in southwest China as the research background, the blasting numerical simulation of the sand-mud interbedded surrounding rock tunnel was carried out using the dynamic analysis program, and the corresponding blasting optimization scheme was obtained. Subsequently, based on fuzzy mathematical theory, the evaluation system of blasting effect of sand-mud interbedded tunnel was established by combining the evaluation criteria of tunnel smooth blasting quality. Immediately afterwards, the weights of each influencing factor index were determined, and the blasting shaping effect of the original blasting scheme and the optimized blasting scheme was evaluated. Finally, the results have shown that the optimized tunnel blasting profile effect was better than the original blasting scheme. The corresponding research results have certain guiding significance for similar tunnel blasting effect evaluation and blasting parameter design.

Application of hydrogel microneedles in the oral cavity.

Microneedles are a transdermal drug delivery system in which the needle punctures the epithelium to deliver the drug directly to deep tissues, thus avoiding the influence of the first-pass effect of the gastrointestinal tract and minimizing the likelihood of pain induction. Hydrogel microneedles are microneedles prepared from hydrogels that have good biocompatibility, controllable mechanical properties, and controllable drug release and can be modified to achieve environmental control of drug release in vivo. The large epithelial tissue in the oral cavity is an ideal site for drug delivery via microneedles. Hydrogel microneedles can overcome mucosal hindrances to delivering drugs to deep tissues; this prevents humidity and a highly dynamic environment in the oral cavity from influencing the efficacy of the drugs and enables them to obtain better therapeutic effects. This article analyzes the materials and advantages of common hydrogel microneedles and reviews the application of hydrogel microneedles in the oral cavity.

Hybrid Piezoelectric/Triboelectric Wearable Nanogenerator Based on Stretchable PVDF-PDMS Composite Films.

Hybrid piezoelectric/triboelectric nanogenerators combine the merits of piezoelectric nanogenerators (PENGs) and triboelectric nanogenerators (TENGs), possessing enhanced electrical output and sensitivity. However, the structures of the majority of hybrid nanogenerators are rather complex in integrating both functions, limiting their practical application in wearable electronics. Herein, we propose to construct a piezoelectric/triboelectric hybrid nanogenerator (PT-NG) with a simple structure based on a composite film to simultaneously achieve the coupling of piezoelectric charge generation and triboelectrification with improved energy conversion efficiency. The composite film consists of electrospun PVDF nanofibers embedded in the surface of the PDMS film, which not only forms a rough nanomorphology on the surface of PDMS but also provides structural protection to the PVDF nanofibers by PDMS during compressive deformation. The results have shown that the PT-NG can generate much higher electrical outputs than individual TENG and PENG devices. The PT-NG devices exhibit a high level of mechanical-to-electrical energy conversion efficiency with superior performance in charging capacitors and functioning as self-powered wearable sensors for the detection of different signals from finger movement, the recognition of various gestures, and the monitoring of respiration. More importantly, the composite device possesses an impressive structure durability, maintaining its layered structure over 5000 testing cycles without noticing any obvious damage on the nanofibers or detachment between the layers. Our results have demonstrated that the combining of piezoelectric nanofibers and triboelectric substrate is an efficient way to fabricate highly efficient energy harvesting devices for intelligent identification and health monitoring.

Oral nutritional supplement helps to improve nutritional status of dialysis dependent patients: a systematic review and meta-analysis of randomized controlled trials.

Background: The prevention and treatment of malnutrition holds remarkable implications in the overall management of dialysis patients. However, there remains a dearth of comprehensive evaluations regarding the impact of oral nutrition supplement (ONS) on all pertinent dimensions of malnutrition in the dialysis population. Methods: A systematic search was conducted in MEDLINE, EMBASE, and Cochrane Central Library. RCTs that had assessed the effects of oral nutritional supplement in dialysis-dependent populations were considered eligible. Outcomes included laboratory indicators, anthropometric measures, nutritional indices, dialysis adequacy, body composition analysis measures, and systemic inflammation indicators. The risk of bias was assessed according to Cochrane guidelines. Weighted mean difference (WMD) or standardized mean difference (SMD) with 95% confidence intervals (CIs) were pooled using a random-effects model. Results: In all, 22 RCTs with 1,281 patients were included. The pooled analyses revealed the serum ALB, BMI, nPCR, and MIS improved by 1.44 g/L (95% CI: 0.76, 2.57), 0.35 kg/m2 (95% CI: 0.17, 0.52), 0.07 g/(kg d) (95% CI, 0.05, 0.10), and -2.75 (95% CI, -3.95, -1.54), respectively following ONS treatments when compared to control treatments. However, no significant differences were observed in relation to the other outcomes examined. 15 studies were rated as having high risk of bias. Visual inspection of the funnel plot and Egger test argued against the presence of publication bias. Conclusion: ONS treatments helps to improve the nutritional status of dialysis dependent patients. More evidence is needed from future investigations with longer study duration and standardized procedures to support long-term use of ONS in this population. Systematic review registration: https://www.crd.york.ac.uk/prospero/, Identifier CRD 42023441987.

