Sentinel System Research Articles

External validity in distributed data networks.

While much has been written about how distributed networks address internal validity, external validity is rarely discussed. We aimed to define key terms related to external validity, discuss how they relate to distributed networks, and identify how three networks (the US Food and Drug Administration's Sentinel System, the Canadian Network for Observational Drug Effect Studies [CNODES], and the National Patient Centered Clinical Research Network [PCORnet]) deal with external validity. We define external validity, target populations, target validity, generalizability, and transportability and describe how each relates to distributed networks. We then describe Sentinel, CNODES, and PCORnet and how each approaches these concepts, including a sample case study. Each network approaches external validity differently. As its target population is US citizens and it includes only US data, Sentinel primarily worries about lack of external validity by not including some segments of the population. The fact that CNODES includes Canadian, United States, and United Kingdom data forces them to seriously consider whether the United States and United Kingdom data will be transportable to Canadian citizens when they meta-analyze database-specific estimates. PCORnet, with its focus on study-specific cohorts and pragmatic trials, conducts more case-by-case explorations of external validity for each new analytic data set it generates. There is no one-size-fits-all approach to external validity within distributed networks. With these networks and comparisons between their findings becoming a key part of pharmacoepidemiology, there is a need to adapt tools for improving external validity to the distributed network setting.

Six Years of FDA's Postmarket Active Risk Identification and Analysis System (ARIA) in the Sentinel Initiative: Implications for Real World Evidence Generation.

Congress mandated the creation of a postmarket active risk identification and analysis (ARIA) system containing data on 100 million individuals for monitoring risks associated with drug and biologic products using data from disparate sources to complement the US Food and Drug Administration's (FDA's) existing postmarket capabilities. We report on the first six years of ARIA utilization in the Sentinel System (2016 -2021). The FDA has used the ARIA system to evaluate 133 safety concerns; 54 of these evaluations have closed with regulatory determinations while the rest remain in progress. If the ARIA system and FDA's Adverse Event Reporting System are deemed insufficient to address a safety concern, then FDA may issue a postmarket requirement to a product's manufacturer. One-hundred-ninety-seven ARIA insufficiency determinations have been made. The most common situation for which ARIA was found to be insufficient is the evaluation of adverse pregnancy and fetal outcomes following in utero drug exposure, followed by neoplasms and death. ARIA was most likely to be sufficient for thromboembolic events, which have high positive predictive value in claims data alone and do not require supplemental clinical data. The lessons learned from this experience illustrate the continued challenges using administrative claims data, especially to define novel clinical outcomes. This analysis can help to identify where more granular clinical data are needed to fill gaps to improve the use of real-world data for drug safety analyses and provide insights into what is needed to efficiently generate high-quality real-world evidence for efficacy.

Designing a Wastewater-Based Epidemiology Study at the U.S. Air Force Academy: Using Severe Acute Respiratory Syndrome Coronavirus 2 to Test a Sentinel System forEarly Disease Outbreak Detection.

The presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) in wastewater has been proposed as a sentinel surveillance epidemiological tool for detection of infectious disease at a community level and as a complementary approach to syndromic surveillance of infectious disease outbreaks. We have designed a study to test the presence and quantity of SARS-CoV2, the virus responsible for COVID19, in the wastewater treatment facility (WWTF) of the U.S. Air Force Academy. Wastewater samples were tested in the laboratory to quantify the amount of SARS-CoV2 RNA using reverse transcription-quantitative polymerase chain reaction. Raw SARS-CoV2 viral titer in wastewater was normalized to the viral titer of a fecal marker, pepper mild mottle virus, to correct for dilutions. Temporal and spatial trends of COVID19 were analyzed. Furthermore, we compared wastewater analysis results against clinical data to assist public health decisions. Preliminary data suggest that wastewater analysis can provide temporal and spatial trends of COVID19. The geographically discrete WWTF at the U.S. Air Force suggests that wastewater testing is a useful approach to developing a comprehensive sentinel surveillance system. Together with ongoing syndromic surveillance data, this proof-of-concept study seeks to determine whether early detection of SARS-CoV2 in a closed system WWTF correlates to changes in community and clinically reported COVID19. The well-documented population served by the geographically discrete WWTF at the U.S. Air Force Academy may serve to better elucidate the adjunctive role of wastewater testing in a comprehensive surveillance system. These results may be of particular interest to the DoD and local commanders given the WWTFs under their immediate control and the information that these studies may provide in support of operational readiness through early detection of disease outbreaks.

