Analysis of new-onset seizures following use of COVID-19 vaccinations in children based on VAERS.

BACKGROUND: Recently, there have been some reports of seizures related with COVID-19 vaccinations. However, no studies have systematically investigated the relationship between seizures and various COVID-19 vaccines. RESEARCH DESIGN AND METHODS: This research aimed to analyze the characteristics and risk signals of new-onset seizures in children caused by various COVID-19 vaccines based on the data of the Vaccine Adverse Event Reporting System (VAERS). To identify potential risk signals, a disproportionality analysis was conducted. The reporting odds ratio (ROR) and the Proportional Reporting Ratio (PRR) were used to detect signals. RESULTS: A total of 695 children with new-onset seizures events associated with COVID-19 vaccinations were retrieved from the VAERS database. Compared with influenza vaccinations, the percentage and rate of COVID-19 vaccinations related seizures was all reduced. The median onset time of seizures was 1 day after COVID-19 vaccines. No signal was detected for an association between the COVID-19 vaccines and new-onset seizures, neither when compared with influenza vaccines nor with non-COVID-19 vaccines. CONCLUSION: No statistically significant risk signal of COVID-19 vaccine-related seizures was found in this study. However, it is still necessary to monitor the possibility of new-onset seizures when children are immunized with COVID-19 vaccines.

Development of a Risk Prediction Model for Infection After Kidney Transplantation Transmitted from Bacterial Contaminated Preservation Solution.

Background: The risk of transplant recipient infection is unknown when the preservation solution culture is positive. Methods: We developed a prediction model to evaluate the infection in kidney transplant recipients within microbial contaminated preservation solution. Univariate logistic regression was utilized to identify risk factors for infection. Both stepwise selection with Akaike information criterion (AIC) was used to identify variables for multivariate logistic regression. Selected variables were incorporated in the nomograms to predict the probability of infection for kidney transplant recipients with microbial contaminated preservation solution. Results: Age, preoperative creatinine, ESKAPE, PCT, hemofiltration, and sirolimus had a strongest association with infection risk, and a nomogram was established with an AUC value of 0.72 (95% confidence interval, 0.64-0.80) and Brier index 0.20 (95% confidence interval, 0.18-0.23). Finally, we found that when the infection probability was between 20% and 80%, the model oriented antibiotic strategy should have higher net benefits than the default strategy using decision curve analysis. Conclusion: Our study developed and validated a risk prediction model for evaluating the infection of microbial contaminated preservation solutions in kidney transplant recipients and demonstrated good net benefits when the total infection probability was between 20% and 80%.

Impact of iodinated oil in proton therapy on relative stopping power of liver post-cTACE.

Objective. Conventional transarterial chemoembolization (cTACE) is a common treatment for hepatocellular carcinoma (HCC), often with unsatisfactory local controls. Combining cTACE with radiotherapy shows a promise for unresectable large HCC, with proton therapy preserving healthy liver tissue. However, the proton therapy benefits are subject to the accuracy of tissue relative stopping power (RSP) prediction. The RSP values are typically derived from computed tomography (CT) images using stoichiometric calibration. Lipiodol deposition significantly increases CT numbers in liver regions of post-cTACE. Hence, it is necessary to evaluate the accuracy of RSP in liver regions of post-cTACE.Approach. Liver, water, and iodinated oil samples were prepared. Some liver samples contained iodinated oil. The water equivalent path length (WEPL) of sample was measured through the pullbacks of spread-out Bragg peak (SOBP) depth-dose profiles scanned in a water tank with and without sample in the beam path. Measured RSP values were compared to estimated RSP values derived from the CT number based on the stoichiometric calibration method.Main results. The measured RSP of water was 0.991, confirming measurement system calibration. After removing the RSP contribution from container walls, the pure iodinated oil and liver samples had RSP values of 1.12 and 1.06, while the liver samples mixed with varying oil volumes (5 ml, 10 ml, 15 ml) showed RSP values of 1.05, 1.05 and 1.06. Using the stoichiometric calibration method, pure iodinated oil and liver samples had RSP values of 2.79 and 1.06. Liver samples mixed with iodinated oil (5 ml, 10 ml, 15 ml) had calculated RSP values of 1.21, 1.34, and 1.46. The RSP discrepancy reached 149.1% for pure iodinated oil.Significance.Iodinated oil notably raises CT numbers in liver tissue. However, there is almost no effect on its RSP value. Proton treatment of post-cTACE HCC patients can therefore be overshooting if no proper measures are taken against this specific effect.

A denoising method based on deep learning for proton radiograph using energy resolved dose function.

