Purpose: The pharmacokinetic (PK) profile of direct-acting antivirals, namely ledipasvir/sofosbuvir (LDV/SOF), might be altered in patients with acute lymphoblastic leukemia (ALL), affecting the optimum dose needed for hepatitis C virus treatment. Limited data are available evaluating the population PK of LDV/SOF and SOF metabolite GS-331007. We aimed to study whether ALL could affect population PK parameters of LDV, SOF, and the SOF major metabolite GS-331007 in hepatitis C virus-infected children, develop and validate a predictive PK model of LDV/SOF disposition in this special population, and identify their explained and unexplained sources of variability.
Methods: Population PK modeling was performed using MonolixSuite software using the non-linear mixed effect modeling approach. Different compartmental models, absorption models, and lag times for absorption parameters were tested to find out the best-fitting base model. For final model development, data-driven systematic covariate analysis using conditional sampling for the stepwise approach based on the correlation tests method has been performed. The final models were then evaluated using internal validation approaches.
Findings: The PK results of 22 fully compliant patients were included in the population PK analysis. LDV and SOF were best described by a 1-compartment model with zero-order absorption and lag time, while the 2-compartment model with first-order absorption and lag time was the best-fitting model for the SOF metabolite. The internal validation approach confirmed the good predictive power of the selected models. The patients' weight explained the variability in the volume of distribution of LDV and the systemic clearance of SOF and LDV. The final SOF model also included a statistically significant covariate of steatosis stage on its volume of distribution, while the final GS-331007 model included mean corpuscular volume values on GS-331007 central compartment volume, packed cell volume, and direct bilirubin values on metabolite intercompartmental clearance.
Implications: The presence of ALL did not explain any variability in the developed population PK models for SOF, LDV, and GS-331007. Despite weight being a significant covariate in the final models suggesting that weight-based dosing of LDV/SOF is better than fixed dosing, the fixed dosing (45/200 mg LDV/SOF) is more practical in terms of simplicity in dosing children at home besides the proved efficacy and safety through both the clinical outcomes and PK exposure results. Weight-based dosing is still hindered due to the absence of exposure-response analysis, and the unavailability of dose-flexible formulas in the market. Future studies are required to support these findings.
Clinicaltrials:
Gov identifier: NCT03903185.
Purpose: The goal of this study was to develop and validate an online dynamic nomogram system for early differential diagnosis of influenza A and B.
Methods: Patients with severe influenza A and B admitted to Henan Children's Hospital from January 2019 to January 2022 were used as the modeling group (n = 161), and patients admitted from January to September 2023 were used as the validation group (n = 52). Univariate logistic regression and multivariate logistic regression were used to identify the risk variables of severe influenza A and B in children in the modeling group. The selected variables were used to build the nomogram, and the C-index, decision curve analysis, calibration curves, and receiver operating characteristic curves were used to assess the differentiation, calibration of the models, and external validation of the above models with validation group data.
Findings: Fever for >3 days, vomiting, lymphocyte count (LY), and duration from onset to hospitalization were independent factors for the identification of severe influenza A and B. We created a dynamic nomogram (https://ertong.shinyapps.io/influenza/) that can be accessed online. The C-index was 0.92. In the modeling group, the AUC of the prediction model was 0.92 (95% CI, 0.87-0.98), the calibration curve showed a good fit between the predicted probability and the actual probability, with high comparability, and the decision curve analysis showed that the nomogram model had significant clinical benefits. The application of this model in external verification predicts that the AUC of the verification group is 0.749 (95% CI, 0.61-0.88), and the validation results were in good agreement with reality.
Implications: Fever for >3 days, vomiting, lymphocyte count, and duration from onset to hospitalization have an impact on the differentiation of severe influenza A from severe influenza B. The prediction value and clinical benefit of the nomogram model are satisfactory.
Purpose: Down syndrome regression disorder (DSRD) is a rare neuropsychiatric condition affecting otherwise healthy individuals with Down syndrome. Multiple studies on DSRD have revealed that immunotherapy with intravenous immunoglobulin (IVIg) is both safe and effective, although site of infusion has never been studied. This study sought to evaluate the safety and tolerability of IVIg in individuals with DSRD receiving home-based infusions.
Methods: A single-center, retrospective chart review evaluating infusion reactions was performed for individuals meeting criteria for DSRD and having received IVIg infusions between 2019 and 2024. Adverse events (AEs) were evaluated for severity and need for alterations in infusion plan. A cohort of individuals receiving home-based infusions was compared with a cohort of individuals receiving infusions at an academic medical center.
Findings: A total of 315 individuals (162 institutional infusions [51%] and 153 home infusions [49%]) met the inclusion criteria. There were no statistical differences between the demographic and clinical features of the cohorts. Individuals receiving home infusions had the same rate of AE during an infusion (P = 0.14), although they did have a lower number of total AEs (P < 0.001). Individuals receiving home infusions experienced a lower number of behavioral issues with infusions (P = 0.03) and had significantly lower discontinuations of infusions secondary to behavioral issues (P = 0.04).
