Search

We sought to examine predictors of pulmonary embolism response team (PERT) utilization and identify those who could benefit from advanced therapy.PERT and advanced therapy use remain low. Current risk stratification tools heavily weight age and comorbidities, which may not always correlate with presentation's severity.We prospectively studied patients with CT-confirmed PE between January 2019 and December 2019 at our hospital. PERT activation was left to the treating physician. Multivariable analyses were utilized to identify predictors of PERT activation and advanced therapy. Using the log odd ratio of each significant predictor of advanced therapy, we created a scoring system and a score of 2 was associated with the highest use. Primary outcomes were 30- and 90-day all-cause mortality, readmission, and major bleed.Of the 307 patients, PERT was activated in 22.5%. While abnormal vital signs and right ventricular (RV) strain were associated with PERT activation, pulmonary embolism severity index (PESI) was not. Advanced therapy use was significantly higher in the PERT cohort (35% vs 2%). Predictors of advanced therapy use were composite variable (heart rate 110 or systolic blood pressure 100 or respiratory rate 30 or oxygen saturation 90%) and right-to-left ventricular ratio 0.9. PERT patients with advanced therapy use, when compared to the no-PERT patients who could have qualified (score of 2), had significantly lower 30- and 90-day mortality and 30-day readmission without difference in major bleed.PERT has important therapeutic impact, yet no guidelines to direct activation. We recommend a multidisciplinary approach for higher acuity pulmonary embolism cases and physician education regarding PERT and the scope of advanced therapy use.

The study aims to identify the current situation of fisheries in the Arab Republic of Egypt. The study dealt with the organizational culture and its impact on economic feasibility, the most important factors affecting economic feasibility, and in order to achieve the objectives of the study, the descriptive approach was used. This is to ensure the validity of the study hypotheses. The study found the following results: There is statistical indication that there is a difference in the opinions of the respondents about the influence of the organizational culture (the focus of researchers and research in fisheries management) on the economics of fisheries, as the first hypothesis is confirmed. There is statistical indication that there is a difference in the opinions of the respondents about the effect of organizational culture (an axis related to employees in fisheries management) on the economics of fisheries, as the second hypothesis is confirmed. There is statistical indication that there is a discrepancy in the opinions of the respondents about the most important factors affecting the economic viability of fisheries, as the third hypothesis is confirmed. Among the most important recommendations made by researchers are the following: Attention must be paid to the organizational culture of fisheries management and focus on the human element (employees, researchers and workers) in order to streamline and flow production processes and raise the organizational efficiency of fisheries management. Research authorities must be consulted as they help solve economic problems and have a positive impact on the economic viability of fisheries and research bodies such as the Institute of Marine Sciences, colleges of fish wealth and others. It is imperative to distinguish those who obtained degrees, both materially and morally, which encourages researchers to make more efforts to develop the fisheries sector in the Arab Republic of Egypt. Paying attention to the organizational culture elements that positively affect the economic viability of fisheries, such as cooperation between leaders and researchers, cooperation between various disciplines, the assistance of Egyptian researchers and specialists, support of specialists for fisheries guidance, and employee support through specialists in the field of fisheries. There is no doubt that the study and analysis of economic feasibility related to fisheries can be used to develop the features of strategies that benefit policy makers and aim to rationalize fisheries management systems by focusing on the main and pivotal role of the economy, as dispensing with it when planning is considered an economic suicide for fisheries management (Food and Agriculture Organization) 2016.

The study aims to study the role of management accounting methods in reducing the risks of strategic decisions in the business organization environment. For achieve the study goals the extrapolation method was used in the conceptual study and prepare the field aspect on the questionnaire list that directed to the items sampled which amount to 106 item sample and the statistical analysis is used in ascertain the veracity of the study assumptions. The study reached the following results: 1) There are enough statistical evidences ascertain the invalidity of the first subsidiary assumption, it means that there is an intangible relationship between the use of effective management accounting methods to reduce the risks associated with strategic decisions. 2) There are enough statistical evidences ascertain the invalidity of the second subsidiary assumption, it means that there is an intangible relationship between the environment surrounding business organizations (internal or external environment) and effective decision-making in organizations. 3) There are enough statistical evidences ascertain the invalidity of the third subsidiary assumption, it means that there is an intangible relationship between the use of effective management accounting methods to increase efficiency in business organizations. The most important recommendations of the researcher include the following: 1) Attention to use management accounting methods when making strategic decisions. 2) Attention to the environmental factors surrounding the organizationbefore starting to make strategic decisions. 3) Attention to the strategic decision-making process because it leads to risks that threaten the organization.

The study aims to improve the activity of supplying ships with fuel (Bunkering) in the ports located on the axis of the Suez Canal region, attracting local and foreign investments and developing the necessary logistic services that are compatible with environmental requirements, which is considered one of the most important factors in the development of this activity like followed by the largest international ports (operating) working in bunkering activity, In order to achieve the objectives of the study, the descriptive approach was used to prepare the theoretical framework for the study and prepare the field study by preparing a questionnaire list that was directed to the sample items which amounted to 384 sample that workers in the bunkering activity in each of the Egyptain General Petroleum Corporation and companies working in the bunkering activity and the response rate reached 356 sample with 92.7%, and various statistical analysis methods and computer assistance were used through the SPSS program. The study reached the following results: Storage warehouse spaces cause a hindrance to the development bunkering activity in the port. Barges is one of the reasons for the deterioration of bunkering activity, in terms of efficiency and performance . Companies suffering from inefficiency and accordance of marine barges with environmental requirements. The role of environmental management in encouraging workers to innovation new methods reducing pollution . The most important recommendations reached by the researchers : Interesting to the efficiency of the storage warehouses to improve the bunkering activity and increasing their storage areas. Interesting to barges and increasing their capabilities in terms of: the storage area, pumping rate, heating and mixing, to become competitive, modern and competitive with followed in the global competing ports. Warning about workers using protective masks during charging and discharging operations. Attention to the procedures of continuous monitoring and follow-up in the various locations to protect the work environment and the surrounding environment from pollution. Interesting to the efficiency and conformity of the "barges" marine supply to environmental requirements and IMO regulations.

Purpose: To present the 6-month results of the Stromal Cell–Derived Factor-1 Plasmid Treatment for Patients with Peripheral Artery Disease (STOP-PAD) trial. The trial was an attempt to alter the course of chronic limb-threatening ischemia (CLTI) with a biological agent vs placebo after successful arterial revascularization at or below the knee. Materials and Methods: The multicenter, randomized, double-blinded, placebo-controlled, phase 2B STOP-PAD trial ( ClinicalTrials.gov identifier NCT02544204) randomized 109 patients (mean age 71 years; 68 men) with Rutherford category 5 or 6 CLTI and evidence of persistent impaired forefoot perfusion following recent successful revascularization to 8- (n=34) or 16-mg (n=36) intramuscular injections of a non-viral DNA plasmid–based treatment vs placebo (n=34). The primary efficacy outcome was the 6-month wound healing score evaluated by an independent wound core laboratory; the primary safety endpoint was major adverse limb events (MALE), a composite of major amputation plus clinically-driven target lesion revascularization at 6 months. Results: Only one-third of the patients had complete wound healing at 6 months in the placebo (31%), 8-mg injection (33%), and 16-mg injection (33%) groups. In addition, the observed increase in the toe-brachial index from baseline to 6 months was statistically significant in each group; however, this did not result in lower rates of MALE at 6 months (24% in the placebo, 29% in the 8-mg injection, and 11% in the 16-mg injection groups). During the 6-month period, 6 patients (6%) died, and 24 patients (23%) had an amputation [only 4 (4%) major]. Conclusion: Combining revascularization and biological therapy failed to improve outcomes in CLTI at 6 months. STOP-PAD has provided insights for future trials to evaluate biological therapy.