Objective.Proton radiograph has been broadly applied in proton radiotherapy which is affected by scattered protons which result in the lower spatial resolution of proton radiographs than that of x-ray images. Traditional image denoising method may lead to the change of water equivalent path length (WEPL) resulting in the lower WEPL measurement accuracy. In this study, we proposed a new denoising method of proton radiographs based on energy resolved dose function curves.Approach.Firstly, the corresponding relationship between the distortion of WEPL characteristic curve, and energy and proportion of scattered protons was established. Then, to improve the accuracy of proton radiographs, deep learning technique was used to remove scattered protons and correct deviated WEPL values. Experiments on a calibration phantom to prove the effectiveness and feasibility of this method were performed. In addition, an anthropomorphic head phantom was selected to demonstrate the clinical relevance of this technology and the denoising effect was analyzed.Main results.The curves of WEPL profiles of proton radiographs became smoother and deviated WEPL values were corrected. For the calibration phantom proton radiograph, the average absolute error of WEPL values decreased from 2.23 to 1.72, the mean percentage difference of all materials of relative stopping power decreased from 1.24 to 0.39, and the average relative WEPL corrected due to the denoising process was 1.06%. In addition, WEPL values correcting were also observed on the proton radiograph for anthropomorphic head phantom due to this denoising process.Significance.The experiments showed that this new method was effective for proton radiograph denoising and had greater advantages than end-to-end image denoising methods, laying the foundation for the implementation of precise proton radiotherapy.

Immunosuppressive therapy for progressive idiopathic membranous nephropathy: a cost-effectiveness analysis in China.

BACKGROUND: This study aims to evaluate the cost-effectiveness of immunosuppressive therapy for patients with progressive idiopathic membranous nephropathy (IMN) from the Chinese healthcare system perspective. METHODS: To estimate the cost-effectiveness of four regimens namely cyclophosphamide, cyclosporine, rituximab and tacrolimus-rituximab in treatment of IMN recommended by the updated Kidney Disease: Improving Global Outcomes (KDIGO) guideline 2021, a Markov model with five discrete states (active disease, remission, dialysis, kidney transplant and death) based on IMN patients aged 50 or above over a 30-years time horizon was constructed. Total costs were imputed from the Chinese healthcare system perspective, and health outcomes were converted into quality-adjusted life years (QALYs). The incremental cost-effectiveness ratio (ICER) was used to describe the results. The willingness-to-pay (WTP) threshold was set at $12,044 (China's 2021 Gross Domestic Product per capita). Sensitivity analyses were performed to test the uncertainties of the results. RESULT: Compared with cyclophosphamide, both cyclosporine (incremental cost $28,337.09, incremental QALY-1.63) and tacrolimus-rituximab (incremental cost $28,324.13, incremental QALY -0.46) were considered at strictly dominated for their negative values in QALYs, and the ICER value of rituximab was positive (incremental cost $9,162.19, incremental QALY 0.44). Since the ICER of rituximab exceeds the pre-determined threshold, cyclophosphamide was likely to be the best choice for the treatment of IMN within the acceptable threshold range. The results of the sensitivity analysis revealed that the model outcome was mostly affected by the probability of remission in rituximab. In a probabilistic sensitivity analysis, cyclophosphamide had 62.4% probability of being cost-effective compared with other regimens when the WTP was $12,044 per QALY. When WTP exceeded $18,300, rituximab was more cost-effective than cyclophosphamide. CONCLUSION: Compared with cyclosporine, rituximab and tacrolimus-rituximab, our model results indicated that cyclophosphamide represented the most cost-effective regimen for patients with progressive IMN in China.

Evidence of potential pro-haemorrhagic drug interactions between CYP3A4 inhibitors and direct oral anticoagulants: Analysis of the FAERS database.

AIMS: There is no consensus on the haemorrhagic risk associated with potential interactions between commonly used CYP3A4 inhibitors and direct oral anticoagulants (DOACs). METHODS: Macrolide antibiotics and azole antimycotics were investigated in this study. Data from Food and Drug Administration Adverse Event Reporting System were retrieved from July 2010 to September 2021. Haemorrhagic signals were expressed by reporting odds ratios (RORs) and 95% confidence intervals (CIs) based on the interaction/noninteraction methodology as (a/c) / (b/d) and considered significant when the lower limit of 95% CI was >1 and the case number of interaction group was ≥3. Subgroup analyses and logistic regression were conducted by adjusting associated factors in haemorrhagic events. RESULTS: From the third quarter of 2010 to the first quarter of 2021, we retrieved 382 853 distinct cases of adverse events associated with DOACs, in which 1128 cases of bleeding were associated with coadministration of CYP3A4 inhibitors and DOACs. The haemorrhagic signal was significant for apixaban when coadministered with clarithromycin (ROR 1.60, 95% CI 1.16-2.20) and posaconazole (ROR 2.69, 95% CI 1.37-5.28). For dabigatran, coadministration with azithromycin (ROR 4.06, 95% CI 2.77-5.95), fluconazole (ROR 2.26, 95% CI 1.52-3.37), itraconazole (ROR 7.52, 95% CI 1.51-37.46) and ketoconazole (ROR 2.06, 95% CI 1.25-3.41) was associated with significantly higher risks of haemorrhages. At the same time, addition of itraconazole to rivaroxaban also indicated significant haemorrhagic signal (ROR 3.58, 95% CI 1.30-9.85). CONCLUSIONS: Macrolide antibiotics and azole antimycotics have potential but different effects on the bleeding risk of DOACs. Close attention is needed when using these drugs together. Such precautions have already been included in some drug labels.