Implications: Rates of AEs and serious AEs in those with DSRD were the same regardless of site of infusion. These data should be considered in policy regarding the appropriateness of home-based infusions as a safe alternative, when suitable for patients and caregivers, for individuals with DSRD.
Purpose: Calcineurin inhibitors (CNIs) are currently the first-line drugs for preventing and treating post-transplant rejection in organ transplant recipients. However, these drugs, especially tacrolimus, have the potential to induce thrombotic microangiopathy (TMA), a rare but potentially fatal complication that can develop following transplantation. This condition has garnered considerable attention within the medical community. Consequently, the study conducted an observational retrospective pharmacovigilance study to investigate the risk signal of thrombotic microangiopathy associated with CNIs.
Methods: A retrospective pharmacovigilance study was conducted to investigate the relationship between CNIs and TMA using data from the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database. A disproportionality analysis was performed to evaluate risk signals.
Findings: A total of 1019 cases of CNIs-associated TMA were identified, with 785 cases attributed to tacrolimus and 234 cases to cyclosporine A. Overall, the incidence of CNIs related TMA was higher compared to the entire database (ROR = 29.76 [27.84-31.82], IC = 4.64 [4.55-4.74]). A stronger signal was observed for tacrolimus-associated TMA compared to cyclosporine A (ROR = 3.72 [3.20-4.23], IC = 0.63 [0.50-0.77]). Additionally, residing in the Americas may be a protective factor against mortality in tacrolimus-related TMA, while for cyclosporine A-related TMA, patients from Asia and female patients have a significantly higher risk of death.
Implications: Clinician awareness of CNIs-associated TMA needs to be heightened, particularly with tacrolimus. Special attention should be given to patients' geographic regions and gender differences.
Purpose: Growing evidence has suggested that the consumption of chia seed can decrease blood pressure and obesity in adults. However, even studies have reported uncertain findings. The current meta-analysis aimed to assess the findings of randomized controlled trials (RCTs) on the efficacy of chia seed supplementation on blood pressure (systolic blood pressure [SBP], diastolic blood pressure [DBP]) and body composition (waist circumference [WC], weight, body mass index [BMI]) in adults.
Methods: A systematic search of the literature was carried out in the PubMed, Web of Knowledge, Scopus, Cochrane Central Library, and EMBASE from inception up to October 2024. Data were extracted and analyzed using a random-effects model, and reported as weighted mean differences (WMD) with 95% confidence intervals (CI).
Findings: A total of eight RCTs involving 372 participants were included in the meta-analysis. The results showed that chia consumption significantly reduced DBP (WMD: -7.49 mmHg; 95% CI: -9.64, -5.34; P < 0.001) and SBP (WMD: -5.61 mmHg; 95% CI: -8.77, -2.44; P = 0.001). Moreover, consuming chia seeds was linked to a notable decrease in WC (WMD: -1.46 cm; 95% CI: -2.68, -0.25; P = 0.01), but it had no significant effect on, BMI (WMD: -0.31 kg/m2; 95% CI: - 0.96, 0.34; P = 0.34) and weight (WMD: 0.09 kg; 95% CI: -0.76, 0.93; P = 0.84).
Implications: Chia consumption can significantly reduce SBP, DBP, and WC in adults, but no significant impact was showed on BMI and weight. To verify these results, more studies involving a greater number of participants are required.
Background: Postoperative nausea and vomiting (PONV) is among the most common adverse events, accompanied with impaired prognosis. This study aimed to investigate independent predictors for PONV after laparoscopic surgery for gynecologic cancers and identify a nomogram model.
Methods: Elderly patients who underwent laparoscopic surgery for gynecologic cancers between 2021 and 2024 were retrospectively enrolled. The primary observational endpoint was set as the occurrence of PONV within 72 h after surgery. Independent risk factors associated with PONV were identified by binary logistic regression, and further incorporated into the nomogram prediction mode by R.
Results: Of 337 enrolled patients, 104 experienced PONV with an overall incidence of 30.9%. Multivariate logistic regression analysis indicated body mass index (BMI) ≥ 24.0 (OR: 2.67, 95% CI: 1.37-5.23, P = 0.004), Afpel score (OR: 6.54, 95% CI: 3.52-12.15, P < 0.001), anxiety (OR: 3.14, 95% CI: 1.16-8.50, P = 0.025), 5-hydroxytryptamine (5-HT) (OR: 1.05, 95% CI: 1.02-1.07, P < 0.001), prostaglandin E2 (PGE2) (OR: 1.05, 95% CI: 1.01-1.08, P = 0.007), and albumin/fibrinogen ratio (AFR) (OR: 0.40, 95% CI: 0.28-0.56, P < 0.001) were six independent risk factors for PONV. The nomogram model based on these factors has good predictive value for PONV, with an AUC of 0.898.