With the ongoing intravenous drug abuse (IVDA) epidemic, the number of IVDA patients with infective endocarditis is increasing. These cases are often characterized by large vegetations complicated by valvular dysfunction, heart failure, and recurrent septic pulmonary emboli demanding surgical intervention. Latter cannot be offered in a good proportion of the patients due to challenging medical and social complexities. Hence, AngioVac system has been used as an alternative therapy; however, it is associated with high procedural mortality. In this document, we describe in detail the successful treatment of a case of large tricuspid valve vegetation, with prohibitive risk for surgery, using a percutaneous catheter-based system, the Triever aspiration catheter with FLEX technology, with the guidance of intracardiac echocardiogram.

The efficacy of biologic therapies in critical limb ischemia (CLI) remains elusive, in part, due to limitations in trial design and patient selection. Using a novel design, we examined the impact of complementing revascularization therapy with intramuscular JVS-100 – a non-viral gene therapy that activates endogenous regenerative repair pathways. In this double-blind, placebo-controlled, Phase 2B trial, we randomized 109 patients with CLI (Rutherford class V or VI) to 8 mg or 16 mg intramuscular injections of placebo versus JVS-100. Patients were eligible if they persistently had reduced forefoot perfusion, by toe–brachial index (TBI) or skin perfusion pressure (SPP), following successful revascularization with angiographic demonstration of tibial arterial flow to the ankle. The primary efficacy end point was a 3-month wound healing score assessed by an independent wound core laboratory. The primary safety end point was major adverse limb events (MALE). Patients’ mean age was 71 years, 33% were women, 79% had diabetes, and 8% had end-stage renal disease. TBI after revascularization was 0.26, 0.27, and 0.26 among the three groups (placebo, 8 mg, and 16 mg injections, respectively). Only 26% of wounds completely healed at 3 months, without any differences between the three groups (26.5%, 26.5%, and 25%, respectively). Similarly, there were no significant changes in TBI at 3 months. Three (2.8%) patients died and two (1.8%) had major amputations. Rates of MALE at 3 months were 8.8%, 20%, and 8.3%, respectively. While safe, JVS-100 failed to improve wound healing or hemodynamic measures at 3 months. Only one-quarter of CLI wounds healed at 3 months despite successful revascularization, highlighting the need for additional research in therapies that can improve microcirculation in these patients. ClinicalTrials.gov Identifier: NCT02544204

OBJECTIVES To assess geriatric nutritional risk index (GNRI) in patients with chronic limb-threatening ischemia (CLTI). BACKGROUND The prevalence of CLTI continues to rise, with major amputation and mortality remaining prominent. Frailty is a vital risk factor for adverse outcomes in cardiovascular care. The GNRI is a nutrition-based surrogate for frailty that has been utilized in Southeast Asia to predict adverse events in CLTI. It has not yet been evaluated in a primarily Western population, nor in the context of wound healing. METHODS Between 8August 2017 and April 2019, we identified patients undergoing endovascular interventions for CLTI at our institution, categorized into low GNRI (≤ 94, frail) versus normal GNRI (> 94, reference). We analyzed the risks of major adverse limb events (MALE), its individual components [mortality, major amputation, and target vessel revascularization (TVR)], amputation free survival (AFS), and wound healing using Kaplan-Meier and multivariate cox-proportional hazard regression analyses. RESULTS A total of 255 patients were included in the analysis, with follow up of 14 ± 9.1 months. Lower GNRI was associated with higher cumulative event rates for MALE (71.0% vs. 43.3%, p < 0.001), mortality (34.3% vs. 15.2%, p

Introduction: The nutrition status plays a key role in the pathogenesis of frailty, and is strongly associated with the prognosis of patients with chronic limb-threatening ischemia (CLTI). The Geriatric Nutritional Risk Index (GNRI) is a widely used, simple, and well established nutritional status screening method. The association between the GNRI and wound healing in patients with CLTI has not been established. Hypothesis: We assessed the hypothesis that GNRI is associated with wound healing in patients with CLTI. Methods: We conducted a single-center retrospective analysis for 172 consecutive CLTI patients who were admitted to our hospital from August 2017 to April 2019 (age 70±14 years; men 62.2%). The GNRI on admission was calculated as follows: [14.89 х albumin (g/dL)] + [41.7 х (bodyweight/ideal body weight)]. According to the GNRI values, 4 grades of nutrition-related risk are defined as major risk (GNRI:98). The amputation-free survival (AFS) and the cumulative wound healing rate are calculated by the log-rank test. The receiver operating characteristic curve was used to obtain a cutoff value for wound heal. Cox proportional hazards regression analysis was performed to explore the independent association between the GNRI and wound heal. Results: The follow-up period was 12±6.7 months. The 1-year AFS in no risk, low risk, moderate risk, and major risk groups were 90%, 74%, 66%, and 62%, respectively ( P =0.045). GNRI was significantly associated with WIfI wound score (W1, 95±8.8; W2, 87±8.0; W3, 84±9.3, P P =0.036). GNRI=95 was selected as cutoff value with maximum discriminative power for wound healing (sensitivity 70%, specificity 60%; Area under the curve, 0.67; 95% confidence interval, 0.59-0.76). GNRI>95 was an independent predictor of wound healing (Hazard ratio, 1.9; 95% confidence interval, 1.0-3.7; P =0.046). Conclusions: The GNRI was significantly associated with AFS and wound healing in patients with CLTI. GNRI=95 is a novel cutoff value to predict wound healing during follow-up.

Objectives We sought to study the impact of COVID-19 pandemic on the presentation delay, severity, patterns of care, and reasons for delay among patients with ST-elevation myocardial infarction (STEMI) in a non-hot-spot region. Background COVID-19 pandemic has significantly reduced the activations for STEMI in epicenters like Spain. Methods From January 1, 2020, to April 15, 2020, 143 STEMIs were identified across our integrated 18-hospital system. Pre- and post-COVID-19 cohorts were based on March 23rd, 2020, whenstay-at-home orders were initiated in Ohio. We used presenting heart rate, blood pressure, troponin, new Q-wave, and left ventricle ejection fraction (LVEF) to assess severity. Duration of intensive care unit stay, total length of stay, door-to-balloon (D2B) time, and radial versus femoral access were used to assess patterns of care. Results Post-COVID-19 presentation was associated with a lower admission LVEF (45 vs. 50%, p = .015), new Q-wave, and higher initial troponin; however, these did not reach statistical significance. Among post-COVID-19 patients, those with >12-hr delay in presentation 31(%) had a longer average D2B time (88 vs. 53 min, p = .033) and higher peak troponin (58 vs. 8.5 ng/ml, p = .03). Of these, 27% avoided the hospital due to fear of COVID-19, 18% believed symptoms were COVID-19 related, and 9% did not want to burden the hospital during the pandemic. Conclusions COVID-19 has remarkably affected STEMI presentation and care. Patients' fear and confusion about symptoms are integral parts of this emerging public health crisis.

PURPOSE In recent years, novel types of real-world evidence (RWE) have played a role in various decision-making processes relating to medicinal products, including regulatory approval, patient access, health technology assessment, safety monitoring, clinical use, and post-approval lifecycle management. We therefore reviewed the potential utility of RWE in the cycle of medicinal product benefit-risk (BR) assessment, communication/risk minimization and evaluation ("BRACE"). METHODS A convenience sample of illustrative studies was drawn from the published literature and examined. Specifically, we examined the purpose for using RWE, the type of RWE used, its novelty and how it might be integrated with other data and activities of the BRACE cycle, and how it contributed to regulatory decision-making. RESULTS Eight studies were selected with each illustrating a different activity in the BRACE cycle ranging from BR assessment in the preapproval setting, post-approval assessment of safety or effectiveness, communicating BR information to patients and healthcare professionals, and evaluating the effectiveness of risk minimization initiatives to support a positive BR balance. CONCLUSIONS RWE has an important role in informing regulatory decision-making regarding the BR management of medicines. With increasing digitalization, facilitating data collection and stakeholder engagement in health, this role is only expected to expand in the future. To reach the full potential of RWE, both regulators and sponsors will need to be familiar with a range of existing and emerging methods for generating and analyzing such evidence appropriately and achieve convergence regarding how different types of RWE can best be used to inform BR management and decision-making.

