Reference set for performance testing of pediatric vaccine safety signal detection methods and systems

BackgroundSafety signal detection in spontaneous reporting system databases and electronic healthcare records is key to detection of previously unknown adverse events following immunization. Various statistical methods for signal detection in these different datasources have been developed, however none are geared to the pediatric population and none specifically to vaccines. A reference set comprising pediatric vaccine-adverse event pairs is required for reliable performance testing of statistical methods within and across data sources.MethodsThe study was conducted within the context of the Global Research in Paediatrics (GRiP) project, as part of the seventh framework programme (FP7) of the European Commission. Criteria for the selection of vaccines considered in the reference set were routine and global use in the pediatric population. Adverse events were primarily selected based on importance. Outcome based systematic literature searches were performed for all identified vaccine-adverse event pairs and complemented by expert committee reports, evidence based decision support systems (e.g. Micromedex), and summaries of product characteristics. Classification into positive (PC) and negative control (NC) pairs was performed by two independent reviewers according to a pre-defined algorithm and discussed for consensus in case of disagreement.ResultsWe selected 13 vaccines and 14 adverse events to be included in the reference set. From a total of 182 vaccine-adverse event pairs, we classified 18 as PC, 113 as NC and 51 as unclassifiable. Most classifications (91) were based on literature review, 45 were based on expert committee reports, and for 46 vaccine-adverse event pairs, an underlying pathomechanism was not plausible classifying the association as NC.ConclusionA reference set of vaccine-adverse event pairs was developed. We propose its use for comparing signal detection methods and systems in the pediatric population.     

Outcomes of non-metastatic triple negative breast cancers: Real-world data from a large Indian cohort

BackgroundTriple negative Breast tumor (TNBC) is an aggressive tumor with sparse data worldwide.MethodsWe analyzed non-metastatic TNBC from 2013 to 2019 for demographics, practice patterns, and survival by the Kaplan Meir method. Prognostic factors for OS and DFS were evaluated using Cox Proportional Hazard model estimator for univariate and multivariable analysis after checking for collinearity among the variables.ResultsThere were 1297 patients with median age of 38 years; 41 (33.3%) among 123 tested were BRCA-positives. Among these 593 (45.7%) had stage III disease, 1279 (98.6%) were grade III, 165 (13.0%) had peri-nodal extension (PNE), 212 (16.0%) lympho-vascular invasion (LVI), and 21 (1.6%) were metaplastic; 1256 (96.8%) received chemotherapy including 820 (63.2%) neoadjuvant with 306 (40.0%) pCR. Grade ≥3 toxicities occurred in 155 (12.4%) including two deaths and 3 s-primaries. 1234 (95.2%) underwent surgery [722 (55.7%) breast conservations] and 1034 (79.7%) received radiotherapy.At a median follow-up of 54 months, median disease-free (DFS) was 92.2 months and overall survival (OS) was not reached. 5-year estimated DFS and OS was 65.9% and 80.3%. There were 259 (20.0%) failures; predominantly distant (204, 15.7%) - lung (51%), liver (31.8%).In multivariate analysis presence of LVI (HR-2.00, p-0.003), PNE (HR-2.09 p-0.003), older age (HR-1.03, p-0.002) and stage III disease (HR-4.89, p-0.027), were associated with poor OS.ConclusionRelatively large contemporary data of non-metastatic TNBC confirms aggressive biology and predominant advanced stage presentation which adversely affects outcomes. The data strongly indicate the unmet need for early detection to optimize care.     

The circulating tumor DNA (ctDNA) alteration level predicts therapeutic response in metastatic breast cancer: Novel prognostic indexes based on ctDNA