Biological Sentinel: An Efficient Engineered Bacterial System for Monitoring and Tracing Regulated Hazardous Chemicals.

Monitoring and tracing of regulated hazardous chemicals is a public security issue of global concern. However, accurately recording historical exposure remains challenging. Here, we designed a Biological Sentinel System (BOSS) for in situ and long-term monitoring of hazardous chemical exposure using a chemical-induced base-editing system that activates antibiotic resistance screening, producing an obvious colorimetric signal. Exposure events can be written into an inheritable genomic DNA sequence, which can be read using gene sequencing. As a proof of concept, we demonstrated the accurate detection of cocaine and 2,4-dinitrotoluene using BOSS under simulated application scenarios. In addition, we integrated alternative biosensors to illustrate the modularity and extensibility of this monitoring platform. This work provides a promising paradigm for developing engineered microorganisms as an alternative to electronic monitors for regulated hazardous chemicals.

Postmarket Surveillance for Effective Regulation of Digital Mental Health Treatments.

Postmarket Surveillance for Effective Regulation of Digital Mental Health Treatments.

Pragmatic guidance for embedding pragmatic clinical trials in health plans: Large simple trials aren't so simple.

There are unique opportunities related to the design and conduct of pragmatic trials embedded in health insurance plans, which have longitudinal data on member/patient demographics, dates of coverage, and reimbursed medical care, including prescription drug dispensings, vaccine administrations, behavioral healthcare encounters, and some laboratory results. Such trials can be large and efficient, using these data to identify trial-eligible patients and to ascertain outcomes. We use our experience primarily with the National Institutes of Health Pragmatic Trials Collaboratory Distributed Research Network, which comprises health plans that participate in the US Food & Drug Administration's Sentinel System, to describe lessons learned from the conduct and planning of embedded pragmatic trials. Information is available for research on more than 75 million people with commercial or Medicare Advantage health plans. We describe three studies that have used or plan to use the Network, as well as a single health plan study, from which we glean our lessons learned. Studies that are conducted in health plans provide much-needed evidence to drive clinically meaningful changes in care. However, there are many unique aspects of these trials that must be considered in the planning, implementation, and analytic phases. The type of trial best suited for studies embedded in health plans will be those that require large sample sizes, simple interventions that could be disseminated through health plans, and where data available to the health plan can be leveraged. These trials hold potential for substantial long-term impact on our ability to generate evidence to improve care and population health.

Genomic analysis of 1710 surveillance-based Neisseria gonorrhoeae isolates from the USA in 2019 identifies predominant strain types and chromosomal antimicrobial-resistance determinants.

