Charting a Path Forward: Assessing the Science of Chemical Risk Evaluations under the Toxic Substances Control Act in the Context of Recent National Academies Recommendations.

BACKGROUND: In 2016, Congress enacted the Frank R. Lautenberg Chemical Safety for the 21st Century Act ("the Lautenberg Act"), which made major revisions to the main U.S. chemical safety law, the 1976 Toxic Substances Control Act (TSCA). Among other reforms, the Lautenberg Act mandates that the U.S. Environmental Protection Agency (U.S. EPA) conduct comprehensive risk evaluations of chemicals in commerce. The U.S. EPA recently finalized the first set of such chemical risk evaluations. OBJECTIVES: We examine the first 10 TSCA risk evaluations in relation to risk science recommendations from the National Academies to determine consistency with these recommendations and to identify opportunities to improve future TSCA risk evaluations by further implementing these key approaches and methods. DISCUSSION: Our review of the first set of TSCA risk evaluations identified substantial deviations from best practices in risk assessment, including overly narrow problem formulations and scopes; insufficient characterization of uncertainty in the evidence; inadequate consideration of population variability; lack of consideration of background exposures, combined exposures, and cumulative risk; divergent approaches to dose-response assessment for carcinogens and noncarcinogens; and a flawed approach to systematic review. We believe these deviations result in underestimation of population exposures and health risks. We are hopeful that the agency can use these insights and have provided suggestions to produce chemical risk evaluations aligned with the intent and requirements of the Lautenberg Act and the best available science to better protect health and the environment-including the health of those most vulnerable to chemical exposures. https://doi.org/10.1289/EHP9649.

Pembrolizumab plus chemotherapy for first-line treatment of metastatic nonsquamous non-small-cell lung cancer: a network meta-analysis.

AIM: A systematic review and network meta-analysis were conducted to evaluate the efficacy of pembrolizumab + pemetrexed + platinum relative to other regimens in metastatic nonsquamous non-small-cell lung cancer (NSq-NSCLC). PATIENTS & METHODS: Eligible studies evaluated first-line regimens in NSq-NSCLC patients without known targetable mutations. Relative treatment effects were synthesized with random effects proportional hazards Bayesian network meta-analyses. RESULTS: The hazard ratio (HR) for overall survival (OS) for pembrolizumab + pemetrexed + platinum was statistically significant over all platinum-doublet (HR range: 0.42-0.61), platinum-doublet + bevacizumab (HR range: 0.44-0.53) and platinum-doublet + atezolizumab regimens (HR range: 0.56-0.62). Additionally, pembrolizumab + pemetrexed + platinum numerically improved OS over atezolizumab + paclitaxel + carboplatin + bevacizumab (HR: 0.65; 95% credible interval: 0.43, 1.01). Pembrolizumab + pemetrexed + platinum had 95.6% probability of being the best treatment regimen for OS. CONCLUSION: Pembrolizumab + pemetrexed + platinum is likely the most efficacious first-line regimen for metastatic NSq-NSCLC.

Anticipatory Nausea, Risk Factors, and Its Impact on Chemotherapy-Induced Nausea and Vomiting: Results From the Pan European Emesis Registry Study.

CONTEXT: Anticipatory (prechemotherapy) nausea (AN) is a classic conditioned symptom not responding well to current antiemetics. Minimal work has been done to assess its risk factors and impact on chemotherapy-induced nausea and vomiting (CINV). OBJECTIVES: To evaluate risk factors for AN and assess its impact on CINV development. METHODS: We analyzed data (n = 991) from a prospective observational multisite study in eight European countries over three cycles of chemotherapy. Patient/treatment characteristics were collected before chemotherapy. History of nausea/vomiting (yes/no), patient expectation of CINV (0-100 mm visual analog scale, [VAS]), and prechemotherapy anxiety (0-100 mm VAS) also were collected before chemotherapy. A patient-completed diary during each chemotherapy cycle obtained information on AN in the 24 hours before chemotherapy administration and nausea and vomiting (episodes of vomiting and severity of nausea) daily for five days after administration of chemotherapy (0-100 mm VAS). RESULTS: AN was reported by 8.3%-13.8% of patients, increasing in frequency and intensity over each cycle. Every 1 mm increase in AN on the VAS was significantly associated with 2%-13% of increase in the likelihood of CINV (all P-values <0.05). Key predictors of AN in Cycle 1 included metastatic disease and prechemotherapy anxiety. However, predictors of AN in subsequent cycles included prechemotherapy anxiety and AN and CINV experience in the previous cycle, the latter being the strongest predictor (odds ratio = 3.30-4.09 for CINV outcomes over the cycles). CONCLUSION: AN is a challenging symptom, and its prevention needs to consider better CINV prevention in the previous cycles as well as managing prechemotherapy anxiety.