Hepatic failure associated with immune checkpoint inhibitors: An analysis of the Food and Drug Administration Adverse Event Reporting System database.

BACKGROUND: Hepatic failure induced by immune checkpoint inhibitors (ICIs) has been reported in only a few case series and case reports. OBJECTIVE: We aimed to explore the association between ICIs and hepatic failure and characterize the clinical features of ICI-associated hepatic failure in the pharmacovigilance database. METHODS: Data from the first quarter (Q1) of 2015 to the fourth quarter (Q4) of 2021 in the US Food and Drug Administration Adverse Event Reporting System (FAERS) database were retrieved for disproportionality and Bayesian analysis. Reporting odds ratios (ROR) and information component (IC) were used to evaluate correlations between ICIs and hepatic failure. RESULTS: Hepatic failure occurred in 0.19% (18,454/9,647,655) of all cases in the FAERS database, of which 654 cases were associated with ICIs. The overall median time from ICIs initiation to hepatic failure onset was 38 days, 72.3% of the adverse events occurred within the first 3 months, and 68.65% of the cases died after developing hepatic failure. In general, a strong signal was shown between ICIs and hepatic failure (ROR025  = 2.70, IC025  = 1.39). For the three categories of ICIs, programmed cell death 1 ligand 1 inhibitors (ROR025  = 3.09, IC025  = 1.57) had a higher risk signal than programmed cell death protein 1 inhibitors and cytotoxic T lymphocyte-associated protein 4 inhibitors. For monotherapy, atezolizumab showed the strongest risk signal (ROR025  = 4.07, IC025  = 1.90). The combination of nivolumab and ipilimumab showed stronger signals of hepatic failure compared with nivolumab or ipilimumab alone (nivolumab + ipilimumab vs. ipilimumab: ROR025  = 1.40, IC025  = 0.16; nivolumab + ipilimumab vs. nivolumab: ROR025  = 1.24, IC025  = 0.34). Considering the concomitant agents used with ICIs, the majority of these regimens showed stronger signals than ICI monotherapy, such as acetaminophen (ICIs + acetaminophen vs. ICIs: ROR025  = 1.06, IC025  = 0.32). CONCLUSIONS: ICIs had possible strong signals associated with hepatic failure, and most cases of hepatic failure occurred within the first 3 months and had poor outcomes, which should attract clinical attention.

Hepatitis B virus reactivation associated with Janus kinase (JAK) inhibitors: a retrospective study of pharmacovigilance databases and review of the literature.

BACKGROUND: Recently, there have been clinical reports of hepatitis B virus reactivation (HBVr) related with Janus kinase (JAK) inhibitors. However, there were no studies to investigate the association between HBVr and different JAK inhibitors. RESEARCH DESIGN AND METHODS: This study was a retrospective review utilizing the FAERS pharmacovigilance database and a systematic literature search for all cases of HBVr reported with JAK inhibitors. Disproportionality analysis and Bayesian analysis were used in data detection to screen the suspected HBVr after the administration of different JAK inhibitors, based on the FDA Adverse Event Reporting System (FAERS) pharmacovigilance database from Q4 2011 to Q1 2022. RESULTS: There were a total number of 2097 (0.02%) reports of HBVr in FAERS, of which 41 (1.96%) were associated with JAK inhibitors. Baricitinib appeared to have the strongest signal among four JAK inhibitors, based on the highest reporting odds ratio (ROR = 4.45, 95% confidence interval [CI] 1.67-11.89). Ruxolitinib also showed signals, whereas no signals were detected among Tofacitinib and Upadacitinib. CONCLUSION: While there may be an association between JAK inhibitors and HBVr, it appears to be a numerically uncommon occurrence. Further studies are needed to optimize the safety profiles of JAK inhibitors.