Heart disease continues to affect health outcomes globally, accounting for a quarter of all deaths in the United States. Despite the improvement in the development and implementation of guideline-directed medical therapy, the risk of adverse cardiac events remains substantially high. Historically, it has been debated whether omega-3 polyunsaturated fatty acids provide clinical benefit in cardiac disease. The recently published REDUCE-IT trial demonstrated a statistically significant absolute risk reduction of 4.8% in its primary endpoint (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina) with the use of icosapent ethyl, which is a highly purified eicosapentaenoic acid (EPA) ethyl ester. However, the mechanism of action of omega-3 fatty acids is not commonly discussed. Moreover, the use of EPA was not without risk, as the incidence of atrial fibrillation was increased along with a trend towards increased bleeding risk. Thus, our aim is to help explain the function of purified EPA ethyl ester, especially at the molecular level, which will ultimately lead to a better understanding of their clinically observable effects.

Despite promising results in initial trials, renal denervation failed to achieve its efficacy end points as a treatment for resistant hypertension in the SYMPLICITY HTN-3 trial, the largest trial of this treatment to date (N Engl J Med 2014; 370:1393-1401). Is renal denervation dead, or will future trials and newer technology revive it?

The number and complexity of regulatory and legislative policy initiatives for benefit–risk (B-R) assessments and the challenges associated with operationalizing and integrating these initiatives in the drug development process have increased exponentially in the last 10 years. Although there are some similarities in the approaches being used among regions, there are no unifying principles for a consistent approach to address various regulatory agency requirements. Therefore, some sponsors might end up with marketing authorization in one region but not in another, in spite of using the same available benefits and risks evidence without obvious differences between regions. Fortunately, however, there has been a recent global effort by the International Conference on Harmonization (ICH) to develop guidance which provides greater specificity on the format and structure of B-R evidence that is submitted with marketing applications in Module 2 of the Common Technical Document (CTD). The guidance was fi...

Recent small single-center data indicate that the current hemodynamic parameters used to diagnose critical limb ischemia are insensitive. We investigated the validity of the societal guidelines-recommended hemodynamic parameters against core laboratory-adjudicated angiographic data from the multicenter IN.PACT DEEP (RandomIzed AmPhirion DEEP DEB vs StAndard PTA for the treatment of below the knee Critical limb ischemia) Trial.Of the 358 patients in the IN.PACT DEEP Trial to assess drug-eluting balloon vs standard balloon angioplasty for infrapopliteal disease, 237 had isolated infrapopliteal disease with an available ankle-brachial index (ABI), and only 40 of the latter had available toe pressure measurements. The associations between ABI, ankle pressure, and toe pressure with tibial runoff, Rutherford category, and plantar arch were examined according to the cutoff points recommended by the societal guidelines. Abnormal tibial runoff was defined as severely stenotic (≥70%) or occluded and scored as one-, two-, or three-vessel disease. A stenotic or occluded plantar arch was considered abnormal.Only 14 of 237 patients (6%) had an ABI 0.4. Abnormal ankle pressure, defined as 50 mm Hg if Rutherford category 4 and 70 mm Hg if Rutherford category 5 or 6, was found only in 37 patients (16%). Abnormal toe pressure, defined as 30 mm Hg if Rutherford category 4 and 50 mm Hg if Rutherford category 5 or 6, was found in 24 of 40 patients (60%) with available measurements. Importantly, 29% of these 24 patients had an ABI within normal reference ranges. A univariate multinomial logistic regression found no association between the above hemodynamic parameters and the number of diseased infrapopliteal vessels. However, there was a significant paradoxic association where patients with Rutherford category 6 had higher ABI and ankle pressure than those with Rutherford category 5. Similarly, there was no association between ABI and pedal arch patency.The current recommended hemodynamic parameters fail to identify a significant portion of patients with lower extremity ulcers and angiographically proven severe disease. Toe pressure has better sensitivity and should be considered in all patients with critical limb ischemia.

The environment kept its miraculous balance due to God's power till man, intentionally or non-intentionally, started to corrupt God's creation. This led to a huge problem, namely damaging the environment. Hence, the researcher decided to study and analyze costs, environmental returns of water industrial facilities of Toshka project of agricultural expansion under the title " A proposed Model to Measure Cost & Return in Water Facilities with the aim of Assessing Environmental Performance- Applied Study on Toshka Project" . This is due to the importance quality of accounting information for decision-making and conducting a research study of the opinions of a sample of those responsible for industrial facilities of Toshka Project. For the theoretical part of the studyk, light was shed on care of these facilities of environmental issues and nature of environmental costs borne by these facilities. The researcher also examined concept and nature of environmental costs and means of approaching them. As for the applied part, it is the research study and building a measurement model of cost & return. Through a questionnaire form distributed on those working at industrial facilities at Toshka Project, results and recommendations to achieve goals of the research were attained, the most important of which are: Firstly, Results: There is no moral relationship of statistically significance between rationalizing costs in water facilities and the results of the environmental performance of these facilities. There is no moral- relationship of statistically significance between cost rationalization, revenue of water facilities & the amount of environmental pollution. There is no moral relationship of statistically significance among the results of suggested model for measuring the cost & revenue of water facilities & rationalizing environmental performance of Toshka Project. Secondly: Recommendations: Paying attention to laying out qualified cadres in the accountant units & operational ones related to environment. Activating the laws that make the facilities conform to their responsibilities towards the environment & paying attention to research & study for indicating the role of environmental legislations & their effects on environmental costs. Paying attention to evaluation as a tool for improving the facilities performance periodically as well as research and study of accountancy information in evaluating environmental performance .

Pulmonary Embolism (PE) is associated with high morbidity and mortality; however, with the advent of multidisciplinary Pulmonary Embolism Response Teams (PERT) and advanced therapies, those may be preventable. We evaluated the treatment and 30-day outcomes of all PE admitted to our hospital. We

Purpose Quantitative benefit-risk (B-R) assessments are used to characterize treatment by combining key benefits and risks into a single metric but have historically been done for the "average" patient. Our aim was to conduct an individualized assessment for the oral antiplatelet vorapaxar by combining trial and real-world data to further personalize the treatment profiles. Methods Using linked UK health care databases, we developed risk prediction equations for key ischemic and bleeding events using Cox proportional hazards models. Trial hazard ratios, relative to placebo, were applied to baseline risk estimates to compute expected attributable risks, summed to derive a per-patient net clinical benefit (NCB). High risk subgroups were defined a priori, and Gaussian mixture models (GMM) were fit to characterize the NCB distribution and identify subgroups with similar NCBs. Results NCB was consistently positive for all subgroups, likely due to the outcome correlation, and would remain positive with a 12-fold increase in bleeding risk. GMMs identified three distinct NCB subgroups. Compared with the middle/lower NCB subgroups, those with a higher NCB tended to be older, female, and have higher CV disease burden. Conclusions Personalized B-R assessments are feasible and clinically valuable and can be used to better predict who would benefit most from therapy.

Benefit-risk assessment is the foundation for decision making throughout the life cycle of medical products. Because patients are the beneficiaries of the efficacy of medical treatments and also bear their possible risks, their perspectives and judgments about value and the relative importance of benefits and risks should be at the heart of the medical decision-making process. Patient engagement is now at a tipping point; there have been a growing number of patient engagement initiatives over the past several years, but there remains the need for a common language, alignment on engagement approaches and best practices, and a shared vision regarding a desired future state. This article discusses insights gleaned from the DIA conference, "Patient Engagement in Benefit-Risk Assessment throughout the Life Cycle of Medical Products" (September 2015). It highlights the changes that will need to occur within the patient, medical-product sponsor, and regulatory cultures in order for patient engagement to become integrated into the medical-product development process and life cycle maintenance. Furthermore, it emphasizes that reaching the desired future state will require a conscious commitment from all stakeholders to work collaboratively to develop shared solutions and to map a common path forward.