Incidence and predictors of anticipatory nausea and vomiting in Asia Pacific clinical practice--a longitudinal analysis.

PURPOSE: Some patients experience nausea and/or vomiting (NV) before receipt of chemotherapy. Our objective was to evaluate the impact of prior chemotherapy-induced NV (CINV) on the incidence of anticipatory NV in later cycles. METHODS: This multicenter, prospective non-interventional study enrolled chemotherapy-naïve adults scheduled to receive highly or moderately emetogenic chemotherapy (HEC/MEC) for cancer in six Asia Pacific countries, excluding those with emesis within 24 h before cycle 1 chemotherapy. On day 1 before chemotherapy, patients answered four questions regarding emesis in the past 24 h, nausea, expectation of post-chemotherapy nausea, and anxiety in the past 24 h, the latter three scored from 0-10 (none-maximum). Multivariate logistic regression was used to assess the impact of prior CINV on anticipatory NV in cycles 2 and 3. RESULTS: Five hundred ninety-eight patients (59% female) were evaluable in cycle 2 (49% HEC, 51% MEC). The incidence of anticipatory emesis was low before cycles 2 and 3 (1.5-2.3%). The incidence of clinically significant anticipatory nausea (score of ≥3) was 4.8, 7.9, and 8.3% before cycles 1, 2, and 3, respectively, with adjusted odds ratio (OR), 3.95 (95% confidence interval (CI), 2.23-7.00; p < 0.001) for patients with clinically significant nausea in prior cycles, compared with none. The adjusted ORs for other anticipatory NV endpoints ranged from 4.54-4.74 for patients with prior CINV. The occurrence of clinically significant anxiety in the prior cycle also resulted in a significantly increased likelihood of anticipatory nausea. CONCLUSIONS: These findings highlight the importance of preventing CINV in cycle 1 to reduce anticipatory NV in subsequent cycles.

Impact of CINV in earlier cycles on CINV and chemotherapy regimen modification in subsequent cycles in Asia Pacific clinical practice.

PURPOSE: We sought to describe the impact of chemotherapy-induced nausea and vomiting (CINV) in prior cycles on CINV and chemotherapy regimen modification in subsequent cycles. METHODS: Eligible patients in this multinational prospective observational study were adults (≥18 years old) receiving their first single-day highly or moderately emetogenic chemotherapy (HEC or MEC). Multivariate logistic regression was used to assess the impact of CINV in prior cycles on CINV in subsequent cycles. Other independent variables included in the model were the cycle number, age, sex, and emetogenicity of regimen. RESULTS: There were 598 evaluable patients in cycle 2 and 533 in cycle 3, half receiving HEC and half MEC. Patients who experienced complete response (no emesis or rescue antiemetics) in earlier cycles, relative to those with no complete response, had an adjusted odds ratio (OR) of 5.9 (95% confidence interval (CI), 4.14-8.50) for experiencing complete response in subsequent cycles. Prior CINV was a significant and consistent predictor of subsequent CINV for all CINV endpoints: for emesis, OR 12.7 (95% CI, 8.47-18.9), for clinically significant nausea, OR 7.9 (95% CI, 5.66-10.9), and for clinically significant nausea and/or vomiting, OR 7.2 (5.17-10.1). Modifications to chemotherapy were recorded for 26-29% of patients in cycles 2 and 3, with CINV as the major reason for the modification for 5-9% of these patients. CONCLUSIONS: CINV in prior cycles was a strong and consistent predictor of CINV in subsequent cycles, while the incidence of chemotherapy regimen modification due to CINV was low in individual cycles.

Antiemetic therapy in Asia Pacific countries for patients receiving moderately and highly emetogenic chemotherapy--a descriptive analysis of practice patterns, antiemetic quality of care, and use of antiemetic guidelines.