Pharmacokinetics and Dosing Regimens of Direct Oral Anticoagulants in Morbidly Obese Patients: An Updated Literature Review.

Data on the impact of morbid obesity (body mass index [BMI] ≥ 40 kg/m2) on the pharmacokinetics (PK), pharmacodynamics (PD) of direct oral anticoagulants (DOACs) are relatively limited, making it difficult to design optimal dosing regimens in morbidly obese patients.To review literature on PK/PD profile, efficacy, and safety of DOACs in venous thromboembolism (VTE) and nonvalvular atrial fibrillation (AF) patients with morbid obesity and make recommendations regarding optimal dosing regimens in these patient populations.A detailed literature search was conducted (from inception to June 22, 2022) for relevant articles involving PK/PD and clinical data on DOACs use in morbidly obese patients with VTE or AF, or healthy volunteers.A total of 28 studies were identified. DOAC-specific PK variations and clinical outcomes have been observed. Obesity may have a modest effect on PK/PD of dabigatran, apixaban, or rivaroxaban. Dabigatran was effective in AF patients with morbid obesity but might increase the risk of gastrointestinal bleeding. Standard dosing of apixaban or rivaroxaban is effective and safe for VTE and AF patients with morbid obesity. Trough edoxaban concentration and anti-Xa activity were similar in different BMI groups (18.5 to >40 kg/m2), and standard dosing of edoxaban may be effective and safe for AF patients.Current evidence suggests dabigatran should be used with caution in patients with AF as it might increase the risk of gastrointestinal bleeding; Standard dosing of apixaban or rivaroxaban can be used in VTE or AF patients; Standard dosing of edoxaban may be considered in AF patients.

Safety, efficacy and prognosis of anticoagulant therapy for portal vein thrombosis in cirrhosis: a retrospective cohort study.

BACKGROUND: The role of anticoagulants in the treatment of cirrhotic PVT remains controversial. This study aimed to analyze the safety and efficacy of anticoagulant therapy in patients with cirrhotic portal vein thrombosis (PVT) and its impact on prognosis. METHODS: A retrospective cohort study was conducted for PVT patients with liver cirrhosis in our hospital. The primary outcome of the study was the PVT recanalization rate. Other outcomes included bleeding rate, liver function, and mortality. Cox and Logistic regression were used to explore the risk factors of outcomes. RESULTS: This study included 77 patients that 27 patients in the anticoagulant group and 50 in the non-anticoagulant group. Anticoagulant therapy was associated with higher rate of PVT recanalization (44.4% vs 20.0%, log-rank P = 0.016) and lower rate of PVT progression (7.4% vs 30.0%, log-rank P = 0.026), and without increasing the rate of total bleeding (14.8% vs 24%, P = 0.343), major bleeding (3.7% vs 6%, P = 0.665) and variceal bleeding (3.7% vs 16%, P = 0.109). The safety and efficacy of different anticoagulants were similar. The Child-Pugh grade of the anticoagulant therapy group was better than that of the non-anticoagulant therapy group (P = 0.030). There was no significant difference in the 2-year survival rate of the two groups. CONCLUSION: Anticoagulants could increase the PVT recanalization rate and reduce the PVT progression rate without increasing the rate of bleeding. Anticoagulants may be beneficial to improving the liver function of patients with cirrhotic PVT. There was no significant difference in the safety and efficacy of different anticoagulants in the treatment of cirrhotic PVT.

Allograft rejection following immune checkpoint inhibitors in solid organ transplant recipients: A safety analysis from a literature review and a pharmacovigilance system.

AIM: This study aimed to systematically characterize transplant rejection after immune checkpoint inhibitors (ICIs) initiation in solid organ transplant recipients (SOTRs). METHODS: Data were extracted from the US FDA Adverse Event Reporting System (FAERS) database and case reports in the literature. Disproportionality analysis including information component and reported odds ratio (ROR) was performed to access potential risk signals. RESULTS: A total of 168 patients with transplant rejection after ICIs usage were identified in the FAERS database, and 89 cases were identified in the literature review. ICIs were significantly associated with transplant rejection (ROR025 : 2.2). A strong risk signal was found for combination therapy with pembrolizumab and ipilimumab compared to monotherapy. CONCLUSION: Immune checkpoint inhibitors were significantly associated with transplant rejection in SOTRs.

Haematopoietic cytopenia associated with cyclin-dependent kinase 4/6 inhibitors: A real-world study of data from the food and drug administration adverse event reporting system database.

