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.     

Enhanced surveillance of tetanus toxoid,reduced diphtheria toxoid,and acellular pertussis (Tdap) vaccines in pregnancy in the Vaccine Adverse Event Reporting System (VAERS), 2011–2015

BackgroundIn October 2011, the Advisory Committee on Immunization Practices (ACIP) issued updated recommendations that all pregnant women routinely receive a dose of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine.ObjectivesWe characterized reports to the Vaccine Adverse Event Reporting System (VAERS) in pregnant women who received Tdap after this updated recommendation (2011–2015) and compared the pattern of adverse events (AEs) with the period before the updated recommendation (2005–2010).MethodsWe searched the VAERS database for reports of AEs in pregnant women who received Tdap vaccine after the routine recommendation (11/01/2011–6/30/2015) and compared it to published data before the routine Tdap recommendation (01/01/2005–06/30/2010). We conducted clinical review of reports and available medical records. The clinical pattern of reports in the post-recommendation period was compared with the pattern before the routine Tdap recommendation.ResultsWe found 392 reports of Tdap vaccination after the routine recommendation. One neonatal death but no maternal deaths were reported. No maternal or neonatal deaths were reported before the recommendation. We observed an increase in proportion of reports for stillbirths (1.5–2.8%) and injection site reactions/arm pain (4.5–11.9%) after the recommendation compared to the period before the routine recommendation for Tdap during pregnancy. We noted a decrease in reports of spontaneous abortion (16.7–1%). After the 2011 Tdap recommendation, in most reports, vaccination (79%) occurred during the third trimester compared to 4% before the 2011 Tdap recommendation. Twenty-six reports of repeat Tdap were received in VAERS; 13 did not report an AE. One medical facility accounted for 27% of all submitted reports.ConclusionsNo new or unexpected vaccine AEs were noted among pregnant women who received Tdap after routine recommendations for maternal Tdap vaccination. Changes in reporting patterns would be expected, given the broader use of Tdap in pregnant women in the third trimester.     

丙泊酚复合瑞芬太尼喉罩全麻的效果分析与研究

目的 探讨丙泊酚复合瑞芬太尼喉罩全身麻醉(全麻)的效果。方法 62例腹腔镜、泌尿科、骨科、肛肠科、妇科等手术治疗的患者,随机分为实验组和对照组,每组31例。对照组采用常规气管插管静脉复合全麻,实验组给予靶控输注丙泊酚复合瑞芬太尼喉罩全麻。比较两组患者插入喉罩(插管)、插管1 min、插管3 min、拔出喉罩(拔管)1 min、拔管3 min时心率(HR)和平均动脉压(MAP)水平;不良反应发生情况、麻醉效果;全麻起效时间、维持全麻时间、术后苏醒时间。结果 实验组插管时、插管1 min、插管3 min、拔管1 min、拔管3 min的HR水平分别为(77.52±6.36)、(73.26±5.56)、(72.01±4.69)、(75.35±7.63)、(72.34±6.79)次/min,均低于对照组的(92.34±7.85)、(87.97±5.25)、(78.85±5.20)、(95.69±9.21)、(85.63±7.43)次/min,差异均具有统计学意义(P<0.05)。实验组插管时、插管1 min、插管3 min、拔管1 min、拔管3 min的MAP水平分别为(90.25±6.73)、(87.65±7.98)、(88.79±7.65)、(88.09±5.61)、(88.52±5.16)mm Hg(1 mm Hg=0.133 kPa),均低于对照组的(109.51±7.85)、(103.27±12.43)、(102.52±8.21)、(106.74±7.68)、(104.62±7.71)mm Hg,差异均具有统计学意义(P<0.05)。实验组不良反应发生率3.23%低于对照组的19.35%,差异具有统计学意义(P<0.05)。实验组麻醉总有效率96.77%均高于对照组的80.65%,差异均具有统计学意义(P<0.05)。实验组全麻起效、维持全麻、术后苏醒时间分别为(1.61±0.23)、(100.59±6.72)、(17.99±3.52)min,均短于对照组的(2.93±0.41)、(123.61±7.85)、(36.87±4.16)min,差异均具有统计学意义(P<0.05)。结论 针对腹腔镜等手术患者应用丙泊酚复合瑞芬太尼喉罩全麻对血液动力学影响小,不良反应发生率低,麻醉效果良好,降低对机体损伤,值得推广应用。     