An exercise ankle–brachial index (ABI) test can provide further insight into the functional significance of peripheral artery disease (PAD). The variability in its use, associated patient factors and its relation to patients’ symptoms are unknown. From the international PORTRAIT registry, we identified 1131 patients with PAD. We fit a hierarchical logistic regression model, adjusting for patient factors, country and site, to examine predictors of and variation in ordering exercise ABI testing. We also examined the associations between test components and health status as quantified by the Peripheral Artery Questionnaire (PAQ) using semi-parametric regression methods. Testing was ordered in 22% in the United States versus 80% in the Netherlands and 90% in Australia. Testing was likely to be performed if the patient was male, younger, had typical symptoms and a higher resting ABI, with substantial variability across sites (median odds ratio=5.9, 95% CI: 3.2–19.5). Adjusting for country and site, the resting ABI and all exercise ABI metrics were associated with the PAQ Physical Limitation score. In addition, important components of the test, namely time to onset of claudication, pain-free walking distance (PFWD), and maximum walking distance (MWD), were also associated with PAQ Symptoms and Summary scores. More importantly, even after adjusting for resting ABI, a patient with a post-exercise ABI of 0.29 (25th percentile), compared to 0.61 (75th percentile), achieved 4.4 (95% CI: 0.4–8.4, p=0.031) points less on the PAQ Physical Limitation score. Exercise ABI test use is remarkably variable, and less used in the United States. Its data, specifically PFWD and MWD, might help in objectively assessing the impact of PAD on patients’ functioning and quality of life.

Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for cancer. Due to the mechanism of action of ICIs, inflammatory reactions against normal tissue were an anticipated side effect of these agents; these immune-related adverse events have been documented and are typically low grade and manageable. Myocarditis has emerged as an uncommon but potentially life-threatening adverse reaction in patients treated with ICIs. Assessment and characterization of ICI-associated myocarditis is challenging because of its low incidence and protean manifestations. Nevertheless, the seriousness of ICI-associated myocarditis justifies a coordinated effort to increase awareness of this syndrome, identify patients who may be at risk, and enable early diagnosis and appropriate treatment. The “Checkpoint Inhibitor Safety Working Group,” a multidisciplinary committee of academic, industry, and regulatory partners, convened at a workshop hosted by Project Data Sphere, LLC, on December 15, 2017. This meeting aimed to evaluate the current information on ICI-associated myocarditis, determine methods to collect and share data on this adverse reaction, and establish task forces to close the identified knowledge gaps. In this report, we summarize the workshop findings and proposed steps to address the impact of ICI-associated myocarditis in patients with cancer.

The purpose of this study was to investigate the effect of post-exercise ankle-brachial index (ABI) on the incidence of lower extremity (LE) revascularization, cardiovascular outcomes, and all-cause mortality in patients with normal and abnormal resting ABI.The clinical and prognostic value of post-exercise ABI in the setting of normal or abnormal resting ABI remains uncertain.A total of 2,791 consecutive patients with ABI testing between September 2005 and January 2010 were classified into group 1: normal resting (NR)/normal post-exercise (NE); group 2: NR/abnormal post-exercise (AE); group 3: abnormal resting (AR)/NE; and group 4: AR/AE. Abnormal post-exercise ABI was defined as a drop of20% from resting ABI as per the American College of Cardiology/American Heart Association guidelines. The primary endpoint was incidence of LE revascularization. Secondary endpoints were major adverse cardiovascular events (MACE) and all-cause mortality. Associations between post-exercise ABI and outcomes were adjusted using multivariable Cox proportional hazard and propensity analyses.Compared with group 1 (NR/NE), group 2 (NR/AE) had increased LE revascularization (propensity-matched adjusted hazard ratio [HR]: 6.63, 95% confidence interval [CI]: 3.13 to 14.04; p0.001) but no differences in MACE or all-cause mortality. When resting ABI was abnormal, group 4 (AR/AE) compared with group 3 (AR/NE), abnormal post-exercise ABI was still associated with increased LE revascularization (adjusted HR: 1.59, 95% CI: 1.11 to 2.28; p = 0.01), which persisted after propensity matching (adjusted HR: 2.32, 95% CI: 1.52 to 3.54; p0.001). Compared with group 1 (NR/NE) and after propensity matching, group 4 (AR/AE) had a significant increase in MACE (adjusted HR: 1.44, 95% CI: 1.09 to 1.90; p = 0.009) and a trend toward increased all-cause mortality (adjusted HR: 1.37, 95% CI: 0.99 to 1.88; p = 0.052); however, group 3 (AR/NE) did not.Post-exercise ABI appears to offer both clinical (lower extremity revascularization) and prognostic information in those with normal and abnormal resting ABI.

Objectives To quantify changes in ankle and toe pressure from pre- to post-endovascular revascularization for critical limb ischemia (CLI) and examine their association with major adverse limb events (MALE). Background Despite societal guidelines recommendation of routine hemodynamic surveillance following revascularization, little is known about hemodynamic assessment in CLI. Methods Among the 358 patients with CLI from the international multicenter IN.PACT DEEP trial, ankle and toe pressures measurements were available at both baseline and after intervention in 270 and 44 patients, respectively. The change in ankle and toe pressures in response to endovascular revascularization and its association with 1-year MALE (target limb revascularization, amputation, or death) were examined using Kaplan–Meier curves and multivariable Cox proportional hazard analyses. Corresponding optimal cutoff points were also identified. Results The mean increase in ankle and toe pressures following revascularization was 33 and 13 mmHg, respectively. Patients with an improvement of ankle pressure >73 mmHg or toe pressure >1 mmHg had similarly the lowest incidence of MALE (23%), while the highest rate of MALE (50%) was found in those whose toe pressure failed to improve by at least 1 mmHg following intervention. In addition, an increase in ankle pressure >73 mmHg was numerically protective against MALE, and more importantly, an increase in toe pressure of >1 mmHg provided statistically significant protection from MALE (adjusted HR = 0.15, 95% CI: 0.04–0.57, P = 0.005). Conclusions Improvements in toe pressure post revascularization are incremental and rarely normalize. Toe pressure, compared to ankle pressure, is more useful in CLI and predicts future MALE.

Critical limb ischemia (CLI) is associated with significant morbidity, mortality, and increased health care expenses. Revascularization has a central role in the treatment of CLI. Following publication of BASIL (bypass versus angioplasty in severe ischemia of the leg) trial a decade ago, an "endovascular first" approach had gained momentum and the technologies available for endovascular therapy have exponentially increased. Both the development of technology and technique, highlighted in this review, have allowed operators to treat complex infrapopliteal lesions which are central to CLI pathology.The role of atherectomy remains controversial but for calcified lesions it has become an accepted adjunctive tool for plaque modification. The place of drug delivery technologies requires further trials. The use of a drug-coated balloon (DCB) makes intuitive sense; however, choice of excipient, lower limit of vessel size, and impact on remodeling and thrombosis remain uncertain. The optimal treatment of infrapopliteal disease remains an area of active investigation. The endpoints in CLI trials continue to be challenging and calibration of patency in relation to wound healing remains a moving target. In addition, unaccounted variables continue to confound interpretation of CLI trials-including quality and nature of wound care, status of pedal-plantar loop patency, and management of underlying diabetes and other comorbidities. In summary, these challenges will also need to be addressed as the CLI field continues to mature in the twenty-first century.