OBJECTIVE: The haematopoietic cytopenia (HC) of the cyclin-dependent kinase (CDK)4/6 inhibitors was evaluated using the Food and Drug Administration Adverse Event Reporting System (FAERS). METHOD: Data from 1 January 2015 to 31 December 2021 has been retrieved from the FAERS database. Disproportionality analysis and Bayesian analysis were utilized in the data mining. The reporting odds ratio (ROR) with 95% confidence interval (CI) for HC was calculated for each CDK 4/6 inhibitor agent. Clinical features of the patients were collected and compared between death outcome and non-death outcome groups. Time to onset (TTO), proportion of deaths, life-threatening and hospitalizations of CDK 4/6 inhibitors-associated HC were also studied. RESULTS: A total of 17,235 cases of HC associated with CDK 4/6 inhibitors were identified with a median age of 65 years (interquartile range [IQR] 57-73). Palbociclib appeared the strongest signal, with the highest (ROR 9.64, 95% CI 9.46-9.83), followed by ribociclib (ROR 6.38, 95% CI 6.04-6.73) and then abemaciclib (ROR 2.72, 95% CI 2.49-2.97). Patients aged 18-64 had a higher proportion of deaths than those aged 65-84 (12.21% vs. 9.91%, p = 0.001). In Africa and Asia, the proportions of deaths were higher (31.65% and 26.13%, respectively). The median TTO was 26 days (IQR 14-65) for abemaciclib, 33 days (IQR 15-134) for palbociclib and 23 days (IQR 14-69) for ribociclib, respectively. The highest proportion of deaths, life-threatening and hospitalizations all occurred in abemaciclib (13.00%, 5.42% and 44.04%, respectively). CONCLUSIONS: Greater proportions of deaths occurred in Africa and Asia. HC may occur early in any CDK 4/6 inhibitor regimen. Abemaciclib had the highest proportion of deaths, life-threatening and hospitalizations. Health care workers should be more concerned about CDK 4/6 inhibitors. The higher proportions of serious events, including deaths, from Africa and Asia, as well as for abemaciclib, deserve further investigations through additional pharmacoepidemiological approaches.

Effect of Carbapenem-Resistant Klebsiella pneumoniae Infection on the Clinical Outcomes of Kidney Transplant Recipients.

Background: Carbapenem-resistant Klebsiella pneumoniae (CRKP) infection has proven to be difficult to control and typically presents with devastating effects. Methods: This retrospective study was conducted on the renal recipients at our institution between January 2021 to January 2022. Clinical data was collected to identify factors associated with CRKP infection and clinical outcomes. Results: There were 104 cases out of 186 total renal recipients who presented with at least one infection within 3 months after KT, and 14 cases developed unfavorable clinical outcomes. We identified 16 confirmed CRKP infected cases with the incidence of 8.60%. Possible donor derived infection (DDI) (OR = 6.743; 95% CI: 1.477-30.786; P = 0.014) were independent risk factors for the occurrence of CRKP infection of renal recipients in our analysis, CRKP infection (OR = 20.723; 95% CI: 3.448-124.547; P = 0.001) and pneumonia (OR = 28.458; 95% CI: 1.956-413.984 P = 0.014) were independent risk factors for the occurrence of unfavorable clinical outcomes following KT, and the occurrence of unfavorable clinical outcomes following KT were significantly associated with CRKP infection (r = 0.535; P < 0.001) and antibiotic regimen containing ceftazidime/avibactam (CZA) (r = -0.655; P = 0.006). The use of CZA was significantly different in the comparison of antibiotic regimens between the CRKP infected renal recipients with unfavorable outcomes and CRKP infected patients with favorable outcomes. Conclusion: It is possible that DDI can lead to CRKP infection, and CRKP infection and pneumonia were closely correlated with poor prognosis. The use of CZA may play a role in avoiding the unfavorable outcomes of CRKP infected recipients.

[Effects of resveratrol on inhibiting pyroptosis of intestinal cancer cells].