PURPOSE: This paper reports prescribing patterns for prophylaxis of chemotherapy-induced nausea and vomiting (CINV) after highly or moderately emetogenic chemotherapy (HEC or MEC) for cancer in six Asia Pacific countries. METHODS: In a prospective noninterventional study, 31 sites in Australia, China, India, Singapore, South Korea, and Taiwan recorded details of CINV prophylaxis for the acute phase (first 24 h) and delayed phase (days 2-5) after single-day HEC or MEC for adult patients. Additional information on CINV prophylactic medications was collected from 6-day patient diaries. Primary antiemetic therapies were defined as corticosteroids, the 5-hydroxytryptamine-3 receptor antagonists (5HT3-RAs), and neurokinin-1 receptor antagonists (NK1-RAs). RESULTS: Evaluable patients in cycle 1 numbered 648 (318 [49%] HEC and 330 [51%] MEC) of mean (SD) age of 56 (12) years, including 58% women. For the acute phase after HEC, overall (and country range), 96% (91-100%) of patients received a 5HT3-RA, 87% (70-100%) a corticosteroid, and 43% (0-91%) an NK1-RA. CINV prophylaxis for the HEC delayed phase was more variable: including 22% (7-65%) 5HT3-RA, 52% (12-93%) corticosteroid, and 46% (0-88%) NK1-RA. For the MEC acute phase, 97% (87-100%) of patients received 5HT3-RA and 86% (73-97%) a corticosteroid. For the MEC delayed phase, 201 patients (61%) received a primary antiemetic, including 5HT3-RA (41%), corticosteroid (37%), and/or NK1-RA (4%). CONCLUSIONS: The 5HT3-RAs were prescribed consistently in all countries, while prescribing of other antiemetic therapies was variable, and corticosteroids were under-prescribed for CINV prophylaxis, particularly in the delayed phase.

Rationale and design of the Pan Australasian chemotherapy-induced emesis burden of illness study.

BACKGROUND: Preventing and managing chemotherapy-induced nausea and vomiting (CINV) remain important goals. The objective of the Pan Australasian chemotherapy-induced emesis burden of illness (PrACTICE) study was to describe the incidence of CINV after highly or moderately emetogenic chemotherapy (HEC or MEC) for cancer in current clinical practice in Australia and five Asian countries (China, India, Singapore, South Korea, and Taiwan). STUDY DESIGN: This prospective, observational study of CINV was conducted at 31 sites in these six countries from August 2011 through September 2012 and enrolled male and female adult patients (≥18 years of age) naïve to HEC and MEC who were scheduled to receive at least two cycles of single-day chemotherapy. The primary effectiveness endpoint was complete response, defined as no vomiting or use of rescue therapy, during chemotherapy cycle 1 in the overall phase (0-120 h), acute phase (0-24 h), and delayed phase (>24-120 h). Study outcomes were analyzed descriptively. Primary outcomes, CINV incidence, and treatment patterns (chemotherapy, CINV prophylaxis, rescue medication prescription, and rescue medication use) were assessed by phase (overall, acute, delayed), by cycle (as appropriate), within and across countries, and by level of chemotherapy emetogenicity (HEC vs. MEC). The impact of CINV in cycle 1 on CINV in cycle 2 was analyzed for all patients with evaluable data for cycle 2. No site-specific analyses were performed. The remainder of this special series of papers reports on the results of this study.

Baseline patient characteristics, incidence of CINV, and physician perception of CINV incidence following moderately and highly emetogenic chemotherapy in Asia Pacific countries.

PURPOSE: This paper describes the incidence of chemotherapy-induced nausea and vomiting (CINV) after highly or moderately emetogenic chemotherapy (HEC or MEC) for cancer in six Asia Pacific countries. METHODS: Sequential adult patients naïve to chemotherapy and scheduled to receive at least two cycles of single-day HEC or MEC were enrolled in this prospective observational study. Patients completed the Multinational Association of Supportive Care in Cancer (MASCC) Antiemesis Tool on post-chemotherapy days 2 and 6 to record acute-phase (first 24 h) and delayed-phase (days 2-5) CINV. RESULTS: There were 648 evaluable patients (318 HEC, 330 MEC) from Australia (n = 74), China (153), India (88), Singapore (57), South Korea (151), and Taiwan (125). Mean (SD) patient age was 56 (12) and 58% of patients were women; the most common primary cancers were breast (27%), lung (22%), and colon (20%). Overall in cycle 1, complete response (no emesis or rescue antiemetics) was recorded by 69% (95% confidence interval (CI), 66-73) of all evaluable patients, with country percentages ranging from 55 to 78% (p < 0.001). After HEC, no emesis was recorded by 75% and no nausea by 38% of patients. After MEC, 80% had no emesis and 50% no nausea. Acute-phase CINV was better controlled than delayed-phase CINV, and the control of nausea was the lowest of any CINV measure in all phases. In a CINV perception survey, physicians tended to overestimate emesis rate and underestimate nausea rate. CONCLUSIONS: CINV remains a substantial problem, and country-specific information about CINV can be useful in developing strategies to improve outcomes for patients undergoing chemotherapy.