ObjectiveElectronic health records are increasingly used to investigate associations between antidiabetic therapy and cancer. Misclassification can impact results, especially if differential between comparators. The objective of this study was to estimate cancer misclassification when using primary care or hospital data alone. ApproachAdults aged ≥40 years with an insulin or oral antidiabetic prescription in Clinical Practice Research Datalink (CPRD) primary care data at least a year after start of data collection, and no record of type 1 diabetes, were included. Patients were matched by year of birth (stepwise within 5 years), sex and GP practice to up to 1 non-diabetic patient. The cohort was restricted to those eligible for Hospital Episode Statistics (HES) linkage with follow-up during the study period (01/04/97-31/12/06). Follow-up started at the maximum of the registration date with the practice, practice up-to-standard date (a CPRD quality metric), and start of study period. Follow-up ended at the minimum of when the patient left the practice, the date CPRD last collected data from the practice, and end of study period. Cancer was identified in CPRD via Read codes and in HES via ICD10 codes. For each cancer case in CPRD, analysis evaluated whether there was a corresponding record in HES coded with same, different or unspecified site. Analysis was repeated for cancers identified in HES. Results53,585 diabetic patients were matched to 47,435 non-diabetic patients. 83% of cancer cases in CPRD had a corresponding record in HES (78% with the same type). Misclassification varied by cancer site, ranging from 3% (stomach cancer) to 57% (nonmelanoma skin cancer). 83% of cancer cases in HES had a corresponding record in CPRD, with all misclassification rates

Purpose The aim of this study is to determine (i) the positive predictive value (PPV) of an algorithm using clinical codes to identify incident glaucoma and cataract events in the Clinical Practice Research Datalink (CPRD) and (ii) the ability to capture the correct timing of these clinical events. Methods A total of 21 339 and 5349 potential cataract and glaucoma cases, respectively, were identified in CPRD between 1 January 1990 and 31 December 2010. Questionnaires were sent to the general practitioners (GP) of 1169 (5.5%) cataract and 1163 (21.7%) glaucoma cases for validation. GPs were asked to verify the diagnosis and the timing of the diagnosis and to provide other supporting information. Results A total of 986 (84.3%) valid cataract questionnaires and 863 (74.2%) glaucoma questionnaires were completed. 92.1% and 92.4% of these used information beyond EMR to verify the diagnosis. Cataract and glaucoma diagnoses were confirmed in the large majority of the cases. The PPV (95% CI) of the cataract and glaucoma Read code algorithm were 92.0% (90.3–93.7%) and 84.1% (81.7–86.6%), respectively. However, timing of diagnosis was incorrect for a substantial proportion of the cases (20.3% and 32.8% of the cataract and glaucoma cases, respectively) among whom 30.4% and 49.2% had discrepancies in diagnosis timing greater than 1 year. Conclusions High PPV suggests that the algorithms based on the clinical Read codes are sufficient to identify the cataract and glaucoma cases in CPRD. However, these codes alone may not be able to accurately identify the timing of the diagnosis of these eye disorders. Copyright © 2014 John Wiley & Sons, Ltd.

An association between infection and an individual's blood group has been reported in the adult medical literature. This association has so far not been investigated in the neonate, and may be reflected in the differences in susceptibilities of neonates to bacterial sepsis. The aim of this study is to investigate the association between ABO phenotype and the incidence of sepsis in very low birth weight infants. This is a retrospective data analysis. All very low birth weight infants admitted to The George Washington University Medical Center between November 1997 and March 2003 were classified according to blood groups into group 1: Phenotype O and A (possible B-antibody (ab)); and group 2: Phenotype B and AB (without B-ab). Multivariate regression analysis was performed to determine statistically significant differences in sepsis between the two groups. Data on 164 infants was analyzed. One hundred and twenty five infants (76.2%) had blood group A or O and 39 infants (23.8%) had blood group B or AB. Mean gestational age was 27.6 ± 2.4 weeks and mean birth weight was 984.5 ± 295 g. Groups were not significantly different in gestational age, birth weight, gender, and race. After controlling for confounding variables, there was no difference between the groups in the incidence of sepsis (34% vs. 33%, P = 0.24). ABO blood group phenotype was not correlated with sepsis in the very low birth weight infants in our unit.

Purposes The purposes of this study were to determine (i) the positive predictive value (PPV) of multiple Read codes used to identify congenital cardiac malformation (CCM) cases in the UK Clinical Practice Research Datalink (CPRD); (ii) the accuracy of the diagnosis date; and (iii) the source of information that the general practitioners (GPs) use for validating the diagnosis suggested by the code. Methods Eight hundred eighty-eight records with Read diagnostic and procedures codes for CCM, between January 1996 and November 2010, were identified from CPRD. Questionnaires were sent to GPs to verify the diagnoses and date of the code-identified events. Results A total of 719 questionnaires were returned (81% response rate). The PPV of the CCM codes was 93% (670/719). Thirty-one percent of cases had a different event date than the one recorded in the electronic medical record (EMR); 10% of these differing dates were within 30days of the code-identified CCM date. GPs used a variety of data sources to confirm CCM diagnoses. Although the EMR was the most frequently used data source (70%), 66% reported using consultation letters, 9% reported using clinical notes or paper charts, and 35% of GPs reported using the hospital record to confirm the CCM diagnosis. Conclusions Clinical Practice Research Datalink Read codes for CCMs have 93% PPV and most likely point to true cases. However, the accuracy of diagnosis dates and the age at diagnosis may not be as reliable. The findings of this study indicate that GPs use information beyond what is available for researchers in the EMR to confirm clinical diagnoses when responding to validation questionnaires. Published 2013. This article is a U.S. Government work and is in the public domain in the USA. key words—Clinical Practice Research Datalink; Read/OXMIS codes; validation of congenital cardiac malformation; heart defects; congenital abnormalities; pharmacoepidemiology

This study investigates the potential association between montelukast use and psychiatric adverse events by monitoring changes in antidepressant medication dispensing rates before and after initiating montelukast.The primary study group of montelukast initiators was identified using the Wolters Kluwer's SOURCE Lx® pharmacy claims database (WK). This group included 232,159 patients ≤45 years old who had at least two montelukast prescriptions from 2003 to 2007. Comparison groups comprised of 264,704 fluticasone initiators and 89,635 long-acting β-agonist corticosteroid (LABA/ICS) initiators were also identified. Antidepressant medication dispensing rates in these three groups were determined using WK, and changes in rates before and after the first asthma controller medication prescription date were evaluated using interrupted time-series analysis (ITS). ITS was performed separately for four age categories, with a focus on youth (12-17 years) and young adult (18-24 years).For patients 18-24 years old, antidepressant medication dispensing rates increased significantly after initiating montelukast [1.93% (1.55-2.32%, p 0.001)] but also after initiating fluticasone and LABA/ICS [1.72% (1.30-2.15%, p 0.001) and 2.76% (2.35-3.17%, p 0.001)]. Similar patterns were observed across the three medication groups for other age categories but these differences were not all significant.Small increases in antidepressant medication dispensing rates occurred after initiating montelukast. However, similar increases were observed in the fluticasone and LABA/ICS comparison groups. The results of this study cannot support a specific association between initiation of montelukast treatment and an increase in psychiatric adverse effects.

PURPOSE: The major concern associated with isotretinoin treatment is its high teratogenic potential. Therefore ensuring use of contraception while on therapy is an important strategy for at-risk patients and has been emphasized in all risk management programs. iPledge the latest and most rigorous isotretinoin program requires among other stipulations monthly assessments of contraceptive use for patients undergoing isotretinoin treatment. The purpose of this study is to evaluate isotretinoin usage patterns and assess concomitant use of isotretinoin and contraceptives before and after iPledge. METHODS: Female patients aged 13-45 years with a new prescription for isotretinoin products during 2004-2008 were identified in the IMS Health longitudinal prescription claims database. Monthly concomitant use of isotretinoin and contraceptives was estimated. Segmented regression analysis of interrupted time series data was used to assess changes in monthly proportion of concomitant use in the 24 months preceding versus following iPledge implementation. RESULTS: The number of isotretinoin prescriptions decreased after iPledge implementation. A small but significant increase in monthly proportion of patients concomitantly using isotretinoin and contraceptive therapies was observed immediately after iPledge implementation (1.3% p-value = 0.02) particularly among younger patients (2.5% p-value < 0.01). No changes in the proportion of concomitancy over time (i.e. slope) between the periods before and after iPledge implementation were observed. CONCLUSION: The findings of this pharmacy prescription claims-based study suggest a small increase in concomitant use of isotretinoin and contraceptives coincident with the time of implementation of iPledge particularly among younger women. Published 2013. This article is a U. S. Government work and is in the public domain in the USA.

