Beyond the black box: drug- and device-associated hypersensitivity events

Charles L Bennett1,2, Olatokunbo S Adegboro2, Elizabeth A Calhoun2, Dennis Raisch3,41Jesse Brown VA Medical Center, Chicago, IL, USA; 2University of Illinois School of Public Health, Chicago, IL, USA; 3University of New Mexico College of Pharmacy, Albuquerque, NM, USA; 4Veteran Affairs Cooperative Studies Program, Clinical Research Pharmacy, Albuquerque, NM, USABackground: Drug- and device-associated hypersensitivity reactions are serious toxicities that can result in respiratory failure or acute cardiac ischemic events, or even severe hypersensitivity syndromes such as Stevens–Johnson syndrome. These toxicities are usually poorly described in the “black box” warnings section of the product labels.Methods: Adverse event reports contained in databases maintained by the Project on Medical Research on Adverse Drug Events and Reports (Med-RADAR), product labels, safety advisories disseminated by pharmaceutical manufacturers, the Food and Drug Administration (FDA), and the Centers for Disease Control and Prevention (CDC) were reviewed.Results: Adverse event reports identified three health care workers who developed nevirapineassociated Stevens–Johnson syndrome following occupational exposure to HIV-infected blood or blood products; four persons with localized hypersensitivity and fatal cardiac events associated with rapamycin- or paclitaxel-coated coronary artery stent placements; and six persons with breast cancer who developed severe or fatal anaphylaxis after receiving adjuvant chemotherapy with Cremophor-EL containing paclitaxel. Safety advisories from the FDA, CDC, and the relevant pharmaceutical manufacturers were ambiguous in their description in “black box” warning sections of package inserts describing these serious and potentially fatal toxicities. Conclusion: Improvements are needed in pharmacovigilance and subsequent dissemination of safety advisories for drug/device-associated hypersensitivity reactions.Keywords: adverse events, hypersensivity, toxicity, dru

University students and faculty have positive perceptions of open/alternative resources and their utilization in a textbook replacement initiative

This is contribution no. 16-114-J from the Kansas Agricultural Experiment Station. The Kansas State University Open/Alternative Textbook Initiative provides grants to faculty members to replace textbooks with open/alternative educational resources (OAERs) that are available at no cost to students. Open educational resources are available for anyone to access, while alternative educational resources are not open. The objective of this study was to determine the perceptions towards OAERs and the initiative, of students enrolled in, and faculty members teaching, courses using OAERs. A survey was sent out to 2,074 students in 13 courses using the OAERs. A total of 524 (25.3%) students completed the survey and a faculty member from each of the 13 courses using OAERs was interviewed. Students rated the OAERs as good quality, preferred using them instead of buying textbooks for their courses, and agreed that they would like OAERs used in other courses. Faculty felt that student learning was somewhat better and it was somewhat easier to teach using OAERs than when they used the traditional textbooks. Nearly all faculty members preferred teaching with OAERs and planned to continue to do so after the funding period. These results, combined with the tremendous savings to students, support the continued funding of the initiative and similar approaches at other institutions

Evaluating Loss to Follow-Up in Newborn Hearing Screening in a Southern State

Objective: The aim of this study was to examine loss to follow-up on the usage of diagnostic or intervention services for South Carolina infants screened or diagnosed with hearing loss and the risk factors associated with loss to follow up. Design: A cross sectional analysis of data from South Carolina was used to examine loss to follow-up on the use of audiologic evaluation services after initial newborn hearing screening and receipt of intervention services after confirmation of hearing loss. Results: Three percent (3.1%) of all children screened in the state of South Carolina did not pass their newborn hearing screening test in 2013 with less than half (49.1%) of those children not reported to have used audiologic diagnostic services within one month of their initial screening test. Factors significant with receipt of services include birth weight, mother’s education, insurance type, and rurality. The degree of hearing loss was a significant determinant of receiving intervention at some point in time. Conclusions: The highest risk children are “lost follow-up” for both the initial diagnostic services and follow-up intervention services in South Carolina. Interventions targeted at specific groups are needed to improve the delivery of hearing services and prevent a public health shortfall

An assessment of the screening method to evaluate vaccine effectiveness: the case of 7-valent pneumococcal conjugate vaccine in the United States.