Antiemetic guideline consistency and incidence of chemotherapy-induced nausea and vomiting in US community oncology practice: INSPIRE Study.

PURPOSE: Consensus guidelines for preventing chemotherapy-induced nausea and vomiting (CINV) are variably implemented in practice. The purpose of this study was to evaluate the impact of guideline-consistent/guideline-inconsistent CINV prophylaxis (GCCP/GICP) on the incidence of no CINV after cycle 1 of highly or moderately emetogenic chemotherapy (HEC or MEC). PATIENTS AND METHODS: This prospective observational study enrolled chemotherapy-naive adult outpatients who received single-day HEC or MEC at four oncology practice networks, all using electronic health record (EHR) systems, in Georgia, Tennessee, and Florida. Results from the Multinational Association of Supportive Care in Cancer Antiemesis Tool, a validated tool to measure CINV, administered 5 to 8 days postchemotherapy, were merged with EHR data. The primary end point, no CINV, defined as no emesis and no clinically significant nausea (score < 3 on 0-10 scale), was compared between cohorts using logistic regression. RESULTS: A total of 1,295 patients were enrolled (mean age, 59.3 years; 70.0% female; 35.5% HEC). The overall prevalence of GCCP was 57.3%. When corticosteroids were prescribed on days 2 to 4 after all HEC, GCCP for HEC increased from 28.7% to 89.8%; when NK1-receptor antagonists were prescribed after all MEC, GCCP for MEC increased from 73.1% to 97.8%. Over 5 days postchemotherapy, the incidence of no CINV was significantly higher in the GCCP cohort than the GICP cohort (53.4% v 43.8%; P < .001). The adjusted odds of no CINV with GCCP was 1.31 (95% CI, 1.07 to 1.69; P = .037). CONCLUSION: Increased adherence to antiemetic guidelines could significantly reduce the incidence of CINV after HEC and MEC.

Evaluation of risk factors predicting chemotherapy-related nausea and vomiting: results from a European prospective observational study.

CONTEXT: Demographic, personal, clinical, and behavioral factors predicting chemotherapy-induced nausea and vomiting (CINV) have been assessed in the past, but inconsistencies exist in the literature, studies have methodological shortcomings, and many risk factors have been examined in cross-sectional studies and univariate analyses. OBJECTIVES: To evaluate the predictive power of personal and treatment-related characteristics in the development of CINV, using a large and prospectively evaluated sample of a heterogeneous group of cancer patients receiving routine chemotherapy. METHODS: This was a multicountry, multisite prospective study over three cycles of chemotherapy. Adult patients from eight European countries about to receive highly and moderately emetogenic chemotherapy were recruited. Clinicians completed a case report form at or before the initial chemotherapy treatment, recording patient demographic and baseline clinical characteristics. Participants completed a daily patient diary for six days per chemotherapy cycle describing their CINV experience. Baseline patient data also included a history of nausea/vomiting (yes/no), patient expectation of nausea (0-100 mm visual analogue scale [VAS]), prechemotherapy anxiety (0-100 mm VAS), and prechemotherapy nausea (0-100 mm VAS) measured during the 24-hour period before chemotherapy initiation. RESULTS: There were 991 evaluable patients with complete Cycle 1 data, 888 for Cycle 2 data, and 769 for Cycle 3 data. A complex picture of predictor variables was shown, with different contribution of variables to the acute, delayed, and overall phases of CINV. Key predictor variables included the use of antiemetics inconsistent with international guidelines, younger age, prechemotherapy nausea, and no CINV complete response in an earlier cycle (all at P < 0.05). Anxiety, history of nausea/vomiting, and expectations of nausea were important predictors for some phases and cycles but not consistently across the CINV pathway. CONCLUSION: The results of this study provide clarity for the relative contribution of a set of characteristics in the development of CINV. Following evidence-based clinical antiemetic guidelines is of paramount importance, alongside treating patients with increased risk for CINV more aggressively, which both could lead to more optimal CINV management. These data can assist clinicians in making decisions about the antiemetic management of their patients.

The need for better public health decisions on chemicals released into our environment.

Protecting the health of the public-particularly the most vulnerable groups, such as children-requires rethinking current approaches to reducing environmental risks. We review the evolving understanding of the relationship between exposure to chemicals in the environment and disease, as well as the current state of managing those chemicals. We present recommendations to improve current approaches, including changing the burden of proof so that chemicals are not presumed safe in the absence of scientific data. We also propose modernizing approaches to assessing health risks.