Purpose Research on the association of maternal selective serotonin reuptake inhibitor (SSRI) use and cardiac malformations in the offspring has yielded conflicting findings. We therefore sought to further investigate the association using data from a large population-based cohort in the UK. Methods The study population consisted of 149464 pregnancies ending in a live birth between January/1996 and November/2010 from the Clinical Practice Research Datalink’s Mother Baby Link. We created propensity-score matched cohorts of first-trimester SSRI users who did not use other antidepressants in the same gestational period (‘SSRI users’, n=3046) and non-antidepressant users (no use from the 3 months before pregnancy through the second trimester of pregnancy, ‘non-users’; n=8991). Weighted logistic regression was used to estimate the odds ratio (OR) and 95% confidence interval (CI) of cardiac malformations overall and septal defects diagnosed in the first year of life, or in the first 6 years of life. Results Sixteen infants with cardiac malformations were identified among SSRI users; 10 of them were septal defects. Among non-users, there were 48 infants with cardiac malformations, 26 of whom had septal defects. The OR (95% CI) for cardiac malformations was 1.00 (0.50; 2.00), and for septal defects was 1.15 (0.46; 2.87). Results were similar for cardiac malformations diagnosed in the first 6 years of life, and in several sensitivity analyses that were also implemented. Conclusions The results of this study are most compatible with no association between maternal use of SSRIs in early pregnancy and cardiac malformations or septal defects in the offspring. Published 2013. This article is a U.S. Government work and is in the public domain in the USA. key words—congenital abnormalities; heart defects; propensity score; SSRIS; weighted logistic regression; mother–baby link; pharmacoepidemiology

Purpose Research on medication safety in pregnancy often utilizes health plan and birth certificate records. This study discusses methods used to link mothers with infants, a crucial step in such research. Methods We describe how eight sites participating in the Medication Exposure in Pregnancy Risk Evaluation Program created linkages between deliveries, infants and birth certificates for the 2001–2007 birth cohorts. We describe linkage rates across sites, and for two sites, we compare the characteristics of populations linked using different methods. Results Of 299260 deliveries, 256563 (86%; range by site, 74–99%) could be linked to infants using a deterministic algorithm. At two sites, using birth certificate data to augment mother–infant linkage increased the representation of mothers who were Hispanic or non-White, younger, Medicaid recipients, or had low educational level. A total of 236460 (92%; range by site, 82–100%) deliveries could be linked to a birth certificate. Conclusions Tailored approaches enabled linking most deliveries to infants and to birth certificates, even when data systems differed. The methods used may affect the composition of the population identified. Linkages established with such methods can support sound pharmacoepidemiology studies of maternal drug exposure outside the context of a formal registry. Copyright © 2013 John Wiley & Sons, Ltd. key words—birth certificates; Medicaid; pregnancy outcome/epidemiology; medical record linkage; pharmacoepidemiology

This study aims to estimate the prevalence of and temporal trends in prenatal antipsychotic medication use within a cohort of pregnant women in the U.S. We identified live born deliveries to women aged 15–45 years in 2001–2007 from 11 U.S. health plans participating in the Medication Exposure in Pregnancy Risk Evaluation Program. We ascertained prenatal exposure to antipsychotics from health plan pharmacy dispensing files, gestational age from linked infant birth certificate files, and ICD-9-CM diagnosis codes from health plan claims files. We calculated the prevalence of prenatal use of atypical and typical antipsychotics according to year of delivery, trimester of pregnancy, and mental health diagnosis. Among 585,615 qualifying deliveries, 4,223 (0.72 %) were to women who received an atypical antipsychotic and 548 (0.09 %) were to women receiving a typical antipsychotic any time from 60 days before pregnancy through delivery. There was a 2.5-fold increase in atypical antipsychotic use during the study period, from 0.33 % (95 % confidence interval: 0.29 %, 0.37 %) in 2001 to 0.82 % (0.76 %, 0.88 %) in 2007, while the use of typical antipsychotics remained stable. Depression was the most common mental health diagnosis among deliveries to women with atypical antipsychotic use (63 %), followed by bipolar disorder (43 %) and schizophrenia (13 %). The number and proportion of pregnancies exposed to atypical antipsychotics has increased dramatically in recent years. Studies are needed to examine the comparative safety and effectiveness of these medications relative to other therapeutic options in pregnancy.

Purpose To validate an algorithm that uses delivery date and diagnosis codes to define gestational age at birth in electronic health plan databases. Methods Using data from 225 384 live born deliveries to women aged 15–45 years in 2001–2007 within eight of the 11 health plans participating in the Medication Exposure in Pregnancy Risk Evaluation Program, we compared (1) the algorithm-derived gestational age versus the “gold-standard” gestational age obtained from the infant birth certificate file and (2) the prenatal exposure status of two antidepressants (fluoxetine and sertraline) and two antibiotics (amoxicillin and azithromycin) as determined by the algorithm-derived versus the gold-standard gestational age. Results The mean algorithm-derived gestational age at birth was lower than the mean obtained from the birth certificate file among singleton deliveries (267.9 vs 273.5 days) but not among multiple-gestation deliveries (253.9 vs 252.6 days). The algorithm-derived prenatal exposure to the antidepressants had a sensitivity and a positive predictive value of ≥95%, and a specificity and a negative predictive value of almost 100%. Sensitivity and positive predictive value were both ≥90%, and specificity and negative predictive value were both >99% for the antibiotics. Conclusions A gestational age algorithm based upon electronic health plan data correctly classified medication exposure status in most live born deliveries, but trimester-specific misclassification may be higher for drugs typically used for short durations. Copyright © 2013 John Wiley & Sons, Ltd.

To describe the prevalence, trends, and patterns in use of antidiabetic medications to treat hyperglycemia and insulin resistance before and during pregnancy in a large U.S. cohort of insured pregnant women.Pregnancies resulting in live births were identified (N=437,950) from 2001 to 2007 among 372,543 females 12-50 years of age at delivery from 10 health maintenance organizations participating in the Medication Exposure in Pregnancy Risk Evaluation Program. Information for these descriptive analyses, including all antidiabetic medications dispensed during this period, was extracted from electronic health records and newborn birth certificates.A little more than 1% (1.21%) of deliveries were to women dispensed antidiabetic medication in the 120 days before pregnancy. Use of antidiabetic medications before pregnancy increased from 0.66% of deliveries in 2001 to 1.66% of deliveries in 2007 (P.001) because of an increase in metformin use. Most women using metformin before pregnancy had a diagnosis code for polycystic ovaries or female infertility (67.2%), whereas only 13.6% had a diagnosis code for diabetes. The use of antidiabetic medications during the second or third trimester of pregnancy increased from 2.8% of deliveries in 2001 to 3.6% in 2007 (P.001). Approximately two thirds (68%) of women using metformin before pregnancy did not use any antidiabetic medications during pregnancy.Antidiabetic medication use before and during pregnancy increased from 2001 to 2007, possibly because of increasing prevalence of gestational diabetes mellitus, type 1 and type 2 diabetes, and other conditions associated with insulin resistance.III.

Prior studies have assessed the prognostic value of a decrease, not an increase, of the post-exercise ankle–brachial index (ABI) among patients with normal resting results. Thus, we sought to evaluate the prognostic significance of an increase in post-exercise ABI among these patients. From a single center vascular laboratory database between September 2005 and January 2010, we retrospectively identified 1437 consecutive patients with a normal resting ABI (1.00–1.40) and available post-exercise results. We classified them into group 1 (normal subjects; post-exercise ABI drop ⩽ 20%, 58%) and group 2 (post-exercise ABI increase, 42%) after excluding those with an ABI drop > 20% (peripheral artery disease) as they had known disease ( n=192). The primary outcome was to assess the risk of ischemic events, defined as a composite of unadjudicated death, stroke, or myocardial infraction (MACE). Associations between groups and outcomes were examined using multivariable Cox proportional hazard and propensity analyses. Both groups had similar prevalence of cardiovascular comorbidities. In unadjusted analysis, group 2 was more likely to have MACE ( p = 0.001). After adjusting for all baseline characteristics, an increase in post-exercise ABI compared to normal subjects was associated with a higher MACE (adjusted HR: 1.70, 95% CI: 1.14–2.53; p=0.009). This association stayed statistically significant after propensity matching (adjusted HR: 1.80, 95% CI: 1.17–2.76; p=0.007). This hypothesis-generating analysis showed that an increase in post-exercise ABI appears to identify a population with a higher risk for MACE. A prospective study of this association and mechanisms of risk should be conducted.