Clinical Efficacy of New Antiepileptic Drugs in Refractory Partial Epilepsy: Experience in the United States With Three Novel Drugs

Summary: A number of new antiepileptic drugs (AEDs), including topiramate (TPM), felbamate (FBM), and gabapentin (GBP), are approved or believed to be close to approval for marketing in the United States. Key efficacy findings for these AEDs in refractory partial epilepsy were reviewed. Large and significant drug-placebo differences were observed with TPM in two large dose-finding trials conducted in the United States. The minimal effective dose of TPM in the population studied was determined to be approximately 200 mg/day, and doses above 600 mg/day produced good efficacy but little incremental benefit versus the lower dosages for the overall study population. FBM is active in partial epilepsy, although seizure reduction is less marked and drug interactions complicate the findings. GBP is also active in this population, but only the 1,800 mg/day dosage was significantly better than placebo with respect to percent re-sponders. It may be useful to explore higher dosage ranges for both FBM and GBP if they can be well tolerated.     

Adverse drug reactions: physicians' opinions versus a causality assessment method

Since spontaneous reporting of adverse drug reactions depends on the physician's opinion of the relationship between the drug and the adverse event, we compared physicians' opinions with the scores obtained by the causality assessment method used in France. During a 2 month period, all physicians who reported adverse drug reactions (ADRs) to our pharmacovigilance centre expressed their opinions on the causal link by means of visual analogue scales. ADR reports were then assessed with the French causality assessment method by a clinical pharmacologist who was blind to physicians' opinions.The assessment by both physicians and the standardized method was performed for 75 ADR cases involving 120 drugs. Physicians used a wide range of assessments, with a preponderance of extreme scores, resulting in a U-shaped distribution, while the standardized method gave generally low scores. Scores given by physicians were very high (causality considered very likely or likely) in 60% of cases and very low (causality considered unlikely or dubious/possible) in 32% of cases. Scores obtained using the causality assessment method were low (causality dubious/possible) in 89% of cases and causality considered likely in only 11 cases, essentially in cases with positive rechallenge. Complete agreement occurred in only 6% of cases. Adding complete agreement and minor discrepancies raised the percentage to 49%.     

Adverse reactions to non-ionic contrast media with special regard to high-risk patients

Non-ionic contrast media (CM) are proven to be significantly safer than the high osmolar ionic contrast media (HOCM). Nevertheless deaths are reported after administration of non-ionic agents. The aim of the study was to investigate the rate of adverse reactions to non-ionic CM with special regard to high-risk patients and the effects of premedication with H1-and H2-receptor antagonists.In a prospective study conducted over about 2 years 12 995 examinations with intravenous or intra-arterial non-ionic CM were evaluated. Premedication with H1-and H2-antagonists was used in 1276 high-risk patients with known adverse reaction to CM, history of allergy or severe cardiac or pulmonary disease. 229 patients received no premedication inspite of known risk factors. In total, there were 143 (1.10%) adverse reactions (mild in 0.58%, moderate in 0.41% and severe in 0.05%). In high-risk patients there were adverse reactions in 4.37% without and in 1.57% with premedication. There were no severe adverse reactions in the high-risk patients after premedication. The age of the patient, CM dosage and CM concentration were not shown to be risk factors in the present study. In conclusion, the additional premedication with H1- and H2-antagonists could be an effective agent to reduce the risk of mild and moderate adverse reactions and to avoid severe adverse reactions in high-risk patients. Correspondence to: U. Fink     

磁共振增强扫描中欧乃影不良反应的临床观察及预防措施

目的探讨欧乃影在临床应用中不良反应的发生和预防措施。方法观察2003年10月至2006年7月所作1000例增强扫描者静脉注射欧乃影0.2mL/kg(其量浓度(c)为0.5mol/L)后,不良反应发生的情况。结果1000例患者中,出现不良反应6例,其中,非过敏反应3例,轻度过敏反应3例,无中度及重度过敏反应。结论欧乃影在磁共振增强扫描中不良反应发生率低,临床应用安全。