Resource utilization and costs associated with chemotherapy-induced nausea and vomiting (CINV) following highly or moderately emetogenic chemotherapy administered in the US outpatient hospital setting.

PURPOSE: Chemotherapy-induced nausea and vomiting (CINV), common adverse events of chemotherapy, may be associated with considerable healthcare resource utilization. This study was conducted to describe CINV-associated healthcare visits and costs following a first cycle of highly or moderately emetogenic chemotherapy (HEC or MEC). METHODS: This retrospective cohort study used the Premier Perspective™ Database to identify adult patients who received their first HEC or MEC and at least one antiemetic agent from 2003 to 2007 at US hospital-based outpatient facilities. Hospital visits with a CINV-related ICD-9 diagnosis were included from the chemotherapy administration date to 30 days later or 1 day before the second chemotherapy, whichever was first. CINV costs were hospital-reported costs. RESULTS: Of 19,139 patients (HEC, 16%; MEC, 84%), mean (SD) age was 59 (14) years; 59% were female; 66% were white. CINV prophylaxis included 5-HT3 antagonists (85%), dexamethasone (76%), and NK-1 antagonists (2%). Overall, 13.8% of patients had a CINV-associated visit (HEC, 18%; MEC, 13%): 0.2% for acute CINV (day of chemotherapy, excluding chemotherapy administration visit) and 13.7% for delayed CINV. CINV-associated visits included inpatient (IP, 64%), outpatient (OP, 26%), and emergency room (ER, 10%) visits. Mean (SD) costs of CINV visits were $5,299 ($6,639); for IP, $7,448 ($7,271); OP, $1,494 ($2,172); and ER, $918 ($1,071). Mean per-patient CINV-associated costs across all patients were $731 ($3,069). Sensitivity analysis excluding visits where CINV was a secondary diagnosis code resulted in a CINV incidence of 4.4%, a mean CINV visit cost of $4,043, and a mean per-patient CINV-associated cost across all patients of $176. CONCLUSIONS: CINV visits in the first HEC or MEC cycle were common and costly, especially inpatient hospitalizations in the delayed phase. Strategies to reduce CINV in the delayed phase could reduce healthcare utilization and costs.

Science and decisions: advancing risk assessment.

At the request of the U.S. Environmental Protection Agency (EPA), the National Research Council (NRC) recently completed a major report, Science and Decisions: Advancing Risk Assessment, that is intended to strengthen the scientific basis, credibility, and effectiveness of risk assessment practices and subsequent risk management decisions. The report describes the challenges faced by risk assessment and the need to consider improvements in both the technical analyses of risk assessments (i.e., the development and use of scientific information to improve risk characterization) and the utility of risk assessments (i.e., making assessments more relevant and useful for risk management decisions). The report tackles a number of topics relating to improvements in the process, including the design and framing of risk assessments, uncertainty and variability characterization, selection and use of defaults, unification of cancer and noncancer dose-response assessment, cumulative risk assessment, and the need to increase EPA's capacity to address these improvements. This article describes and summarizes the NRC report, with an eye toward its implications for risk assessment practices at EPA.

State-of-the-science workshop report: issues and approaches in low-dose-response extrapolation for environmental health risk assessment.

Low-dose extrapolation model selection for evaluating the health effects of environmental pollutants is a key component of the risk assessment process. At a workshop held in Baltimore, Maryland, on 23-24 April 2007, sponsored by U.S. Environmental Protection Agency and Johns Hopkins Risk Sciences and Public Policy Institute, a multidisciplinary group of experts reviewed the state of the science regarding low-dose extrapolation modeling and its application in environmental health risk assessments. Participants identified discussion topics based on a literature review, which included examples for which human responses to ambient exposures have been extensively characterized for cancer and/or noncancer outcomes. Topics included the need for formalized approaches and criteria to assess the evidence for mode of action (MOA), the use of human versus animal data, the use of MOA information in biologically based models, and the implications of interindividual variability, background disease processes, and background exposures in threshold versus nonthreshold model choice. Participants recommended approaches that differ from current practice for extrapolating high-dose animal data to low-dose human exposures, including categorical approaches for integrating information on MOA, statistical approaches such as model averaging, and inference-based models that explicitly consider uncertainty and interindividual variability.

Utilization and dosage pattern of echinocandins for treatment of fungal infections in US hospital practice.