Revascularization for critical limb ischemia (CLI), the most advanced form of peripheral artery disease, is the only treatment that has shown to reduce amputations.1 Indeed, all societal guidelines have given a class I indication for revascularization in patients with CLI.2,3 However, individuals with CLI frequently present with multilevel disease where >70% have some degree of infrapopliteal involvement, and these lesions are typically occluded and long.4 Although there have been significant advances in the femoropopliteal segment with drug-eluting stents (DES) and drug-coated balloons, little progress has been made for the treatment of infrapopliteal disease.5 Yet, the rates of amputation and mortality continue to decline in patients with CLI, whereas surgical bypass has significantly decreased.6 Given the paucity of advances for infrapopliteal disease, Mustapha et al,7 in this issue of Circulation: Cardiovascular Interventions , examined the current state of angioplasty for the treatment of infrapopliteal disease through conducting a meta-analysis and a systematic review of all studies from 2005 to 2015.7 See Article by Mustapha et al The authors analyzed 52 contemporary studies of 6769 patients with ≈9400 infrapopliteal atherosclerotic lesions in patients with CLI (97%). They found a technical success rate of 91% with a 63% primary patency. Rates of major amputation (15%) and all-cause mortality (15%) were also similar to those of Romiti et al,8 previously published in 2008. The authors concluded that there were suboptimal short- and long-term clinical outcomes with angioplasty in patients with CLI. The authors should be congratulated for conducting this contemporary analysis of patients with CLI undergoing angioplasty alone. However, as indicated by the investigators, the robustness of this meta-analysis is markedly limited because of the incompleteness …

Purpose Large electronic datasets are increasingly being used to evaluate healthcare delivery. The aim of this study was to compare information held by cancer registries with that of the General Practice Research Database (GPRD). Methods A convenience sample of 101 020 patients aged 40+ years drawn from GPRD formed the primary data source. This cohort was derived from a larger sample originally established for a cohort study of diabetes. GPRD records were linked with those from cancer registries in the National Cancer Data Repository (NCDR). Concordance between the two datasets was then evaluated. For cases recorded only on one dataset, validation was sought from other datasets (Hospital Episode Statistics and death registration) and by detailed analysis of a subset of GPRD records. Results A total of 5797 cancers (excluding non-melanomatous skin cancer) were recorded on GPRD. Of these cases, 4830 were also recorded on NCDR (concordance rate of 83.3%). Of the 976 cases recorded on GPRD but not on NCDR, 528 were present also in the hospital records or death certificates. Of the 341 cases recorded on NCDR but not on GPRD, 307 were recorded in these other two datasets. Rates of concordance varied by cancer type. Cancer registries recorded larger numbers of patients with lung, colorectal, and pancreatic cancers, whereas GPRD recorded more haematological cancers and melanomas. As expected, GPRD recorded significantly more non-melanomatous skin cancer. Concordance decreased with increasing age. Conclusion Although concordance levels were reasonably high, the findings from this study can be used to direct efforts for better recording in both datasets. Copyright © 2012 Crown copyright.

The Food and Drug Administration (FDA) issued a Public Health Advisory entitled "Suicidal Thinking in Children and Adolescents Being Treated with Strattera (Atomoxetine)" on September 29, 2005. At FDA's request, the manufacturer subsequently added a boxed warning to the drug's labeling on November 8, 2005.To evaluate whether the boxed warning for suicidal thinking in atomoxetine's labeling was associated with a change in the pattern of attention-deficit/hyperactivity disorder (ADHD) medication use.Patients who had an ADHD diagnosis and were prescribed either atomoxetine or stimulants between January 2004 and December 2007 were selected from IMS LifeLink Health Plan Claims database. In this ecologic analysis, the outcome measure is the incident atomoxetine use rate, defined as the proportion of atomoxetine incident users among all initial ADHD pharmacotherapy users. The impact of the boxed warning was evaluated using interrupted time series analysis.A total of 16,311 patients met the definition of incident ADHD medication users. The incident atomoxetine use rate decreased from January 2004 to September 2005 among all age groups (range, -0.45% to -0.74%); and the rate among adult patients decreased by 11.89% (95% confidence interval, 3.05%-20.74%) from September 2005 to November 2005. No long-term impact was detected.Significant decline of the atomoxetine use rate was observed before the boxed warning in all age groups. No significant change was detected in the atomoxetine use rate among targeted children or adolescents after the FDA's boxed warning concerning suicidal thinking.

Background Little is known about the extent of antiepileptic drug (AED) use in pregnancy, particularly for newer agents. Our objective was to assess whether AED use has increased among pregnant women in the U.S., 2001-2007.

Purpose To evaluate the validity of health plan and birth certificate data for pregnancy research. Methods A retrospective study was conducted using administrative and claims data from 11 U.S. health plans and corresponding birth certificate data from state health departments. Diagnoses, drug dispensings, and procedure codes were used to identify infant outcomes (cardiac defects, anencephaly, preterm birth, and neonatal intensive care unit [NICU] admission) and maternal diagnoses (asthma and systemic lupus erythematosus [SLE]) recorded in the health plan data for live born deliveries between January 2001 and December 2007. A random sample of medical charts (n = 802) was abstracted for infants and mothers identified with the specified outcomes. Information on newborn, maternal, and paternal characteristics (gestational age at birth, birth weight, previous pregnancies and live births, race/ethnicity) was also abstracted and compared to birth certificate data. Positive predictive values (PPVs) were calculated with documentation in the medical chart serving as the gold standard. Results PPVs were 71% for cardiac defects, 37% for anencephaly, 87% for preterm birth, and 92% for NICU admission. PPVs for algorithms to identify maternal diagnoses of asthma and SLE were ≥ 93%. Our findings indicated considerable agreement (PPVs > 90%) between birth certificate and medical record data for measures related to birth weight, gestational age, prior obstetrical history, and race/ethnicity. Conclusions Health plan and birth certificate data can be useful to accurately identify some infant outcomes, maternal diagnoses, and newborn, maternal, and paternal characteristics. Other outcomes and variables may require medical record review for validation. Copyright © 2012 John Wiley & Sons, Ltd.

Background The impact of mechanical ventilation on the incidence of intraventricular hemorrhage (IVH) in very low birth weight (VLBW) infants is unknown, simply because the vast majority of these infants have been routinely intubated and mechanically ventilated. There is a growing interest in the use of early nasal continuous positive airway pressure (ENCPAP) and avoiding mechanical ventilation. Objectives To examine the role of mechanical ventilation since delivery room in determining severe IVH in VLBW infants in two neonatal units that follow the same strategy of respiratory management using ENCPAP. Methods We collected data on delivery room intubation and mechanical ventilation during the first 3 days of life in VLBW infants. Logistic regression model was constructed to test the relationship between early mechanical ventilation and the diagnosis of severe IVH after controlling for significant confounding variables, such as BW, gender, duration of mechanical ventilation, and partial pressure of CO 2 (PCO 2 ). Results Of the studied 340 VLBW, 35 infants had severe IVH; most of them received mechanical ventilation that started either in the delivery room ( n = 12) or during the first ( n = 10) and second ( n = 3) days of life. Severe IVH was independently associated with lower BW, mechanical ventilation in the delivery room, and the cumulative duration of mechanical ventilation during the first 3 days. The adjusted odds ratio for severe IVH in infants intubated in delivery room was (OR = 2.7, CI: 1.1–6.6, P = 0.03). Severe IVH was not associated with gender, prenatal steroids, early sepsis, or patent ductus arteriosus. Conclusions Mechanical ventilation plays a role in predicting severe IVH. Both the time at which ventilation was initiated and the duration of ventilation are important determinants of severe IVH. Risk for severe IVH in infants who were never intubated in delivery room or during the first 3 days of life is miniscule.