PurposeCirculating tumor DNA (ctDNA) has good clinical guiding value for metastatic breast cancer (MBC) patients. This study aimed to apply a novel genetic analysis approach for therapeutic prediction based on ctDNA alterations.MethodThis nonrandomized, multicenter study recruited 223 MBC patients (NCT05079074). Plasma samples were collected for target-capture deep sequencing of ctDNA at baseline, after the 2nd cycle of treatment, and when progressive disease (PD) was evaluated. Samples were categorized into four levels according to the number of ctDNA alterations: level 1 (no alterations), level 2 (1–2 alterations), level 3 (3–4 alterations) and level 4 (≥5 alterations). According to ctDNA alteration level and variant allele frequency (VAF), a novel ctDNA-level Response Evaluation Criterion in Solid Tumors (ctle-RECIST) was established to assess treatment response and predict progression-free survival (PFS).ResultsThe median PFS in level 1 (6.63 months) patients was significantly longer than that in level 2–4 patients (level 2: 5.70 months; level 3–4: 4.90 months, p < 0.05). After 2 cycles of treatment, based on ctle-RECIST, the median PFS of level-based disease control rate (lev-DCR) patients was significantly longer than that of level-based PD (lev-PD) patients [HR 2.42 (1.52–3.85), p < 0.001]. In addition, we found that ctDNA level assessment could be a good supplement to radiologic assessment. The median PFS in the dual-DCR group tended to be longer than that in the single-DCR group [HR 1.41 (0.93–2.13), p = 0.107].ConclusionThe ctDNA alteration level and ctle-RECIST could be novel biomarkers of prognosis and could complement radiologic assessment in MBC.     

G蛋白信号调节因子-13通过调控β-catenin抑制结直肠癌细胞增殖、迁移和侵袭

目的：探究G蛋白信号调节因子-13（RGS13）在结直肠癌（CRC）进展中的作用。方法：使用TCGA数据库和实时荧光定量聚合酶链反应（RT-qPCR）在mRNA水平分析CRC组织和细胞中RGS13 的表达量，使用免疫组织化学染色（IHC）和蛋白质印迹法（Western blot）在蛋白水平进一步分析。用ATP细胞活力检测实验、软琼脂克隆集落形成实验和细胞迁移侵袭实验检测RGS13对CRC细胞增殖、迁移和侵袭的影响，并通过Western blot、RT-qPCR等实验探究其下游分子机制。结果：RGS13在CRC组织与细胞系中低表达（P ＜0.01），RGS13 表达越低，患者的无病生存期越短（P =0.017）。RGS13 的下调可显著促进CRC细胞的增殖、迁移与侵袭（P ＜0.01），表明RGS13在CRC进展中发挥抑癌作用。机制上，RGS13通过下调Wnt/β-catenin信号通路中β-catenin的蛋白水平，进而降低癌基因c-Myc、MMP7 和CCND1等的表达水平（P ＜0.01），发挥对CRC的抑制作用。结论：RGS13可能通过下调β-catenin发挥抑制CRC进展的重要作用。     

Poly(ortho ester) nanoparticles targeted for chronic intraocular diseases: ocular safety and localization after intravitreal injection

Treatment of posterior eye diseases is more challenging than the anterior segment ailments due to a series of anatomical barriers and physiological constraints confronted by drug delivery to the back of the eye. In recent years, concerted efforts in drug delivery have been made to prolong the residence time of drugs injected in the vitreous humor of the eye. Our previous studies demonstrated that poly(ortho ester) (POE) nanoparticles were biodegradable/biocompatible and were capable of long-term sustained release. The objective of the present study was to investigate the safety and localization of POE nanoparticles in New Zealand white rabbits and C57BL/6 mice after intravitreal administration for the treatment of chronic posterior ocular diseases. Two concentration levels of POE nanoparticles solution were chosen for intravitreal injection: 1.5?mg/ml and 10?mg/ml. Our results demonstrate that POE nanoparticles were distributed throughout the vitreous cavity by optical coherence tomography (OCT) examination 14 days post-intravitreal injection. Intraocular pressure was not changed from baseline. Inflammatory or adverse effects were undetectable by slit lamp biomicroscopy. Furthermore, we demonstrate that POE nanoparticles have negligible toxicity assessed at the cellular level evidenced by a lack of glia activation or apoptosis estimation after intravitreal injection. Collectively, POE nanoparticles are a novel and nontoxic as an ocular drug delivery system for the treatment of posterior ocular diseases.     