Efficacy and safety of hypoxia-inducible factor-prolyl hydroxylase inhibitor treatment for anemia in chronic kidney disease: an umbrella review of meta-analyses.

The objective was to provide a comprehensive summary of existing evidence on the efficacy and safety of hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) for the treatment of anemia in chronic kidney disease (CKD). A systematic search was conducted in the Medline, Embase, and Cochrane databases. Only meta-analyses that evaluated the efficacy and safety of HIF-PHI treatment for anemia in CKD were included. The efficacy outcomes included hemoglobin levels and iron metabolism indices, while the safety outcomes were assessed by examining adverse events. The qualities of methodologies and evidence were assessed using the AMSTAR 2 system and the NutriGrade tool, respectively. Fourteen meta-analyses, comprising 105 distinct comparisons, were included. The comparisons were backed by evidence of high, moderate, and low levels, distributed in approximately equal proportions. None of the studies were deemed to possess a high level of confidence. In both the overall and individual treatment groups of HIF-PHI, there was an increase in the levels of hemoglobin, transferrin, and transferrin saturation, while the levels of hepcidin and total iron binding capacity decreased. Serum ferritin exhibited a reduction to some extent, while serum iron did not show significant alterations following HIF-PHI treatments. There were no notable disparities in safety outcomes between the HIF-PHI and erythropoietin stimulating agents or placebo groups. This umbrella review suggests that HIF-PHI treatment can effectively increase hemoglobin levels in CKD patients and enhance iron metabolism by decreasing hepcidin levels and improving iron transport. The safety profiles of HIF-PHIs were generally comparable to those of ESA therapies or placebos.

Artificial intelligence technology and ultrasound-guided nerve block for analgesia in total knee arthroplasty.

BACKGROUND: Knee diseases are more common in middle-aged and elderly people, so artificial knee replacement is also more used in middle-aged and elderly people. Although the patient's pain can be reduced through surgery, often accompanied by moderate pain after surgery and neutralization, which not only increases the psychological burden of the patient, but also greatly reduces the postoperative recovery effect, and may also lead to the occurrence of postoperative adverse events in severe cases. AIM: To investigate the analgesic effect of artificial intelligence (AI) and ultrasound-guided nerve block in total knee arthroplasty (TKA). METHODS: A total of 92 patients with TKA admitted to our hospital from January 2021 to January 2022 were opted and divided into two groups according to the treatment regimen. The control group received combined spinal-epidural anesthesia. The research group received AI technique combined with ultrasound-guided nerve block anesthesia. The sensory block time, motor block time, visual analogue scale (VAS) at different time points and complications were contrasted between the two groups. RESULTS: The time of sensory block onset and sensory block perfection in the research group was shorter than those in the control group, but the results had no significant difference (P > 0.05). Duration of sensory block in the research group was significantly longer than those in the control group (P < 0.05). The time of motor block onset and motor block perfection in the research group was shorter than those in the control group, but the results had no significant difference (P > 0.05). Duration of motor block in the research group was significantly longer than those in the control group. The VAS scales of the research group were significantly lower than that of the control group at different time points (P < 0.05). The postoperative hip flexion and abduction range of motion in the research group were significantly better than those in the control group at different time points (P < 0.05). The incidence of complications was significantly lower in the research group than in the control group (P = 0.049). CONCLUSION: In TKA, the combination of AI technology and ultrasound-guided nerve block has a significantly effect, with fewer postoperative complications and significantly analgesic effect, which is worthy of application.

Population Pharmacokinetics and Exposure-Response Analysis for the CTLA-4 Inhibitor Tremelimumab in Metastatic NSCLC Patients in the Phase III POSEIDON Study.