This study characterized high-quality whole-genome sequences of a sentinel, surveillance-based collection of 1710 Neisseria gonorrhoeae (GC) isolates from 2019 collected in the USA as part of the Gonococcal Isolate Surveillance Project (GISP). It aims to provide a detailed report of strain diversity, phylogenetic relationships and resistance determinant profiles associated with reduced susceptibilities to antibiotics of concern. The 1710 isolates represented 164 multilocus sequence types and 21 predominant phylogenetic clades. Common genomic determinants defined most strains' phenotypic, reduced susceptibility to current and historic antibiotics (e.g. bla TEM plasmid for penicillin, tetM plasmid for tetracycline, gyrA for ciprofloxacin, 23S rRNA and/or mosaic mtr operon for azithromycin, and mosaic penA for cefixime and ceftriaxone). The most predominant phylogenetic clade accounted for 21 % of the isolates, included a majority of the isolates with low-level elevated MICs to azithromycin (2.0 µg ml-1), carried a mosaic mtr operon and variants in PorB, and showed expansion with respect to data previously reported from 2018. The second largest clade predominantly carried the GyrA S91F variant, was largely ciprofloxacin resistant (MIC ≥1.0 µg ml-1), and showed significant expansion with respect to 2018. Overall, a low proportion of isolates had medium- to high-level elevated MIC to azithromycin ((≥4.0 µg ml-1), based on C2611T or A2059G 23S rRNA variants). One isolate carried the penA 60.001 allele resulting in elevated MICs to cefixime and ceftriaxone of 1.0 µg ml-1. This high-resolution snapshot of genetic profiles of 1710 GC sequences, through a comparison with 2018 data (1479 GC sequences) within the sentinel system, highlights change in proportions and expansion of select GC strains and the associated genetic mechanisms of resistance. The knowledge gained through molecular surveillance may support rapid identification of outbreaks of concern. Continued monitoring may inform public health responses to limit the development and spread of antibiotic-resistant gonorrhoea.

A fish-parasite sentinel system in an assessment of the spatial distribution of polychlorinated biphenyls

The spatial distribution of polychlorinated biphenyls (PCBs), in the Zemplínska Šírava water reservoir and adjacent tributaries in the Bodrog River Basin were investigated using a fish-parasite sentinel system. PCB concentrations were detected in various fish matrices (dorsal and abdominal muscles, liver and intestine) of the Wels catfish (Silurus glanis) and its intestinal cestode Glanitaenia osculata. PCB concentrations in the fish from the water reservoir, located closest to the chemical plant, the primary source of the PCB pollution, were the highest. The analysis of these contaminants in catfish matrices showed the highest concentrations in the abdominal muscle, followed by the dorsal muscle, liver and intestine. Concentrations of ∑PCBs exceeding the limits for food set by European regulations were measured in the muscle tissue of catfish at all sites, even in the Bodrog River, 60 km away from the primary source of contamination, posing a significant risk to humans in the Zemplín region. For the first time, the ability of cestode G. osculata to accumulate higher amounts of PCBs compared to fish matrices has been demonstrated. Due to the enormous ability of the parasites to accumulate PCBs, we recommend this approach for alternative biomonitoring of PCBs in contaminated aquatic environments.

Short-term stability of wastewater samples for storage and shipment in the context of the EU Sewage Sentinel System for SARS-CoV-2

In the context of an EU-wide surveillance system for SARS-CoV-2 in wastewater, recommended by the European Commission, this study aims to provide scientific support to the adequacy of transport and storage conditions of samples both in terms of duration and samples temperature. Three laboratories in Slovenia, Cyprus and Estonia investigated the short-term, one-week, isochronous stability of wastewater samples by RT-qPCR based detection of SARS-CoV-2 genes. The results were tested for statistical significance to determine uncertainty of quantification and shelf-life, at testing temperatures of + 20 °C and − 20 °C, relative to reference at + 4 °C. Samples were collected from three urban wastewater treatment plant influents and analysed respectively for SARS-CoV-2 genes N1, N2 (Laboratory 1), N2, E (Laboratory 2) and N3 (Laboratory 3), with various analytical methods. For a period of 7/8 days at + 20 °C, decreasing trends of measured concentrations were observed for all genes resulting in instability according to the statistical analysis, while at − 20 °C the trend of variation was stable only for N1, N2 (Laboratory 1) and N3 (Laboratory 3). Trends for gene E concentrations at − 20 °C (Laboratory 2) could not be tested statistically for stability because of lack of data. Over a period of just 3 days at + 20 °C, the variation was statistically non-significant indicating stability for genes N1, E and N3 for laboratories 1, 2 and 3, respectively. Nonetheless, the outcome of the study presents evidence to support the choice of the selected temperature at which samples shall be preserved during storage before analysis or transport to the laboratory. The conditions (+4 °C, ∼ few days) chosen for EU wastewater surveillance are in accordance with these results, highlighting the importance of stability testing of environmental samples to determine the short-term analytical uncertainty.