Objective: To study the effects of resveratrol (Res) on pyroptosis of colorectal cancer cells . Methods: ①The experiment of dextran sodium sulfate (DSS) induced colon cancer (CRC) in mice: 30 C57BL/6 mice were randomly divided into control group, Azoxymethane (AOM) group, AOM/DSS group, AOM/DSS+Res group and Res group, with 6 mice in each group, the modeling cycle was 70 days in total. Mice in AOM group, AOM/DSS group and AOM/DSS+Res group, at the first day of the first week, were intraperitoneally injected with AOM (10 mg/kg) once, and the ordinary chaw was replaced with high iron feed, and sterile water was given, 1% DSS water was given to AOM/DSS group and AOM/DSS+Res group. The mice in AOM/DSS+Res and Res groups were given resveratrol (50 mg/kg) by oral gavage, When the mold was finished, colon tissue of mice was fixed, embedded and sectionalized. The expressions of NLRP3, Caspase-1 and IL-18 in colon tissues of mice were detected by IHC and Western blot. ②In vitro experiment: HCT 116 cells were given Res (2.4 µg/L) and transfected with miR-31. The Res was divided into 4 groups and labeled with 0 h, 12 h, 24 h and 48 h respectively. The transfected cells were divided into 5 groups: Control group, miR-31 mimic group, miR-31 mimic + Res group, miR-31 inhibitor group, miR-31 inhibitor + Res group. The protein expressions of NLRP3, Caspase-1, GSDMD-N, IL-18 and IL-1ß were detected by Western blot. Results: Animal experiments: Compared with control group, the protein expressions of NLRP3, Caspase-1 and IL-18 in AOM/DSS group were increased significantly (P<0.01). The protein expression levels of NLRP3, Caspase-1 and IL-18 in AOM/DSS+Res group were significantly lower than those in AOM/DSS group (P<0.01). Cell experiments: Compared with the control group, the protein expressions of NLRP3 (P<0.01), GSDMD-N (P<0.05) and IL-18 (P< 0.01) in miR-31 mimic group were increased significantly. The protein expressions of NLRP3, GSDMD-N and IL-18 in miR-31 inhibitor group were decreased significantly (P<0.05). Conclusion: Res inhibited the pyroptosis of colorectal cancer cells through pyroptosis.

Central nervous system adverse events of ceftazidime/avibactam: A retrospective study using Food and Drug Administration Adverse Event Reporting System.

WHAT IS KNOWN AND OBJECTIVE: Many antibiotics are well known for being associated with adverse events (AEs) of central nervous system, ceftazidime/avibactam (CAZ/AVI) is a novel ß-lactam/ß-lactamase inhibitor combinations. In this commentary, we analyzed reports of nervous system disorders associated with CAZ/AVI, meropenem, imipenem, ceftazidime, ceftriaxone, and cefepime in the Food and Drug Administration (FDA) Adverse Event Reporting System database from January 2015 to March 2022. COMMENT: The reporting odds ratios (RORs) method was used to detect the safety signals. Up to 15.62% of CAZ/AVI AEs exhibit nervous system disorders associated with CAZ/AVI. A nervous system disorder signal was detected for CAZ/AVI compared with meropenem, ceftazidime, and ceftriaxone. Compared with meropenem, imipenem, ceftazidime, and ceftriaxone, encephalopathy, myoclonus, reported with CAZ/AVI exhibited significant RORs. WHAT IS NEW AND CONCLUSION: This study found that CAZ/AVI showed a relatively stronger sign nervous system disorder than meropenem, ceftazidime, and ceftriaxone in the real world. The poor clinical outcome of these events should attract clinical attention, especially for patients with older than 65 years old and long treatment courses.

Improvement of proton beam range uncertainty in breast treatment using tissue samples.

Objective.Proton therapy after breast-conserving surgery (BCS) can substantially reduce the dose to lung and cardiac structures. However, these dosimetric benefits are subject to beam range uncertainty in patient. The conversion of the CT-Hounsfield unit (HU) into relative stopping power (RSP) is the primary contribution to range uncertainty. Hence, an accurate HU-RSP conversion is essential.Approach.Real tissue samples, including muscle and adipose, were prepared. The water equivalent path length (WEPL) of these samples was measured under homogeneous conditions using a 12-diode detector array of our time-resolvedin vivorange verification system (IRVS). The HU-RSP conversion was improved using the measured WEPL and HU for adipose tissue. The measured WEPL values were compared with the treatment planning calculation results based on the stoichiometric CT-HU calibration technique. The effect was investigated for both with and without adipose tissue in HU-RSP conversion.Main results.The IRVS was calibrated based on the solid water phantom. The relative differences in WEPL (RSP) between measurements and calculations for muscle, adipose, and water was -1.19% (-0.75%), -4.25%(-4%), and -0.23%(-0.07%), respectively. Based on the improved HU-RSP conversion, the relative differences in WEPL was reduced to -0.97%(-0.62%), -1.50%(-1.46%), and -0.22% (0.00%), respectively.Significance.The WEPL deviation of adipose tissue is larger than the testing limit of 3.5% for beam range robustness in current clinical practice. However, the improved HU-RSP conversion reduced this deviation. The main component of breast tissue is adipose. Hence, the proton treatment of BCS can be undershooting if no proper measures are taken against this specific uncertainty.

Toxicity spectrum of immunotherapy in advanced lung cancer: A safety analysis from clinical trials and a pharmacovigilance system.