OBJECTIVE: With the availability of multiple echinocandins in the US, recommended dosages and dosing schedules vary by agent but actual utilization practices are unknown. The purpose of this study was to describe the utilization and dosage pattern of intravenous echinocandins for treatment of fungal infections in US hospitals. METHODS: The Premier Perspective Database was used to describe echinocandin use in 332 US hospitals. Adult patients hospitalized from January, 2006 through June, 2007 with at least one billing record for anidulafungin (Eraxis ** ), caspofungin (Cancidas dagger ), or micafungin (Mycamine double dagger ) were included. Hospitalizations with > 1 echinocandin or >or= 1 dosage with an FDA approved indication for fungal prophylaxis were excluded. Mixed multivariable models were developed to identify factors associated with mean daily dose. ** Eraxis, a registered trade name owned by Pfizer, Inc., New York, NY, USA dagger Cancidas, a registered trade name owned by Merck & Co., Inc., Whitehouse Station, NJ, USA double dagger Mycamine, a registered trade name owned by Astellas Pharma US, Inc., Deerfield, IL, USA. RESULTS: The number of unique patient hospitalizations was 708 for anidulafungin, 15 739 for caspofungin, and 1199 for micafungin. A single echinocandin was utilized at 88.6% of hospitals. Micafungin patients had the highest prevalence of cancer, bone marrow transplant, solid organ transplant, HIV/AIDS, fungal infection, and neutropenia. Mean day 1 dose of echinocandin therapy was 171.2 +/- 85.4 mg, 79.7 +/- 25.6 mg, and 154.3 +/- 67.3 mg; and mean day 2 onwards dose was 98.7 +/- 39.4 mg, 53.1 +/- 12.5 mg, 122.6 +/- 39.4 mg for anidulafungin, caspofungin and micafungin, respectively. Commonly used loading doses were 200 mg (55.6%) for anidulafungin, 70 mg (57.2%) for caspofungin, and 200 mg (21.2%) for micafungin. The first-day dose of echinocandin therapy (vs. subsequent days) was most strongly associated with mean daily dose. CONCLUSIONS: In hospital practice, the mean dosages were consistent with the recommended loading and maintenance dosages for caspofungin and anidulafungin. Patients frequently received a loading dose of > 150 mg on day 1 of micafungin which was inconsistent with recommended dosing schedules. Micafungin maintenance dosages > 100 mg were also commonly used. Lack of information on reason for initiating echinocandin therapy was an important study limitation.

Adequacy of state capacity to address noncommunicable disease clusters in the era of environmental public health tracking.

OBJECTIVES: We sought to assess the capacity of state public health agencies to address noncommunicable disease clusters (NCCs) and to develop recommendations to enhance agencies' NCC response capacity. METHODS: We conducted an inventory of state public health agency Web sites and administered a Web-based survey of state health agency personnel to examine NCC capacity with respect to responsibility and authority, scope, protocols, trends in NCC investigations, and desired assistance. RESULTS: Twenty-six of the state agency Web sites listed an NCC contact, and 12 mentioned a cluster response team. Thirty-seven states completed the Web-based survey, all addressed cancer clusters, and 30 also responded to other NCCs, such as multiple sclerosis, amyotrophic lateral sclerosis, and autism. CONCLUSIONS: NCCs are of key concern to communities, and all of the survey respondents indicated that citizen reports were an impetus for investigations; yet, state-level capacity to address NCCs was inconsistent and disjointed. State agency personnel were committed to responding to NCC inquiries but were hampered by lack of personnel, resources, and prescribed protocols, as well as inadequate interagency communication. We offer recommendations to address these challenges.

Incidence of chemotherapy-induced nausea and vomiting in Mexico: healthcare provider predictions versus observed.

OBJECTIVE: An understanding of the incidence of chemotherapy-induced nausea and vomiting (CINV) may assist healthcare providers (HCP) when making treatment decisions. We investigated the incidence of CINV after highly or moderately emetogenic chemotherapy (HEC or MEC), in comparison with predictions of CINV by HCP. RESEARCH DESIGN AND METHODS: This prospective study was conducted at nine oncology centers in Mexico. Eligible patients were >/=18 years old and scheduled to receive a single, initial cycle of chemotherapy. Patients recorded nausea severity, episodes of emesis, and rescue medication use for the first 5 days after chemotherapy. HCP predicted the general incidence of acute (day 1) and delayed (days 2-5) CINV. RESULTS: A total of 82 patients were enrolled, with complete data available for 73. Mean age was 50 years; 67 (92%) were women; and 57 (78%) received HEC, while 16 (22%) received MEC. HCP predictions were comparable to the incidence of acute CINV after HEC and MEC and of delayed CINV after MEC. However, HCP predictions underestimated delayed CINV after HEC. 75.4% of patients (95% CI: 62.2-85.9) reported delayed nausea and HCP predicted 41.7% (95% CI: 30.2-55.0); 63.2% of patients (95% CI: 49.3-75.6) reported delayed emesis and HCP predicted 31.8% (95% CI: 21.0-44.5). Limitations of the study include the small sample size, possible selection bias and lack of a standardized antiemetic regimen. CONCLUSIONS: Healthcare providers underestimated the incidence of delayed CINV after HEC. There is a need for a better understanding of the incidence of delayed nausea and emesis, which remain common side-effects of chemotherapy.