The screening method, which employs readily available data, is an inexpensive and quick means of estimating vaccine effectiveness (VE). We compared estimates of effectiveness of heptavalent pneumococcal conjugate vaccine (PCV7) against invasive pneumococcal disease (IPD) using the screening and case-control methods. Cases were children aged 19-35 months with pneumococcus isolated from normally sterile sites residing in Active Bacterial Core surveillance areas in the United States. Case-control VE was estimated for 2001-2004 by comparing the odds of vaccination among cases and community controls. Screening-method VE for 2001-2009 was estimated by comparing the proportion of cases vaccinated to National Immunization Survey-derived coverage among the general population. To evaluate the plausibility of screening-method VE findings, we estimated attack rates among vaccinated and unvaccinated persons. We identified 1,154 children with IPD. Annual population PCV7 coverage with ≥1 dose increased from 38% to 97%. Case-control VE for ≥1 dose was estimated as 75% against all-serotype IPD (annual range: 35-83%) and 91% for PCV7-type IPD (annual range: 65-100%). By the screening method, the overall VE was 86% for ≥1 dose (annual range: -240-70%) against all-serotype IPD and 94% (annual range: 62-97%) against PCV7-type IPD. As cases of PCV7-type IPD declined during 2001-2005, estimated attack rates for all-serotype IPD among vaccinated and unvaccinated individuals became less consistent than what would be expected with the estimated effectiveness of PCV7. The screening method yields estimates of VE that are highly dependent on the time period during which it is used and the choice of outcome. The method should be used cautiously to evaluate VE of PCVs

Footwear Affects Conventional and Sumo Deadlift Performance

Barefoot weightlifting has become a popular training modality in recent years due to anecdotal suggestions of improved performance. However, research to support these anecdotal claims is limited. Therefore, the purpose of this study was to assess the differences between the conventional deadlift (CD) and the sumo deadlift (SD) in barefoot and shod conditions. On day one, one-repetition maximums (1 RM) were assessed for thirty subjects in both the CD and SD styles. At least 72 h later, subjects returned to perform five repetitions in four different conditions (barefoot and shod for both CD and SD) at 70% 1 RM. A 2 X 2 (footwear x lifting style) MANOVA was used to assess differences between peak vertical ground reaction force (VGRF), total mechanical work (WORK), barbell vertical displacement (DISP), peak vertical velocity (PV) and lift time (TIME) during the concentric phase. The CD displayed significant increases in VGRF, DISP, WORK, and TIME over the SD. The shod condition displayed increased WORK, DISP, and TIME compared to the barefoot condition. This study suggests that lifting barefoot does not improve performance as no differences in VGRF or PV were evident. The presence of a shoe does appear to increase the DISP and WORK required to complete the lift, suggesting an increased work load is present while wearing shoes

Determinants of Propranolol’s Selective Effect on Loss Aversion

Research on emotion and decision making has suggested that arousal mediates risky decisions, but several distinct and often confounded processes drive such choices. We used econometric modeling to separate and quantify the unique contributions of loss aversion, risk attitudes, and choice consistency to risky decision making. We administered the beta-blocker propranolol in a double-blind, placebo-controlled within-subjects study, targeting the neurohormonal basis of physiological arousal. Matching our intervention’s pharmacological specificity with a quantitative model delineating decision-making components allowed us to identify the causal relationships between arousal and decision making that do and do not exist. Propranolol selectively reduced loss aversion in a baseline- and dose-dependent manner (i.e., as a function of initial loss aversion and body mass index), and did not affect risk attitudes or choice consistency. These findings provide evidence for a specific, modulatory, and causal relationship between precise components of emotion and risky decision making

Down's syndrome-like cardiac developmental defects in embryos of the transchromosomic Tc1 mouse