Representativeness, Vaccination Uptake, and COVID-19 Clinical Outcomes 2020-2021 in the UK Oxford-Royal College of General Practitioners Research and Surveillance Network: Cohort Profile Summary

The Oxford-Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) is one of Europe's oldest sentinel systems, working with the UK Health Security Agency (UKHSA) and its predecessor bodies for 55 years. Its surveillance report now runs twice weekly, supplemented by online observatories. In addition to conducting sentinel surveillance from a nationally representative group of practices, the RSC is now also providing data for syndromic surveillance. The aim of this study was to describe the cohort profile at the start of the 2021-2022 surveillance season and recent changes to our surveillance practice. The RSC's pseudonymized primary care data, linked to hospital and other data, are held in the Oxford-RCGP Clinical Informatics Digital Hub, a Trusted Research Environment. We describe the RSC's cohort profile as of September 2021, divided into a Primary Care Sentinel Cohort (PCSC)-collecting virological and serological specimens-and a larger group of syndromic surveillance general practices (SSGPs). We report changes to our sampling strategy that brings the RSC into alignment with European Centre for Disease Control guidance and then compare our cohort's sociodemographic characteristics with Office for National Statistics data. We further describe influenza and COVID-19 vaccine coverage for the 2020-2021 season (week 40 of 2020 to week 39 of 2021), with the latter differentiated by vaccine brand. Finally, we report COVID-19-related outcomes in terms of hospitalization, intensive care unit (ICU) admission, and death. As a response to COVID-19, the RSC grew from just over 500 PCSC practices in 2019 to 1879 practices in 2021 (PCSC, n=938; SSGP, n=1203). This represents 28.6% of English general practices and 30.59% (17,299,780/56,550,136) of the population. In the reporting period, the PCSC collected >8000 virology and >23,000 serology samples. The RSC population was broadly representative of the national population in terms of age, gender, ethnicity, National Health Service Region, socioeconomic status, obesity, and smoking habit. The RSC captured vaccine coverage data for influenza (n=5.4 million) and COVID-19, reporting dose one (n=11.9 million), two (n=11 million), and three (n=0.4 million) for the latter as well as brand-specific uptake data (AstraZeneca vaccine, n=11.6 million; Pfizer, n=10.8 million; and Moderna, n=0.7 million). The median (IQR) number of COVID-19 hospitalizations and ICU admissions was 1181 (559-1559) and 115 (50-174) per week, respectively. The RSC is broadly representative of the national population; its PCSC is geographically representative and its SSGPs are newly supporting UKHSA syndromic surveillance efforts. The network captures vaccine coverage and has expanded from reporting primary care attendances to providing data on onward hospital outcomes and deaths. The challenge remains to increase virological and serological sampling to monitor the effectiveness and waning of all vaccines available in a timely manner.

Assessing medical product safety during pregnancy using parameterizable tools in the sentinel distributed database.

The US Food and Drug Administration established the Sentinel System to monitor the safety of medical products. A component of this system includes parameterizable analytic tools to identify mother-infant pairs and evaluate infant outcomes to enable the routine monitoring of the utilization and safety of drugs used in pregnancy. We assessed the feasibility of using the data and tools in the Sentinel System by assessing a known association between topiramate use during pregnancy and oral clefts in the infant. We identified mother-infant pairs using the mother-infant linkage table from six data partners contributing to the Sentinel Distributed Database from January 1, 2000, to September 30, 2015. We compared mother-infant pairs with first-trimester exposure to topiramate to mother-infant pairs that were topiramate-unexposed or lamotrigine-exposed and used a validated algorithm to identify oral clefts in the infant. We estimated adjusted risk ratios through propensity score stratification. There were 2007 topiramate-exposed and 1 066 086 unexposed mother-infant pairs in the main comparison. In the active-comparator analysis, there were 1996 topiramate-exposed and 2859 lamotrigine-exposed mother-infant pairs. After propensity score stratification, the odds ratio for oral clefts was 2.92 (95% CI: 1.43, 5.93) comparing the topiramate-exposed to unexposed groups and 2.72 (95% CI: 0.75, 9.93) comparing the topiramate-exposed to lamotrigine-exposed groups. We found an increased risk of oral clefts after topiramate exposure in the first trimester in the Sentinel database. These results are similar to prior published observational study results and demonstrate the ability of Sentinel's data and analytic tools to assess medical product safety in cohorts of mother-infant pairs in a timely manner.