Cost effectiveness of losartan in patients with hypertension and LVH: an economic evaluation for Sweden of the LIFE trial.

OBJECTIVE: Evaluate the cost effectiveness of losartan compared with atenolol from a Swedish national health system perspective. DESIGN: The Losartan Intervention For Endpoint reduction in hypertension study (LIFE) was a double-masked, randomized trial of losartan versus atenolol in 9193 patients with essential hypertension and left ventricular hypertrophy (LVH) ascertained by electrocardiography. Losartan reduced the primary composite end point of cardiovascular death, myocardial infarction (MI), or stroke by 13% (P = 0.021) and reduced the risk of stroke by 25% (P = 0.001), despite a comparable degree of blood pressure control. METHODS: Life years gained was estimated by combining the absolute risk reduction in stroke with the life years gained by preventing stroke. Quality-adjusted life years (QALYs) gained was estimated by combining the absolute risk reduction in stroke with the QALYs gained by preventing stroke. QALYs were estimated by weighting life years by health-related quality of life (QoL), as measured with visual analogue scale (VAS) data collected in the trial. Net costs were defined as the total of study medication cost, stroke-related costs, and costs of increased survival. Costs are in 2003 Swedish prices. All costs and effects were discounted at a 3% annual rate. RESULTS: Prevention of a stroke resulted in a gain of 5.7 life years and 4.3 QALYs. As a consequence, losartan treatment resulted in a per patient increase of 0.092 life years [95% confidence interval (CI): 0.038, 0.146] and 0.069 QALYs (95% CI: 0.028, 0.109) as compared with atenolol treatment. Losartan reduced direct stroke-related cost per patient by 1141 euros due to a lower cumulative incidence of stroke for losartan at 5.5 years (4.9%) as compared with atenolol (6.5%) (95% CI of difference: 0.7, 2.5). The reduction in stroke-related cost offset 80% of the added cost of losartan drug therapy. After inclusion of study medication cost, net cost per patient was 289 euros higher for losartan than atenolol. The net cost per QALY gained for losartan was 4188 euros (37,813 SEK), which is well within common Swedish benchmark upper values (200-500,000 SEK) for accepted cost-effective interventions. CONCLUSION: Based on the results from the LIFE trial, treatment with losartan compared with atenolol, in hypertensive patients with LVH, is a cost-effective intervention.

The impact of losartan on the lifetime incidence of ESRD and costs in Mexico / El impacto del losartan en la incidencia de por vida de la enfermedad renal de la etapa terminal y sus costos en México

Background. The RENAAL (Reduction of Endpoints in Type 2 Diabetes with the Angiotensin II Antagonist Losartan) study demonstrated that treatment with losartan reduced the risk of ESRD by 29% among hypertensive patients with type 2 diabetes and diabetic nephropathy. The objective of this study was to project the effect of losartan compared to placebo on the lifetime incidence of ESRD and associated costs from a third-party payer perspective in Mexico. Methods. A competing risks method was used to estimate lifetime incidence of ESRD, while accounting for the risk of death without ESRD. The cost associated with ESRD was estimated by combining the cumulative incidence of ESRD with the lifetime cost associated with ESRD. Total cost was estimated as the sum of the cost associated with ESRD from the three main public institutions in Mexico, the lifetime cost of losartan therapy, and other costs (non-ESRD/non-losartan) expected for patients with type 2 diabetes. Survival was estimated by weighting the life expectancies with and without ESRD by the cumulative risk of ESRD. Results. The projected lifetime incidence of ESRD for losartan patients was lower (66%) compared with placebo patients (83%). This reduction in ESRD resulted in a decrease in ESRD-related cost of M$49,737 per patient and a discounted gain of 0.697 life years per patient. After accounting for the cost of losartan and the additional cost associated with greater survival, we projected that treatment with losartan would result in a net savings of M$24,073 per patient. Conclusion. Treatment with losartan in patients with type 2 diabetes and nephropathy not only reduced the within-trial incidence of ESRD but is projected to result in lifetime reductions in ESRD, increased survival, and overall cost savings to public institutions in Mexico.