Blockade of CTLA-4 by tremelimumab combined with anti-PD-L1 durvalumab and chemotherapy provided increased antitumor activity and long-term survival benefits in first-line metastatic non-small cell lung cancer (mNSCLC) in the phase III POSEIDON study. We performed population pharmacokinetic modeling for tremelimumab using data from 1,605 patients across 6 studies (including POSEIDON) in multiple tumors (lung cancer, bladder cancer, malignant mesothelioma, and other solid tumors), and identified a 2-compartment model with linear and time-varying clearance for tremelimumab. Cox proportional hazard regression models were applied to 326 patients with mNSCLC from POSEIDON to evaluate the association between exposure metrics and efficacy end points, adjusting for baseline prognostic covariates. Improved progression-free survival (PFS) and overall survival (OS) in the tremelimumab arm (in combination with durvalumab and chemotherapy) was associated with higher tremelimumab exposure (e.g., minimum concentration at 5th dose (Cmin,dose5 ) and area under the curve at 5th dose (AUCdose5 )). However, further case-matching analyses yielded hazard ratios for the comparison of tremelimumab-treated patients in the Cmin,dose5 quartile 1 (Q1) subgroup with matched chemotherapy-treated patients of 1.04 (95% confidence interval (CI): 0.76-1.44) for OS and 0.99 (95% CI: 0.72-1.36) for PFS, suggesting that the observed apparent exposure-response relationship might be confounded. No relationship between tremelimumab exposure and safety (grade ≥3 treatment-emergent adverse events [AEs], AEs of special interest, or discontinuation due to AEs) was identified. These results support the consistent benefit observed with tremelimumab 75 mg every 3 weeks for up to 5 doses in combination with durvalumab and chemotherapy in POSEIDON as first-line therapy for mNSCLC.

Could extracellular vesicles derived from mesenchymal stem cells be a potential therapy for acute pancreatitis-induced cardiac injury?

Acute pancreatitis (AP) often leads to a high incidence of cardiac injury, posing significant challenges in the treatment of severe AP and contributing to increased mortality rates. Mesenchymal stem cells (MSCs) release bioactive molecules that participate in various inflammatory diseases. Similarly, extracellular vesicles (EVs) secreted by MSCs have garnered extensive attention due to their comparable anti-inflammatory effects to MSCs and their potential to avoid risks associated with cell transplantation. Recently, the therapeutic potential of MSCs-EVs in various inflammatory diseases, including sepsis and AP, has gained increasing recognition. Although preclinical research on the utilization of MSCs-EVs in AP-induced cardiac injury is limited, several studies have demonstrated the positive effects of MSCs-EVs in regulating inflammation and immunity in sepsis-induced cardiac injury and cardiovascular diseases. Furthermore, clinical studies have been conducted on the therapeutic application of MSCs-EVs for some other diseases, wherein the contents of these EVs could be deliberately modified through prior modulation of MSCs. Consequently, we hypothesize that MSCs-EVs hold promise as a potential therapy for AP-induced cardiac injury. This paper aims to discuss this topic. However, additional research is essential to comprehensively elucidate the underlying mechanisms of MSCs-EVs in treating AP-induced cardiac injury, as well as to ascertain their safety and efficacy.

Protective effects of KLF4 on blood-brain barrier and oxidative stress after cerebral ischemia-reperfusion in rats through the Nrf2/Trx1 pathway.

PURPOSE: To investigate the role of KLF4 in CI/R injury and whether Nrf2/Trx1 axis acted as a downstream pathway of KLF4 to exert the protective role in blood-brain barrier destruction after CI/R. METHODS: The tMCAO rat model in vivo was constructed and received the intracerebroventricular injection of 5 µg/kg and 10 µg/kg rhKLF4 before operation. TTC, brain water content, neurological function, ELISA, behavioral tests, HE, TUNEL, and qRT-PCR were performed to detect the protective role of KLF4 on CIR. Double-fluorescence staining and western blot were performed to determine the localization and spatiotemporal expression in brain tissues. Furthermore, we also analyzed the effect of KLF4 on the blood-brain barrier (BBB) and related mechanisms in vivo and in vitro. Nrf2 inhibitor tretinoin was applied, which was intraperitoneally injected into CIR rat. Evans blue staining was conducted. In vitro OGD/R models of bEnd.3 cells were also established, and received KLF4 overexpressed transfection and 12.5 µM tretinoin incubation. The permeability of bEnd.3 cells was evaluated by TEER and FITC-dextran leakage. BBB-related factors and oxidative stress were also analyzed, respectively. The tubular ability of KLF4 on OGD/R bEnd3 cells was also evaluated. RESULTS: In vivo study confirmed that KLF4 was expressed in astrocyte, and its content increased with time. KLF4 protected against brain injury caused by cerebral ischemia-reperfusion, reduced cerebral infarction area and oxidative stress levels, and promoted the recovery of behavioral ability in rats. Simultaneously, mechanism experiments confirmed that the repair effect of KLF4 on cerebral ischemia-reperfusion injury was closely related to the Nrf2/Trx1 pathway. KLF4 exerted the neuroprotective effect through upregulating Nrf2/Trx1 pathway. Consistent with in vivo animal study, in vitro study also confirmed the effect of KLF4 on the permeability of bEnd.3 cells after OGD/R injury through Nrf2/Trx1 pathway. CONCLUSION: Collectively, KLF4 played neuroprotective role in CIR induced MCAO and OGD/R, and the beneficial effects of KLF4 was partly linked to Nrf2/Trx1 pathway.