SDG Final Decade of Action: Resilient Pathways to Build Back Better from High-Impact Low-Probability (HILP) Events

The 2030 Sustainable Development Goals (SDGs) offer a blueprint for global peace and prosperity, while conserving natural ecosystems and resources for the planet. However, factors such as climate-induced weather extremes and other High-Impact Low-Probability (HILP) events on their own can devastate lives and livelihoods. When a pandemic affects us, as COVID-19 has, any concurrent hazards interacting with it highlight additional challenges to disaster and emergency management worldwide. Such amplified effects contribute to greater societal and environmental risks, with cross-cutting impacts and exposing inequities. Hence, understanding how a pandemic affects the management of concurrent hazards and HILP is vital in disaster risk reduction practice. This study reviews the contemporary literature and utilizes data from the Emergency Events Database (EM-DAT) to unpack how multiple extreme events have interacted with the coronavirus pandemic and affected the progress in achieving the SDGs. This study is especially urgent, given the multidimensional societal impacts of the COVID-19 pandemic amidst climate change. Results indicate that mainstreaming risk management into development planning can mitigate the adverse effects of disasters. Successes in addressing compound risks have helped us understand the value of new technologies, such as the use of drones and robots to limit human exposure. Enhancing data collection efforts to enable inclusive sentinel systems can improve surveillance and effective response to future risk challenges. Stay-at-home policies put in place during the pandemic for virus containment have highlighted the need to holistically consider the built environment and socio-economic exigencies when addressing the pandemic’s physical and mental health impacts, and could also aid in the context of increasing climate-induced extreme events. As we have seen, such policies, services, and technologies, along with good nutrition, can significantly help safeguard health and well-being in pandemic times, especially when simultaneously faced with ubiquitous climate-induced extreme events. In the final decade of SDG actions, these measures may help in efforts to “Leave No One Behind”, enhance human–environment relations, and propel society to embrace sustainable policies and lifestyles that facilitate building back better in a post-pandemic world. Concerted actions that directly target the compounding effects of different interacting hazards should be a critical priority of the Sendai Framework by 2030.

Seasonal controls on nearshore dissolved oxygen variability and hypoxia in a coastal embayment

Declining dissolved oxygen (DO) is emerging as an increasingly important stressor in nearshore ecosystems, and there is a growing need to better understand DO dynamics and hypoxia risk in this highly variable environment. In this study, we collected data from monthly cruises on the inner shelf, continuous nearshore moorings inside and outside a small coastal upwelling embayment (San Luis Obispo Bay in Central California), and weekly phytoplankton measurements inside the bay during the upwelling season. Nearshore DO was generally dominated by low-frequency synoptic variability, with increased DO variance near the surface relative to the bottom and inside the bay compared to outside. Two nearshore hypoxic regimes were identified. In the first regime, which occurred during periods of strong upwelling in the spring across all nearshore sites, the nearshore bottom water temperature-DO (T-DO) relationship was aligned with that found offshore, suggesting hypoxia was driven by the direct advection and cross-shelf exchange of low DO subthermocline waters from the shelf. This period also coincided with minimal water-column stratification, small vertical DO differences, and a diatom-dominated phytoplankton assemblage. In the second regime, which occurred during summer months and was characterized by weaker upwelling, strong stratification, and dinoflagellate-dominated phytoplankton assemblage, the near-bottom T-DO relationship inside the bay deviated significantly from that on the shelf offshore. These hypoxic events inside the bay were likely driven by localized respiration and lack of ventilation of bottom waters due to strong stratification. Collectively, these observations reveal a shift in the strength and magnitude of physical versus biological processes driving nearshore DO dynamics. The high spatiotemporal variability of DO dynamics in upwelling bays means that they are likely to be at the forefront of ecosystem impacts of and adaptions to climate change, and may act as sentinel systems or “canaries on the coast.”