Antecedentes. El estudio RENAAL (Reducción de los grados o puntos terminales en la diabetes tipo 2 con losartan, el antagonista de la anglotenslna II) demostró que el tratamiento con losartan redujo el riesgo de la ESRD (enfermedad renal de la etapa terminal) en 29% entre pacientes hipertensos con diabetes tipo 2 y neuropatía diabética. El propósito estudiado fue hacer una proyección del efecto del losartan comparándolo con el placebo en la incidencia de por vida de la ESRD y con los costos asociados de un tercer pagador en perspectiva en México. Métodos. Se utilizó un método de riesgos muy competitivo para calcular la incidencia de por vida de la ESRD, al mismo tiempo que se calculaba el riesgo de muerte sin la ESRD. El costo asociado con la ESRD se calculó confirmando la incidencia acumulativa de la ESRD en relación con el costo de por vida de la terapia con losar-tan y otros costos (sin ESRD o sin losartan) con los que se contaba para pacientes con diabetes tipo 2. La supervivencia se calculó esperando las expectativas de vida con y sin ESRD por el riesgo acumulativo de ESRD. Resultados. La proyectada incidencia de por vida de la ESRD en cuanto a los pacientes con losartan fue más baja (66%) comparada con los pacientes que tomaron placebo (83%). Esta reducción de la ESRD tuvo por resultado una disminución en el costo relacionado con la ESRD de $49,737 por paciente y una ganancia descartada de 0.697 años de vida por paciente. Luego de contabilizar el costo del losartan y el costo añadido asociado con una mayor supervivencia, llegamos a la conclusión de que el tratamiento con losartan daría por resultado un ahorro neto de $24,073 por paciente. Conclusión. El tratamiento mediante losartan en pacientes aquejados de diabetes tipo 2 y neuropatía no sólo redujo la incidencia intraexperimental de la ESRD, sino que además nos ha servido para proyectar que resulte en reducciones de por vida en la ESRD, en una supervivencia incrementada y en un ahorro total de costos en cuanto a las instituciones públicas en nuestro país.

Personal exposure meets risk assessment: a comparison of measured and modeled exposures and risks in an urban community.

Human exposure research has consistently shown that, for most volatile organic compounds (VOCs), personal exposures are vastly different from outdoor air concentrations. Therefore, risk estimates based on ambient measurements may over- or underestimate risk, leading to ineffective or inefficient management strategies. In the present study we examine the extent of exposure misclassification and its impact on risk for exposure estimated by the U.S. Environmental Protection Agency (U.S. EPA) Assessment System for Population Exposure Nationwide (ASPEN) model relative to monitoring results from a community-based exposure assessment conducted in Baltimore, Maryland (USA). This study is the first direct comparison of the ASPEN model (as used by the U.S. EPA for the Cumulative Exposure Project and subsequently the National-Scale Air Toxics Assessment) and human exposure data to estimate health risks. A random sampling strategy was used to recruit 33 nonsmoking adult community residents. Passive air sampling badges were used to assess 3-day time-weighted-average personal exposure as well as outdoor and indoor residential concentrations of VOCs for each study participant. In general, personal exposures were greater than indoor VOC concentrations, which were greater than outdoor VOC concentrations. Public health risks due to actual personal exposures were estimated. In comparing measured personal exposures and indoor and outdoor VOC concentrations with ASPEN model estimates for ambient concentrations, our data suggest that ASPEN was reasonably accurate as a surrogate for personal exposures (measured exposures of community residents) for VOCs emitted primarily from mobile sources or VOCs that occur as global "background" source pollutant with no indoor source contributions. Otherwise, the ASPEN model estimates were generally lower than measured personal exposures and the estimated health risks. ASPEN's lower exposures resulted in proportional underestimation of cumulative cancer risk when pollutant exposures were combined to estimate cumulative risk. Median cumulative lifetime cancer risk based on personal exposures was 3-fold greater than estimates based on ASPEN-modeled concentrations. These findings demonstrate the significance of indoor exposure sources and the importance of indoor and/or personal monitoring for accurate assessment of risk. Environmental health policies may not be sufficient in reducing exposures and risks if they are based solely on modeled ambient VOC concentrations. Results from our study underscore the need for a coordinated multimedia approach to exposure assessment for setting public health policy.