Background: With the increased use of immune checkpoint inhibitors (ICIs) in advanced lung cancer, adverse events (AEs), particularly immune-related AEs (irAEs), have garnered considerable interest. We conducted a comprehensive assessment of the toxicity profile in advanced lung cancer using multi-source medical data. Methods: First, we systematically searched the PubMed, Embase, and Cochrane Library databases (from inception to 10 August 2021) for relevant randomised controlled trials (RCTs) involving ICI-based treatments for advanced lung cancer. The primary outcomes were treatment-related AEs and irAEs, including events that were assigned grade 1-5 and 3-5. The secondary outcomes were grade 5 AEs and irAEs (grade 1-5 and grade 3-5) in specific organs. Network comparisons were conducted for 11 treatments, including chemotherapy (CT), ICI monotherapy (three regimens: programmed death-1 receptor [PD-1] inhibitors, programmed death ligand-1 [PD-L1] inhibitors, and cytotoxic T lymphocyte-associated antigen [CTLA-4] inhibitors), dual-ICI combination therapy (two regimens), and treatment using one or two ICI drugs administered in combination with CT (five regimens). We also conducted a disproportionality analysis by extracting reports of various irAEs associated with ICIs from the FDA Adverse Event Reporting System (FAERS) database. The reporting odds ratios and fatality proportions of different irAEs were calculated and compared. PROSPERO: CRD42021268650. Findings: Overall, 41 RCTs involving 23,121 patients with advanced lung cancer were included. Treatments containing chemotherapy increased the risk of treatment-related AEs compared to ICI-based regimens without chemotherapy. Concerning irAEs, PD-L1 + CTLA-4 + CT was associated with the highest risk of grade 1-5 irAEs, followed by two regimens of dual ICI combination, three regimens of ICI monotherapy, and three regimens of one ICI combined with CT. For 3-5 irAEs, CTLA-4 accounted for most AEs. Detailed comparisons of ICI-based treatment options provided irAE profiles based on specific organs/systems and AE severity. Insights from the FAERS database revealed that signals corresponding to pneumonitis, colitis, thyroiditis, and hypophysitis were observed across all ICI regimens. Further analyses of the outcomes indicated that myocarditis (163 of 367, 44.4%), pneumonitis (1610 of 4497, 35.8%), and hepatitis (290 of 931, 31.1%) had high fatality rates. Interpretation: Included RCTs showed heterogeneity in a few clinical factors, and reports derived from the FAERS database might have involved inaccurate data. Our results can be used as a basis for improving clinical treatment strategies and designing preventive methods for ICI treatment in advanced lung cancer. Funding: This study was supported by the Research Project of Drug Clinical Comprehensive Evaluation and Drug Treatment Pathway (SHYXH-ZP-2021-001, SHYXH-ZP-2021-006), Clinical Research Innovation and Cultivation Fund of Ren Ji Hospital (RJPY-LX-008), Ren Ji Boost Project of National Natural Science Foundation of China (RJTJ-JX-001), and Shanghai "Rising Stars of Medical Talent" Youth Development Program - Youth Medical Talents - Clinical Pharmacist Program (SHWJRS (2019) 072).

The Efficacy and Safety of Anticoagulants in the Treatment of Cirrhotic Portal Vein Thrombosis: A Systematic Review and Meta-Analysis.

OBJECTIVE: To evaluate the efficacy and safety of anticoagulant therapy in patients with cirrhotic PVT, and compare differences in efficacy and safety among different anticoagulants. METHODS: We comprehensively searched Pubmed, Cochrane Library, EMBASE, and ClinicalTrials.gov from inception to April 2022 for studies using anticoagulants for cirrhotic PVT. Meta-analysis was performed to calculate odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: 3 RCTs and 14 cohort studies involving 1270 patients were included. Anticoagulant therapy can increase the recanalization rate compared with non-anticoagulation therapy (OR 4.44, 95% CI 3.11-6.32, I2 = 2.5%) and can decrease the extension rate of cirrhotic PVT (OR 0.33, 95% CI 0.18-0.62, I2 = 41.0%), without increasing the incidence of total bleeding (OR 1.21, 95% CI 0.75-1.97, I2 = 9.8%), major bleeding (OR 0.98, 95% CI 0.49-1.95, I2 = 19.7%), and variceal bleeding (OR 0.35, 95% CI 0.12-1.01, I2 = 39.9%). Subgroup analysis showed that VKA, LMWH, and DOACs could increase the recanalization rate of PVT and were not associated with the risk of bleeding. Studies that compared direct oral anticoagulants (DOACs) with warfarin directly showed that the recanalization rate of PVT in the DOACs group might be higher than that in the warfarin group (OR 30.99, 95% CI 7.39-129.87, I2 = 0.0%), and there was no difference in the rate of total bleeding (OR 0.30, 95% CI 0.01-8.65, I2 = 79.6%). CONCLUSIONS: Anticoagulants are safe and effective in patients with cirrhotic PVT. The rate of PVT recanalization associated with DOACs may be higher than warfarin.