Spironolactone Utilization among Patients with Reduced and Preserved Ejection Fraction Heart Failure

Background: Spironolactone is a mineralocorticoid receptor antagonist indicated for the management of heart failure with reduced ejection fraction (HFrEF). In a previous clinical trial, spironolactone significantly lowered the incidence of heart failure (HF) hospitalizations among HF patients with preserved ejection fraction (HFpEF). Real world utilization of spironolactone in HFrEF and HFpEF is unknown. Methods: We conducted a retrospective cohort study using data from FDA’s Sentinel System. We identified patients with HFrEF or HFpEF using diagnosis and procedure codes from a previously validated algorithm. We required patients to be continuously enrolled in the 183 days prior to HF diagnosis. Follow-up started on the day of HF diagnosis and ended at the earliest occurrence of a spironolactone dispensing, disenrollment, death, or end of data. We calculated the proportion of spironolactone utilization, and for those initiating treatment, we estimated the dose and duration of the first continuous treatment episode. Results: Among 2,009,529 HFrEF patients, 57.8% were male, and mean age was 73.8 ± 12.1 years. Among 9,257,514 HFpEF patients, 42.7% were male, and mean age was 73.0 ± 12.1 years. The proportion of spironolactone utilization following HFrEF diagnosis was 20.7% versus 7.6% after HFpEF. The median time (days) to initiation of spironolactone after HFrEF diagnosis was 90 (IQR: 19–385) versus 286 (IQR: 57–851) after HFpEF diagnosis. The median duration (days) of first treatment episode in HFrEF patients was 120 (IQR: 44–321) and 114 (IQR: 32–301) for HFpEF patients. The median dose was similar (25 mg/day) for both HF cohorts. Conclusion: Findings of low real-world utilization of spironolactone from our large, geographically, and demographically diverse multi-site study in the US are consistent with reports from smaller studies in the literature. Similar spironolactone dosing and duration were observed in both the HFpEF and HFrEF cohorts. Future research characterizing spironolactone treated and untreated HFpEF cohorts will be needed to identify treatment gaps.

Shoreline sentinels of global change show the consequences of extreme events.

Anthropogenic climate change along with the more frequent extreme weather it prompts, are having direct and indirect effects on distributions and abundance of species with consequence for community structure-especially if habitat providers are lost. Rocky shores have long been recognized as tractable experimental arenas for ecology contributing to theory. They have also emerged as important sentinel systems for tracking climate change responses of marine biodiversity and ecosystems, capitalizing on both historic broadscale surveys and time series. Combining these twin traditions is a powerful approach for better understanding and forecasting climate change impacts. Sustained observing allows extreme events to be detected and explored by in-parallel experimentation.