Modeling of Proliferating CD4 and CD8 T-Cell Changes to Tremelimumab Exposure in Patients with Unresectable Hepatocellular Carcinoma.

The STRIDE (Single Tremelimumab Regular Interval Durvalumab) regimen of single-dose tremelimumab 300 mg, plus durvalumab 1,500 mg every 4 weeks demonstrated potential for long-term survival in studies of unresectable hepatocellular carcinoma (uHCC; Study 22 and HIMALAYA). The aim of this analysis was to investigate changes in proliferating CD4+ Ki67+ and CD8+ Ki67+ T cells and their relationship with tremelimumab exposure in patients with uHCC. Median cell count, change from baseline, and percent change from baseline in CD4+ and CD8+ T cells peaked around 14 days after STRIDE. A model of CD4+ and CD8+ T cell response to tremelimumab exposure was developed. Patients with lower baseline T cell counts had a greater percent change from baseline in T cell response to tremelimumab, and baseline T-cell count was included in the final model. With the full covariate model, the half-maximal effective concentration (EC50 ) of tremelimumab was 6.10 µg/mL (standard error = 1.07 µg/mL); > 98.0% of patients were predicted to have a minimum plasma concentration greater than EC50 with tremelimumab 300 or 750 mg. For EC75 (9.82 µg/mL), 69.5% and 98.2% of patients were predicted to exceed the EC75 with tremelimumab 300 and 750 mg, respectively. This analysis supports the clinical hypothesis that combination anti-cytotoxic T-lymphocyte-associated antigen 4 (anti-CTLA-4) and anti-programmed cell death ligand-1 (anti-PD-L1) therapy primes an immune response that may then be sustained by anti-PD-L1 monotherapy and supports the clinical utility of the STRIDE regimen in patients with uHCC. These insights may also help inform dose selection of anti-CTLA-4 plus anti-PD-L1 combination strategies.

Effects of problem-based learning on delivering medical and nursing education: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: There is still a lack of high-level evidence on the effects of problem-based learning (PBL) in general medical and nursing education. AIMS: We aimed to summarize current evidence on the effects of PBL in delivering medical and nursing education from randomized controlled trials (RCTs). METHODS: A systematic search was performed in MEDLINE, EMBASE, Cochrane Central Library, and CINAHL Complete. RCTs that assessed the effects of a PBL module in delivering medical education were eligible. Outcomes included knowledge, performance, and satisfaction. The risk of bias was assessed according to Cochrane handbook guidelines. Standardized mean differences with 95% confidence intervals of each outcome between PBL and control groups were pooled using a random-effects model. RESULTS: In all, 22 RCTs with 1969 participants were included. Both pooled analyses of changes in scores compared with baseline and absolute post-interventional scores favored PBL module in knowledge and performance. The satisfaction degree was also higher in participants receiving PBL methods. Publication bias might exist in satisfaction; however, not in knowledge and performance. Eleven of the 22 studies were assessed as having a high risk of bias. LINKING EVIDENCE TO ACTION: Compared with traditional lecture-based modules, PBL delivered medical education in different medical science specialities more efficiently from both theoretical knowledge and practice skill perspectives. The feedback from participants receiving PBL methods was more positive than that from those receiving traditional methods. However, the high heterogeneity and low quality of the included studies prevented drawing definite conclusions.

Population Pharmacokinetics and Exposure-Response Analysis of Tremelimumab 300 mg Single Dose Combined with Durvalumab 1500 mg Q4W (STRIDE) in Patients with Unresectable Hepatocellular Carcinoma.