Serious Cardiovascular Adverse Events Associated with Hydroxychloroquine/Chloroquine Alone or with Azithromycin in Patients with COVID-19: A Pharmacovigilance Analysis of the FDA Adverse Event Reporting System (FAERS).

BACKGROUND: The use of hydroxychloroquine or chloroquine (HCQ/CQ) as monotherapy or combined with azithromycin for the treatment of coronavirus disease 2019 (COVID-19) may increase the risk of serious cardiovascular adverse events (SCAEs). OBJECTIVE: Our objective was to describe and evaluate the risk of SCAEs with HCQ/CQ as monotherapy or combined with azithromycin compared with that for therapeutic alternatives. METHODS: We performed a disproportionality analysis and descriptive case series using the US FDA Adverse Event Reporting System. RESULTS: Compared with remdesivir, HCQ/CQ was associated with increased reporting of SCAEs (reporting odds ratio [ROR] 2.1; 95% confidence interval [CI] 1.8-2.5), torsade de pointes (TdP)/QTc prolongation (ROR 35.4; 95% CI 19.4-64.5), and ventricular arrhythmia (ROR 2.5; 95% CI 1.6-3.9); similar results were found in comparison with other therapeutic alternatives. Compared with lopinavir/ritonavir, HCQ/CQ was associated with increased reporting of ventricular arrhythmia (ROR 10.5; 95% CI 3.3-33.4); RORs were larger when HCQ/CQ was used in combination with azithromycin. In 2020, 312 of the 575 reports of SCAEs listed concomitant use of HCQ/CQ and azithromycin, including QTc prolongation (61.4%), ventricular arrhythmia (12.0%), atrial fibrillation (8.2%), TdP (4.9%), and cardiac arrest (4.4%); 88 (15.3%) cases resulted in hospitalization and 79 (13.7%) resulted in death. In total, 122 fatal QTc prolongation-related cardiovascular reports were associated with 1.4 times higher odds of reported death than those induced by SCAEs; 87 patients received more than one QTc-prolonging agent. CONCLUSIONS: Patients treated with HCQ/CQ monotherapy or HCQ/CQ + azithromycin may be at increased risk of SCAEs, TdP/QTc prolongation, and ventricular arrhythmia. Cardiovascular risks need to be considered when evaluating the benefit/harm balance of treatment with HCQ/CQ, especially with the concurrent use of QTc-prolonging agents and cytochrome P450 3A4 inhibitors when treating COVID-19.

Coagulation dysfunction events associated with tigecycline: a real-world study from FDA adverse event reporting system (FAERS) database.

BACKGROUND: Tigecycline has broad-spectrum anti-bacterial activity and often used for critically ill patients with complicated infections. Only a few clinical studies have reported the coagulation disorder induced by tigecycline. The aim of this study was to investigate the association between tigecycline and coagulation dysfunction using the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. METHOD: Data from January 2005 to December 2020 in FAERS were retrieved. We investigated the clinical characteristics of the coagulation dysfunction events and conducted disproportionality analysis by using reporting odds ratios (ROR) to compare tigecycline with the full database and other antibiotics. RESULTS: The total number of reports of coagulation dysfunction related to tigecycline as the primary suspect drug was 223. The median time to event of the coagulation dysfunction events was 10 (interquartile range [IQR] 6.75-13) days. 80.72% coagulation-related adverse events appeared within the first 14 days since the initiation of tigecycline administration. The overall ROR (95% CI) for coagulation-related adverse events was 3.55 (3.08, 4.09). The RORs (95% CI) for thrombocytopenia, hypofibrinogenaemia, coagulopathy, activated partial thromboplastin time prolonged, international normalized ratio increased, prothrombin time prolonged were 8.21 (6.34, 10.62), 705.41 (526.81, 944.54), 30.67 (21.92, 42.92), 42.98 (24.85, 74.31), 4.67 (2.51, 8.71), and 27.99 (15.01, 52.19), respectively. In analyses stratified on comparing tigecycline to vancomycin and daptomycin, significant coagulation dysfunction signals were found with the RORs (95% CI) 2.74 (2.34, 3.22) and 3.08 (2.57, 3.70). CONCLUSIONS: We found a strong signal of high frequency of reporting coagulation dysfunction in tigecycline. Health professionals should be aware of the potential coagulation disorders risk and monitor coagulation parameters during anti-bacterial therapy with tigecycline, particularly the need to monitor fibrinogen levels.