Accounting for failure: risk-based regulation and the problems of ensuring healthcare quality in the NHS

In this paper, we examine why risk-based policy instruments have failed to improve the proportionality, effectiveness, and legitimacy of healthcare quality regulation in the National Health Service (NHS) in England. Rather than trying to prevent all possible harms, risk-based approaches promise to rationalise and manage the inevitable limits of what regulation can hope to achieve by focusing regulatory standard-setting and enforcement activity on the highest priority risks, as determined through formal assessments of their probability and consequences. As such, risk-based approaches have been enthusiastically adopted by healthcare quality regulators over the last decade. However, by drawing on historical policy analysis and in-depth interviews with 15 high-level UK informants in 2013–2015, we identify a series of practical problems in using risk-based policy instruments for defining, assessing, and ensuring compliance with healthcare quality standards. Based on our analysis, we go on to consider why, despite a succession of failures, healthcare regulators remain committed to developing and using risk-based approaches. We conclude by identifying several preconditions for successful risk-based regulation: goals must be clear and trade-offs between them amenable to agreement; regulators must be able to reliably assess the probability and consequences of adverse outcomes; regulators must have a range of enforcement tools that can be deployed in proportion to risk; and there must be political tolerance for adverse outcomes.     

The use of neoadjuvant lobar radioembolization prior to major hepatic resection for malignancy results in a low rate of post hepatectomy liver failure

BackgroundNeoadjuvant yttrium-90 transarterial radioembolization (TARE) is increasingly being used as a strategy to facilitate resection of otherwise unresectable tumors due to its ability to generate both tumor response and remnant liver hypertrophy. Perioperative outcomes after the use of neoadjuvant lobar TARE remain underinvestigated.MethodsA single center retrospective review of patients who underwent lobar TARE prior to major hepatectomy for primary or metastatic liver cancer between 2007 and 2018 was conducted. Baseline demographics, radioembolization parameters, pre- and post-radioembolization volumetrics, intra-operative surgical data, adverse events, and post-operative outcomes were analyzed.ResultsTwenty-six patients underwent major hepatectomy after neoadjuvant lobar TARE. The mean age was 58.3 years (17–88 years). 62% of patients (n=16) had primary liver malignancies while the remainder had metastatic disease. Liver resection included right hepatectomy or trisegmentectomy, left or extended left hepatectomy, and sectorectomy/segmentectomy in 77% (n=20), 8% (n=2), and 15% (n=4) of patients, respectively. The mean length of stay was 8.3 days (range, 3–33 days) and there were no grade IV morbidities or 90-day mortalities. The incidence of post hepatectomy liver failure (PHLF) was 3.8% (n=1). The median time to progression after resection was 4.5 months (range, 3.3–10 months). Twenty-three percent (n=6) of patients had no recurrence. The median survival was 28.9 months (range, 16.9–46.8 months) from major hepatectomy and 37.6 months (range, 25.2–53.1 months) from TARE.ConclusionsMajor hepatectomy after neoadjuvant lobar radioembolization is safe with a low incidence of PHLF.     

Aerobic exercise suppresses hepatocellular carcinoma by downregulating dynamin-related protein 1 through PI3K/AKT pathway

ObjectiveExercise, as a common non-drug intervention, is one of several lifestyle choices known to reduce the risk of cancer. Mitochondrial division has been reported to play a key role in the occurrence and transformation of hepatocellular carcinoma (HCC). This study investigated whether exercise could regulate the occurrence and development of HCC through mitosis.MethodsBioinformatics technology was used to analyze the expression level of dynamin-related protein 1 (DRP1), a key protein of mitochondrial division. The effects of DRP1 and DRP1 inhibitor (mdivi-1) on the proliferation and migration of liver cancer cells BEL-7402 were observed using cell counting kit-8, plate colony formation, transwell cell migration, and scratch experiments. Enzyme-linked immunosorbent assay, Western blot and real-time polymerase chain reaction were used to detect the expression of DRP1 and its downstream phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway. A treadmill exercise intervention was tested in a nude mouse human liver cancer subcutaneous tumor model expressing different levels of DRP1. The size and weight of subcutaneous tumors in mice were detected before and after exercise.ResultsThe expression of DRP1 in liver cancer tissues was significantly upregulated compared with normal liver tissues (P < 0.001). The proliferation rate and the migration of BEL-7402 cells in the DRP1 over-expression group were higher than that in the control group. The mdivi-1 group showed an inhibitory effect on the proliferation and migration of BEL-7402 cells at 50 μmol/L. Aerobic exercise was able to inhibit the expression of DRP1 and decrease the size and weight of subcutaneous tumors. Moreover, the expression of phosphorylated PI3K (p-PI3K) and phosphorylated AKT (p-AKT) decreased in the exercise group. However, exercise could not change p-PI3K and p-AKT levels after knocking down DRP1 or using mdivi-1 on subcutaneous tumor.ConclusionAerobic exercise can suppress the development of tumors partially by regulating DRP1 through PI3K/AKT pathway.     