Selected Articles from This Issue

Evaluations of cancer etiology and safety and effectiveness of cancer treatments are predicated on large numbers of patients with sufficient baseline and follow-up data. To assess feasibility of FDA's Sentinel System's electronic healthcare data for surveillance of malignancy onset and examination of product safety, this study by Haug and colleagues examined patterns of enrollment surrounding new-onset cancers. The study found that the FDA Sentinel System's electronic healthcare data may be useful for characterizing relatively short latency cancer risk, examining cancer drug utilization and safety post diagnosis, and conducting surveillance for acute adverse events among patients with cancers. As a national distributed system with electronic health data, the Sentinel system provides opportunity for rapid pharmacoepidemiologic assessments relevant in oncology.This study sought to clarify and extend a 2018 descriptive study by the Centers for Disease Control and Prevention that reported high pediatric cancer incidence in New Hampshire. Statistically comparing national, regional and state data, this new study by Rees and colleagues confirms that the Northeast has the highest pediatric cancer incidence in the country, and that no single state within the Northeast is a statistical outlier. These findings emphasize the need for partnerships between northeastern states’ health departments and epidemiologists, to understand the causes of the region's high burden of pediatric cancer, and to identify possible solutions.Prior studies suggest there are persistent racial/ethnic disparities in overall and breast cancer mortality among women with metastatic disease, yet to what extent comorbidity burden contributes to these disparities is unclear. In this retrospective cohort study of 995 women newly diagnosed with metastatic breast cancer in a large diverse, integrated healthcare system, Wallner and colleagues found that medical comorbidities such as diabetes, and hypertension were common. They also found comorbidities were associated with an increased risk of both overall and breast cancer mortality and may influence disparities in these outcomes among women with metastatic breast cancer. Optimizing the management of comorbidities may therefore help to reduce these disparities and improve mortality outcomes in women with metastatic breast cancer.Lung cancer is the leading cause of cancer-related death. Smith-Byrne and colleagues used two complementary approaches to triangulate the role of circulating isovalerylcarnitine (IVC) in lung cancer aetiology - one based on genetic measurements of IVC in large genome-wide associations studies and one based on direct measurements of IVC in pre-diagnostic samples from population cohorts. The authors observed a protective effect for IVC that was independent of tobacco exposure (ORlog10 = 0.43, 95% CI: 0.29–0.63). Circulating IVC is modifiable through diet and warrants further investigation for a potential role in lung cancer prevention.

Feasibility of Sentinel Cerebral Embolic Protection Device Deployment During Transfemoral Transcatheter Aortic Valve Replacement

Cerebral embolic protection has emerged as a preventive measure for procedural stroke in transcatheter aortic valve replacement (TAVR).1 The Sentinel System (Boston Scientific Corp. Boston, Massachusetts), a 2-filter debris-capturing system, has been the only commercially available protection device in the United States since its approval by the Food and Drug Administration in 2017. In the Sentinel trial, the largest randomized trial (n = 363) so far, the device was successfully deployed in 94.7% of patients.

Should insulin billing procedure codes be considered for exposure ascertainment in pharmacoepidemiology studies?

Objectives: The purpose of the study was to examine whether Healthcare Common Procedure Coding System (HCPCS) billing codes should be used in conjunction with National Drug Codes (NDCs) to establish insulin exposure episodes. Materials and Methods: We identified insulin claims billed by NDCs or HCPCS codes in FDA’s Sentinel System from 2013 to 2018. We created insulin exposure episodes separately based on NDCs only, HCPCS only, and a combination of both NDC and HCPCS. We considered gaps of <30 days between valid billing codes as continuous exposure. Patients were followed until the earliest of (1) episode end date, (2) death, (3) disenrollment, (4) query end date, and (5) evidence of the opposite exposure defining code type (for cohorts defined by only NDCs or only HCPCS). We examined the median duration of incident episodes, requiring no NDC or HCPCS codes in the 183 days (washout period) before the first billing code and prevalent episodes (no washout period required). For patients with more than 1 treatment episode, we calculated median gap length between episodes. Results: We identified 107,528,855 insulin claims using NDCs or HCPCS. Of these, 98.5% were billed using NDCs. HCPCS were largely billed during emergency and ambulatory visits (52.5% and 38%, respectively). We identified 6,350,872 incident and 12,922,593 prevalent NDC episodes; and 6,821,075 incident and 13,465,108 prevalent NDC-HCPCS episodes. The median length of the first incident NDC. NDC episodes was 110 days (IQR: 60; 212); 31 (IQR: 19; 31) days for HCPCS only and 90 (IQR: 19-31) for NDC-HCPCS episodes. The median gap between the first and second episodes was shorter for incident NDC episodes than HCPCS episodes (NDC: 49 [IQR: 17; 132]; HCPCS: 249 [IQR: 93; 550]). Prevalent episodes showed similar trends. Conclusion: HCPCS insulin codes appeared to indicate either 1 time or sporadic occurrences with long gaps between two codes. HCPCS codes in conjunction with NDC codes increased the number but reduced the median length of insulin episodes. Unless studies investigate the effects of insulin administered in specific settings to identify transient adverse reactions treated with insulin, we do not encourage the use of HCPCS to establish insulin exposure episodes.