Aims Cardiac malformations are prevalent in trisomies of human chromosome 21 [Down's syndrome (DS)], affecting normal chamber separation in the developing heart. Efforts to understand the aetiology of these defects have been severely hampered by the absence of an accurate mouse model. Such models have proved challenging to establish because synteny with human chromosome Hsa21 is distributed across three mouse chromosomes. None of those engineered so far accurately models the full range of DS cardiac phenotypes, in particular the profound disruptions resulting from atrioventricular septal defects (AVSDs). Here, we present analysis of the cardiac malformations exhibited by embryos of the transchromosomic mouse line Tc(Hsa21)1TybEmcf (Tc1) which contains more than 90% of chromosome Hsa21 in addition to the normal diploid mouse genome. Methods and results Using high-resolution episcopic microscopy and three-dimensional (3D) modelling, we show that Tc1 embryos exhibit many of the cardiac defects found in DS, including balanced AVSD with single and separate valvar orifices, membranous and muscular ventricular septal defects along with outflow tract and valve leaflet abnormalities. Frequencies of cardiac malformations (ranging from 38 to 55%) are dependent on strain background. In contrast, no comparable cardiac defects were detected in embryos of the more limited mouse trisomy model, Dp(16Cbr1-ORF9)1Rhr (Ts1Rhr), indicating that trisomy of the region syntenic to the Down's syndrome critical region, including the candidate genes DSCAM and DYRK1A, is insufficient to yield DS cardiac abnormalities. Conclusion The Tc1 mouse line provides a suitable model for studying the underlying genetic causes of the DS AVSD cardiac phenotype

Evaluating Loss to Follow-up in Newborn Hearing Screening in a Southern State

Objective: The aim of this study was to examine loss to follow-up (LTFU) for diagnostic or early intervention (EI) services for South Carolina infants screened or diagnosed with hearing loss, and the risk factors associated with LTFU. Design: A cross sectional analysis of data from South Carolina was used to examine LTFU for the use of audiologic evaluation services after initial newborn hearing screening and receipt of EI services after confirmation of hearing loss. Results: Three percent (3.1%) of newborns screened in the state of South Carolina did not pass their hearing screening in 2013. Nearly half (49.1%) of those children had a documented audiologic diagnostic evaluation within one month of their initial screen. Factors significant with documentation of a diagnostic evaluation include birth weight, mother’s race, and mother’s education. The degree of hearing loss was a significant determinant of documented EI services. Conclusions: We found several characteristics that put children at risk for LTFU for both the initial diagnostic services and EI services in South Carolina. Interventions targeted at specific groups are needed to improve the delivery of both diagnostic evaluations and EI services, and prevent a public health shortfall

Optimising psoriatic arthritis therapy with immunological methods to increase standard evaluation: the protocol of an open-label multicentre, parallel-group, two-arm randomised controlled study evaluation precision medicine approach in the treatment of psoriatic arthritis

Introduction Psoriatic arthritis (PsA) affects around 150 000 people in the UK of whom around 50% require treatment with biologics. The most used biologics for PsA target tumour necrosis factor (TNF) or interleukin-17A (IL-17A). About 50% of patients respond to each, but it is not currently possible to predict response for individual patients, necessitating sequential treatment steps. A recent proof of concept study in PsA suggested that using peripheral immunophenotype to choose therapy could improve time to treatment response. This study will test the hypothesis, within an open-label parallel-group biomarker-stratified multicentre randomised controlled trial, which the baseline proportion of CD4+T cells with an activated type 17 immunophenotype (Th17 levels) predicts response to IL-17A or TNF inhibitors in PsA. Additional analyses will identify if the model can be refined by combining additional clinical and immunophenotypic factors. Statistical modelling will be used to predict the likely effectiveness of these approaches compared with standard care. Methods and analysis Patients with PsA eligible to start their first biologic as part of standard care are recruited and baseline blood tests are taken for immunophenotyping. Participants are stratified equally by Th17 levels and randomised 1:1 to receive either TNF (adalimumab) or IL-17A (secukinumab) inhibitors. The primary analysis will establish the interaction between baseline immunophenotype and treatment on the primary outcome (achievement of minimal disease activity criteria at week 24). In secondary analysis, modelling will identify if this prediction model can be optimised further by incorporating clinical phenotypes and additional immunophenotyping techniques. Ethics and dissemination Ethical approval for the study was granted by the North West Preston Research Ethics Committee (ref 21/NW/0016). Dissemination will be via conference presentations and peer-reviewed publications, aiming to impact on treatment guidelines. Trial registration number ISRCTN17228602