To describe a program to study medication safety in pregnancy, the Medication Exposure in Pregnancy Risk Evaluation Program (MEPREP). MEPREP is a multi-site collaborative research program developed to enable the conduct of studies of medication use and outcomes in pregnancy. Collaborators include the U.S. Food and Drug Administration and researchers at the HMO Research Network, Kaiser Permanente Northern and Southern California, and Vanderbilt University. Datasets have been created at each site linking healthcare data for women delivering an infant between January 1, 2001 and December 31, 2008 and infants born to these women. Standardized data files include maternal and infant characteristics, medication use, and medical care at 11 health plans within 9 states; birth certificate data were obtained from the state departments of public health. MEPREP currently involves more than 20 medication safety researchers and includes data for 1,221,156 children delivered to 933,917 mothers. Current studies include evaluations of the prevalence and patterns of use of specific medications and a validation study of data elements in the administrative and birth certificate data files. MEPREP can support multiple studies by providing information on a large, ethnically and geographically diverse population. This partnership combines clinical and research expertise and data resources to enable the evaluation of outcomes associated with medication use during pregnancy.

Background Randomized clinical trials (RCTs) are often positioned at the top of evidence hierarchies. Meta-analyses of RCTs aim to integrate the state of knowledge on a given scientific question, particularly for rare drug-related outcomes. However, although RCTs are valuable tools in our armamentarium, they are rarely designed to evaluate drug safety and are thus susceptible to limitations that may hamper the ability of both RCTs and meta-analyses to fully characterize the safety profiles of drugs. Their potential limitations might be exacerbated in the study of rare outcomes, often encountered in drug safety assessment, when even minor deviations from the intended randomization could impact the stability of the risk estimates. Purpose This article considers the methodological caveats of both RCTs and meta-analyses of RCTs pertinent to the study of drug-related harms. It is intended to stimulate discussion about the impact of these caveats on interpreting findings of RCTs and meta-analyses for drug safety, which would foster more robust, critical evaluations, and thus enhance clinical and regulatory decision-making. Methods Pertinent issues that can influence the interpretation of drug-related harms discussed in this article were based on authors’ expertise and review of the literature. Results Investigators and clinicians should be cognizant of the potential limitations of the secondary use of RCTs and meta-analyses in the assessment of drug-related harms and, when applicable, should consider potential remedies to overcome these limitations. Limitations Only few practical examples are included in the article due to the fact that many of the discussed caveats are not examined and/or reported in many publications. In addition, the confidential nature of data reviewed at a regulatory agency forestalls an in depth discussion of examples pertaining to specific drugs. Furthermore, our ability to quantify the extent of encountering, or the actual impact of, the caveats addressed in this review on the RCTs findings is limited. It is worth noting that the mere encounter of a given caveat does not mean that it will obviate the utility of drug safety information from a given trial. The extent of its impact is expected to vary based on the specifics of the trial, the drugs studied, the indications, and the nature of the adverse events. Conclusions Although some of the limitations described are inherent in RCTs, some of the sources of bias highlighted in this article could be minimized by careful RCT design, planned follow-up, and improved collection of information on adverse events. As future research sheds more light on pertinent knowledge gaps and issues, the ability to maximize the use of RCTs and meta-analyses of RCTs to address drug safety questions of interest will be greatly enhanced.

Purpose To characterize the nature of a heparin contaminant's clinical effects in cases reported to the Adverse Event Reporting System (AERS). The FDA received reports of heparin-associated adverse events (AEs) starting in late 2007–early 2008 during a national investigation of allergic-type events. The investigation identified Baxter Healthcare-brand heparin product due to its strongest association with the events. Later, oversulfated chondroitin sulfate (OSCS), a heparin-like contaminant, was discovered. Methods This study was a case series of heparin reports in AERS received 1 January 2008 to 31 March 2008. Variables considered were frequency of treatment settings, AEs, mortality; as well as heparin dose and OSCS contamination. Results Five hundred seventy-four AERS cases (unduplicated reports) were identified and included. Of 94 cases with a fatal outcome, 68 reported at least one AE term from the list used to identify an allergic-type event. Nearly 75% of AEs in cases of IV administration (n = 170/233) reportedly occurred within 10 minutes, whereas over half of subcutaneous administration cases (n = 13/23) resulted in times-to-event of greater than 24 hours. Although cases with a time-to-event of less than 10 minutes appeared to correlate with higher levels of OSCS contamination, no clear differences were noted between high- and low-to-absent OSCS concentration lots with respect to AEs observed. Conclusions Intravenous administration and a higher OSCS concentration appeared to correlate with a more rapid onset of event. The FDA continues to monitor AEs associated with heparin use and has taken appropriate regulatory action to ensure a safe heparin drug supply. Published in 2010 by John Wiley & Sons, Ltd.

Purpose To determine if paroxetine versus non-paroxetine selective serotonin reuptake inhibitors (SSRIs) prescribing changed after the June 2003 FDA Paroxetine Public Health Advisory (PPHA) and if antidepressant and antipsychotic prescribing changed after the February 2004 FDA Advisory Committee Meeting (FDACM). Methods Ecologic analysis using estimates of patients dispensed antidepressants and antipsychotics, census data, and promotional spending data. Data sources were SDI: Vector One®, US Census, and IMS Health®. Measures were monthly use levels (number of patients dispensed antidepressants, antipsychotics, paroxetine, and non-paroxetine SSRIs prescriptions by age group per population count). Percent changes pre- to post-PPHA were used to assess changes in paroxetine versus non-paroxetine SSRIs prescribing. Interrupted time series (ITS) analysis was performed to examine use level changes post-FDACM by drug groups (all antidepressants and all antipsychotics). Results Post-PPHA mean paroxetine use levels decreased for all age groups (range: 5.5–34.1%). Mean non-paroxetine SSRIs use levels increased (range: 4.6–17.1%). Post-PPHA changes were greatest for 6–12 and 13–17 year olds. Decreased mean antidepressant drug use levels from pre- to post-FDACM were observed in all groups under 25 years old. A statistically significant decrease in the slopes from pre- to post-FDACM was observed for persons aged 13–17 and 18–24 years. The difference between the forecasted mean use level and the observed mean use level (in 12-month intervals) was statistically significant for all ages combined (−107.26; 95% CI: −166.32, −48.20) and 1–5 (−3.1; 95% CI: −4.62, −1.58), 6–12 (−36.02; 95% CI: −62.92, −9.12) and 25 years, and older groups (−83.17; 95% CI: −153.95, −12.39). For all age groups, decreases in the slopes of antipsychotic drugs use from pre- to post-FDACM were observed, although these slope changes were not statistically significant. The difference between the forecasted mean antipsychotic drugs use level and the observed mean use level (in 12-month intervals) was statistically significantly lower for all age groups. Conclusions Antidepressant use changed post-PPHA and -FDACM, with a differential pattern by age. There was no evidence of increased antipsychotic use post-FDACM. Ecologic data cannot determine if changes were due to depression not treated with medications or the prescribing of fewer antidepressants for other conditions. Published in 2009 by John Wiley & Sons, Ltd.

Background The United States is moving toward active drug safety surveillance using sources such as administrative claims and electronic medical records, but use of these data for studying teratogenicity has been challenging, as they typically do not allow for the easy identification of pregnancies. Our goal was to develop and validate an algorithm for the identification of pregnancies in the general practice research database (GPRD) that could be used to study pregnancy outcomes. Methods The algorithm identified pregnancies in women 15–45-year-old that were pregnant between 1 January 1987 and 31 December 2006. We identified live births, stillbirths, and spontaneous and elective terminations within a woman's record. We validated the algorithm using the additional clinical details maternity (ACDM) file and de-identified free-text records. Results We analyzed 16 035 394 records from 3 093 927 individuals and identified 383 184 women who had a total of 580 356 pregnancies. There were 415 221 full-term live births, 3080 pre- or post-term births, 1834 multi-fetus deliveries, 86 408 spontaneous abortions or miscarriages, 72 164 elective terminations, and 1649 stillbirths or fetal deaths. A marker of pregnancy care was identifiable for 86.3% of the 580 356 pregnancies. The internal validation steps indicated that the algorithm produced consistent results with the ACDM file. Conclusions We were successful in identifying a large number of pregnancies in the GPRD. Our use of a hierarchical approach to identify pregnancy outcomes builds upon the methods suggested in previous work, while implementing additional steps to minimize potential misclassification of pregnancy outcomes. Copyright © 2009 John Wiley & Sons, Ltd.