A novel single-dose regimen of 300 mg tremelimumab in combination with durvalumab (STRIDE) has demonstrated a favorable benefit-risk profile in the phase 1/2 Study 22 trial (in patients with unresectable hepatocellular carcinoma, uHCC) and in the phase 3 HIMALAYA study. The current analysis evaluated the population pharmacokinetics (PopPK) of tremelimumab and durvalumab, and the exposure-response (ER) relationship for efficacy and safety of STRIDE in patients with uHCC. Previous PopPK models for tremelimumab and durvalumab were updated using data from previous studies in various cancers combined with data from Study 22 and HIMALAYA. Typical population mean parameters and associated inter- and intra-individual variability were assessed, as was the influence of covariates. Individual exposure metrics were derived from the individual empirical Bayes estimates as drivers for ER analysis related to efficacy and safety from HIMALAYA. The observed pharmacokinetics of tremelimumab in uHCC were well described by a 2-compartment model with both linear and time-dependent clearance. All identified covariates changed tremelimumab PK parameters by <25%, and thus had minimal clinical relevance; similar results were obtained from durvalumab PopPK analysis. None of tremelimumab or durvalumab exposure metrics were significantly associated with overall survival (OS), progression-free survival (PFS), or adverse events. Baseline aspartate aminotransferase and neutrophil-to-lymphocyte ratio (NLR) were associated with OS (P < .001) by the Cox proportional hazards model. No covariate was identified as a significant factor for PFS. No dose adjustment for tremelimumab or durvalumab is needed based on PopPK covariate analyses or ER analyses. Our findings support the novel STRIDE dosing regimen in patients with uHCC.

Population Pharmacokinetics of Monalizumab in Patients With Advanced Solid Tumors.

Monalizumab is a novel, first-in-class humanized immunoglobulin G4 monoclonal antibody immune checkpoint inhibitor that targets the inhibitory CD94/NKG2A receptors. The objectives of this analysis were to develop a population pharmacokinetic (PK) model of monalizumab, evaluate the impact of clinically relevant covariates on monalizumab PK, and provide dose justification for clinical trials. We developed a monalizumab population PK model to characterize the PK properties of monalizumab in patients with advanced solid tumors or head and neck squamous cell carcinoma. Data from clinical studies D419NC00001 (NCT02671435) and IPH2201-203 (NCT02643550) were pooled for the analysis, resulting in a data set of 3066 PK samples derived from 507 subjects. The PK of monalizumab were reasonably described by a 2-compartment model with first-order elimination. Monalizumab generally exhibited linear PK over a dose range of 22.5-750 mg or 10 mg/kg every 2 weeks. The estimate of clearance was ≈0.255 L/day, and apparent volume of distribution was 6.36 L for a typical individual, consistent with previous findings for endogenous immunoglobulin Gs and other therapeutic monoclonal antibodies. Baseline albumin and body weight were identified as significant covariates of clearance; body weight, sex, and smoking status had a significant impact on volume of distribution; and none of these covariates had impact on peripheral volume of distribution. Although these covariates were identified as statistically significant, they are considered to be not clinically meaningful, as changes in monalizumab exposure were <30%. Therefore, no dose adjustments of monalizumab based on patient or disease characteristics are recommended.

[Role of NLRP3 inflammasome in diabetic neuropathy and prevention and treatment with traditional Chinese medicine].

As one of the most frequent complications of diabetes, diabetic neuropathy often involves peripheral and central nervous systems. Neuroinflammation is the key pathogenic factor of secondary nerve injury in diabetes. NOD-like receptor pyrin domain-containing 3(NLRP3) inflammasome is a group of subcellular multiprotein complexes, including NLRP3, apoptosis associated speck-like protein(ASC), and pro-cysteinyl aspartate specific proteinase 1(pro-caspase-1). NLRP3 inflammasome is an inducer of innate immune responses. Its activation stimulates the inflammatory cascade reaction, promotes the release of inflammatory mediators, triggers cell death and uncontrolled autophagy, activates glial cells, facilitates peripheral immune cell infiltration, and initiates amyoid ß(Aß)-tau cascade reactions. As a result, it contributes to the central nerve, somatic nerve, autonomic nerve, and retinal nerve cell damage secondary to diabetes. Therefore, due to its key role in the neuroinflammation responses of the body, NLRP3 inflammasome may provide new targets for the treatment of diabetic neuropathy. With multi-target and low-toxicity advantages, traditional Chinese medicine plays a vital role in the treatment of diabetic neuropathy. Accumulating evidence has shown that traditional Chinese medicine exerts curative effects on diabetic neuropathy possibly through regulating NLRP3 inflammasome. Although the role of NLRP3 inflammasome in diabetes and related complications has been investigated in the literature, systematical studies on drugs and mechanism analysis for secondary neuropathy are still lacking. In this article, the role of NLRP3 inflammasome in diabetic neuropathy was explored, and the research progress on traditional Chinese medicine in the treatment of diabetic neuropathy through NLRP3 inflammasome was reviewed.