ICD-10 anaphylaxis algorithm and the estimate of vaccine-attributable anaphylaxis incidence in Medicare

BackgroundAnaphylaxis is a rare, serious allergic reaction. Its identification in large healthcare databases can help better characterize this risk.ObjectiveTo create an ICD-10 anaphylaxis algorithm, estimate its positive predictive values (PPVs) in a post-vaccination risk window, and estimate vaccination-attributable anaphylaxis rates in the Medicare Fee For Service (FFS) population.MethodsAn anaphylaxis algorithm with core and extended portions was constructed analyzing ICD-10 anaphylaxis claims data in Medicare FFS from 2015 to 2017. Cases of post-vaccination anaphylaxis among Medicare FFS beneficiaries were then identified from October 1, 2015 to February 28, 2019 utilizing vaccine relevant anaphylaxis ICD-10 codes. Information from medical records was used to determine true anaphylaxis cases based on the Brighton Collaboration’s anaphylaxis case definition. PPVs were estimated for incident anaphylaxis and the subset of vaccine-attributable anaphylaxis within a 2-day post-vaccination risk window. Vaccine-attributable anaphylaxis rates in Medicare FFS were also estimated.ResultsThe study recorded 66,572,128 vaccinations among 21,685,119 unique Medicare FFS beneficiaries. The algorithm identified a total of 190 suspected anaphylaxis cases within the 2-day post-vaccination window; of these 117 (62%) satisfied the core algorithm, and 73 (38%) additional cases satisfied the extended algorithm. The core algorithm’s PPV was 66% (95% CI [56%, 76%]) for identifying incident anaphylaxis and 44% (95% CI [34%, 56%]) for vaccine-attributable anaphylaxis. The vaccine-attributable anaphylaxis incidence rate after any vaccination was 0.88 per million doses (95% CI [0.67, 1.16]).ConclusionThe ICD-10 claims algorithm for anaphylaxis allows the assessment of anaphylaxis risk in real-world data. The algorithm revealed vaccine-attributable anaphylaxis is rare among vaccinated Medicare FFS beneficiaries.     

Antibodies response induced by recombinant virus-like particles from Triatoma virus and chimeric antigens from Trypanosoma cruzi

BackgroundThe infection caused by the protozoan Trypanosoma cruzi affects humans and is called as Chagas disease. Currently, the main measures available to reduce the incidence of this disease are drug treatment and vector control. Traditionally, the development of vaccines occurs mainly through the use of antigenic candidates of the etiologic agent in the form of a vaccine preparation. Virus-like particles (VLPs) are structures analogous to viral capsids composed essentially of structural proteins and are widely used in vaccination protocols because of their immunostimulatory properties. In this context, the objective of this study was to use strategies in a murine immunization model to characterize the immunostimulatory capacity of VLPs from Triatoma virus (TrV-VLPs), analysed in the presence or absence of the aluminium vaccine adjuvant. In parallel, to characterize the immunogenic behaviour of four T. cruzi chimeric recombinant proteins (mix-IBMP) associated with TrV-VLPs or aluminium vaccine adjuvant.MethodWe immunized BALB/c mice once or twice, depending on the strategy, and collected serum samples at 15, 30 and 45 days after the immunization. Subsequently, serum samples from animals immunized with TrV-VLPs were used to determine total IgG, IgG1, IgG2a, IgG2b and IgG3 anti-TrV-VLPs by enzyme-linked immunosorbent assay (ELISA).ResultsData obtained demonstrate the ability of TrV-VLPs to preferably induce IgG2b and IgG3 type antibodies in the absence of aluminium adjuvant. In fact, the use of aluminium did not interfere with the total IgG profile of anti-TrV-VLPs. Interestingly, mix-IBMP had a better profile of total IgG, IgG1 and IgG3 subclasses when mixed with TrV-VLPs.ConclusionIn conclusion, these results suggest the potential of TrV-VLPs as a vaccine adjuvant and the use of T. cruzi chimeric antigens as a rational strategy for the development of vaccines against the experimental model of Chagas disease.