The US Food and Drug Administration Sentinel System: a national resource for a learning health system.

The US Food and Drug Administration (FDA) created the Sentinel System in response to a requirement in the FDA Amendments Act of 2007 that the agency establish a system for monitoring risks associated with drug and biologic products using data from disparate sources. The Sentinel System has completed hundreds of analyses, including many that have directly informed regulatory decisions. The Sentinel System also was designed to support a national infrastructure for a learning health system. Sentinel governance and guiding principles were designed to facilitate Sentinel's role as a national resource. The Sentinel System infrastructure now supports multiple non-FDA projects for stakeholders ranging from regulated industry to other federal agencies, international regulators, and academics. The Sentinel System is a working example of a learning health system that is expanding with the potential to create a global learning health system that can support medical product safety assessments and other research.

Deep inspiration breath-hold radiation therapy in left-sided breast cancer patients: a single-institution retrospective dosimetric analysis of organs at risk doses

BackgroundRadiotherapy can induce cardiac injury in left-sided breast cancer cases. Cardiac-sparing irradiation using the deep inspiration breath-hold (DIBH) technique can achieve substantial dose reduction to vulnerable cardiac substructures compared with free breathing (FB). This study evaluated the dosimetric differences between both techniques at a single institution.MethodsFrom 2017 to 2019, 130 patients with left-sided breast cancer underwent breast-conserving surgery (BCS; n = 121, 93.1%) or mastectomy (ME; n = 9, 6.9%) along with axillary lymph node staging (n = 105, 80.8%), followed by adjuvant irradiation in DIBH technique; adjuvant systemic therapy was included if applicable. 106 (81.5%) patients received conventional and 24 (18.5%) hypofractionated irradiation. Additionally, 12 patients received regional nodal irradiation. Computed tomography (CT) scans in FB and DIBH position were performed for all patients. Intrafractional 3D position monitoring of the patient surface in deep inspiration and breath gating was performed using Sentinel and Catalyst HD 3D surface scanning systems (C-RAD, Catalyst, C‑RAD AB, Uppsala, Sweden). Individual coaching and determination of breathing amplitude during the radiation planning CT was performed. Three-dimensional treatment planning was performed using standard tangential treatment portals (6 or 18 MV). The delineation of cardiac structures and both lungs was done in both the FB and the DIBH scan.ResultsAll dosimetric parameters for cardiac structures were significantly reduced (p < 0.01 for all). The mean heart dose (Dmean) in the DIBH group was 1.3 Gy (range 0.5–3.6) vs. 2.2 Gy (range 0.9–8.8) in the FB group (p < 0.001). The Dmean for the left ventricle (LV) in DIBH was 1.5 Gy (range 0.6–4.5), as compared to 2.8 Gy (1.1–9.5) with FB (p < 0.001). The parameters for LV (V10 Gy, V15 Gy, V20 Gy, V23 Gy, V25 Gy, V30 Gy) were reduced by about 100% (p < 0.001). The LAD Dmean in the DIBH group was 4.1 Gy (range 1.2–33.3) and 14.3 Gy (range 2.4–37.5) in the FB group (p < 0.001). The median values for LAD such as V15 Gy, V20 Gy, V25 Gy, V30 Gy, and V40 Gy decreased by roughly 100% (p < 0.001). An increasing volume of left lung in the DIBH position resulted in dose sparing of cardiac structures.ConclusionFor all ascertained dosimetric parameters, a significant dose reduction could be achieved in DIBH technique.