Conclusions: This study identified an individual nomogram prediction model to visually represent the regression model for predicting PONV after laparoscopic surgery for gynecologic cancers.
Purpose: The efficacy of several novel combinations of anti-programmed cell death protein 1 or its ligand antibodies with chemotherapy, which have become the new standard first-line combination therapy with favorable outcomes, was still not certain in patients with different combined positive score (CPS) grades. This research aimed to evaluate the efficacy of immune checkpoint inhibitor immunotherapy or immunochemotherapy at different CPS grades, compared with chemotherapy.
Methods: Kaplan-Meier (KM) curve reconstruction was employed to assess the overall survival (OS) and progression-free survival (PFS) of patients with gastric cancer. The graphical reconstruction algorithm was used to estimate the time-to-event outcomes from Kaplan-Meier curves of the overall cohort or reported subgroups (depending on CPS). KMSubtraction was used to derive the unreported survival data by matching participants in the overall cohort and known subgroups.
Findings: This analysis included 5072 patients in 5 trials (CheckMate 649, KEYNOTE-859, ORIENT-16, KEYNOTE-062, and JAVELIN Gastric 100). Immunochemotherapy exhibited more effectiveness than chemotherapy in most cases. For the overall cohort, sintilimab + chemotherapy exhibited the best effect in OS (hazard ratio [HR], 0.65; 95% CI, 0.55-0.76). Nivolumab + chemotherapy (HR, 0.75; 95% CI, 0.67-0.84), sintilimab + chemotherapy (HR, 0.52; 95% CI, 0.41-0.65), and pembrolizumab + chemotherapy (HR, 0.68; 95% CI, 0.58-0.81) exhibited favorable outcomes in OS in patients with a CPS ≥1, 5, and 10, respectively, and similarly in PFS. Avelumab + chemotherapy performed similarly to chemotherapy in OS but had poor PFS in the reported subgroup.
Implications: Finding suggests that immune checkpoint inhibitors combined with chemotherapy could enrich patients with benefits regardless of CPS grades, though subtle efficacy in low CPS subgroups. This study compared the efficacy of different immunotherapies combined with chemotherapy in patients with gastric cancer, but we acknowledge some differences between reconstructed and original data. Hopefully there will be more research investigating comparisons between current therapies rather than with chemotherapy only in the future.
Background: Breast cancer patients receiving chemotherapy may develop a serious complication called febrile neutropenia (FN). We aimed to validate and compare three existing FN prediction models for breast cancer patients receiving chemotherapy in Taiwan.
Patients and methods: This was a retrospective observational real-world study. Data were acquired from the clinical research databases of three study hospitals. Breast cancer patients who have received at least one antineoplastic chemotherapy drug were chosen for the analysis. For evaluating the occurrence of FN, we used both broad (a body temperature above 38°C with an absolute neutrophil count (ANC) below 0.5 × 109/L or a body temperature above 38°C with a diagnosis of neutropenia) and narrow definitions (having both fever and neutropenia diagnoses or having both neutropenia and infection diagnoses). Sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) were calculated for each selected FN model.
Results: Among the 1903 patients identified, when the broad and narrow definitions of FN were applied, 70 (3.7%) and 60 (3.2%) patients developed FN in the first cycle, respectively. Using the broad FN definition, Aagaard's model was the highest in sensitivity (90.0%), followed by Chantharakhit's (40.0%) and Chen's (7.2%); in specificity, Chen's (93.6%) was the highest. In addition, the accuracy was highest with the Chen model (90.4%). All three models' PPVs were low, ranging from 0.5% to 4.2%, but all three models' NPVs were over 96.3%. When the narrow FN definition was used, Chantharakhit's model showed a relatively high improvement in sensitivity (53.3%) and PPV (3.9%) while negligible increases or even slight decreases were seen in the other two models and in the other performance indicators of Chantharakhit's model.
Conclusion: The results of this study provide important information for clinicians when selecting models to identify patients at high-risk of FN. As the model performance observed was less than satisfactory, improving the prediction ability of the models is needed.
Purpose: To determine the relationship between HLA-B gene mutations and levofloxacin-induced toxic epidermal necrolysis (TEN).
Methods: A 71-year-old Chinese woman developed TEN after oral administration of solifenacin (5 mg) and levofloxacin (0.5 g) for cystitis. HLA-B*5801 and HLA-B*1502 alleles were detected using real-time PCR.
Findings: After supportive therapy (antiallergic treatments, plasma exchange, etc) and withdrawal of the culprit medication levofloxacin, the patient was discharged with re-epithelialization of the exfoliated skin. The patient was HLA-B*1502 allele positive and HLA-B*5801 allele negative.
Implications: This is the first report of levofloxacin-induced TEN suspected to be caused by mutations in the HLA-B*1502 allele.
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