Comparative safety of conjugated estrogens/bazedoxifene versus estrogen/progestin combination hormone therapy among women in the United States: a multidatabase cohort study.

OBJECTIVE: To assess the risk of select safety outcomes including endometrial cancer, endometrial hyperplasia, and breast cancer among women using conjugated estrogens/bazedoxifene (CE/BZA) as compared with estrogen/progestin combination hormone therapy (EP). METHODS: We conducted a new-user cohort study in five US healthcare claims databases representing more than 92 million women. We included CE/BZA or EP new users from May 1, 2014, to August 30, 2019. EP users were propensity score (PS) matched to users of CE/BZA. Incidence of endometrial cancer, endometrial hyperplasia, breast cancer, and eight additional cancer and cardiovascular outcomes were ascertained using claims-based algorithms. Rate ratios (RR) and differences pooled across databases were estimated using random-effects models. RESULTS: The study population included 10,596 CE/BZA and 33,818 PS-matched EP new users. Rates of endometrial cancer and endometrial hyperplasia were slightly higher among CE/BZA users (1.6 and 0.4 additional cases per 10,000 person-years), although precision was limited because of small numbers of cases (endometrial cancer: RR, 1.50 [95% confidence interval {CI}, 0.79-2.88]; endometrial hyperplasia: RR, 1.69 [95% CI, 0.51-5.61]). Breast cancer incidence was lower in CE/BZA users (9.1 fewer cases per 10,000 person-years; RR, 0.79; 95% CI, 0.58-1.05). Rates of other outcomes were slightly higher among CE/BZA users, but with confidence intervals compatible with a wider range of possible associations. CONCLUSIONS: CE/BZA users might experience slightly higher rates of endometrial cancer and endometrial hyperplasia, and a lower rate of breast cancer, than EP users in the first years of use.

Delayed pregnancy detection and return to fertility with extended levonorgestrel-containing oral contraceptives: A real world setting cohort study.

PURPOSE: As part of the European risk management plan of a 91-day extended levonorgestrel-containing combined oral contraceptive (COCLNG ), a study was performed to assess its safety. This analysis was conducted to examine delayed pregnancy detection and return to fertility with extended combined oral contraceptives (COC). METHODS: We conducted a retrospective cohort study in new users of 91-day COCLNG or 28-day COCLNG within a US-based healthcare claims database from 2006 to 2017. Delayed pregnancy detection during current COCLNG exposure was defined as the time between estimated pregnancy start and first prenatal care encounter. Additionally, the time between estimated pregnancy start and COCLNG discontinuation was measured. To measure return to fertility, pregnancy rates were estimated among females who discontinued treatment. 91-day COCLNG users were propensity score-matched to 28-day COCLNG users. Hazard ratio for pregnancy was calculated using Cox proportional hazards models. RESULTS: The 91-day and 28-day COCLNG users had 25 593 and 76 586 treatment episodes, respectively. The median time to pregnancy detection was 64.5 and 61.0 days (p = 0.24) in users of 91-day COCLNG and 28-day COCLNG . The median exposure time to treatment after estimated pregnancy start was 54.0 and 38.0 days (p < 0.01). In the fertility analysis, pregnancy rates were 54.82 (95% CI, 50.05-59.93) and 69.30 (95% CI, 64.98-73.82) per 1000 person-years in extended COCLNG discontinuers and 28-day COCLNG discontinuers. The adjusted hazard ratio of pregnancy was 0.77 (95% CI, 0.69-0.85). CONCLUSIONS: Small differences were observed for pregnancy rates and delayed pregnancy detection between 91-day extended COCLNG and 28-day COCLNG , which may be related to the longer days' supply of extended COCLNG . Differences in the fertility analysis may be related to unmeasured residual confounding.

Inpatient Constipation Among Migraine Patients Prescribed Anti-calcitonin Gene-Related Peptide Monoclonal Antibodies and Standard of Care Antiepileptic Drugs: A Retrospective Cohort Study in a United States Electronic Health Record Database.

INTRODUCTION: Erenumab, an anti-calcitonin gene-related peptide (CGRP) receptor monoclonal antibody (mAb), was approved by the US Food and Drug Administration in May 2018. Constipation with serious complications was added to the Warning and Precautions section in the erenumab Prescribing Information in October 2019 after events were observed during post-marketing surveillance. We aimed to assess and compare the risk of inpatient constipation, and, separately, inpatient constipation with serious complications, among patients with migraine treated with CGRP mAbs and standard of care antiepileptic drugs (AEDs). METHODS: Within Optum's Electronic Health Record Research Database, patients with migraine who initiated erenumab, other CGRP mAbs, and AEDs were identified from May 2018 through March 2020. Erenumab initiators were propensity score-matched separately to initiators of other CGRP mAbs and AEDs. Incident inpatient constipation events, and serious complications, were identified using multiple risk windows for outcome assessment (30-, 60-, 90-day risk windows, and all available follow-up). Odds ratios (ORs) were calculated comparing inpatient constipation risk among matched erenumab initiators relative to comparators. RESULTS: We identified 17,902 erenumab, 13,404 other CGRP mAb, and 49,497 AED initiators who met study criteria. Among matched initiators, the risk of inpatient constipation was 0.46% (95% confidence interval (CI) 0.35-0.60) for erenumab and 0.44% (95% CI 0.33-0.58) for other CGRP mAbs within the 90-day risk window, with a corresponding OR of 1.06 (95% CI 0.72-1.55). Among matched erenumab and AED initiators, inpatient constipation risk was 0.53% (95% CI 0.42-0.66) and 0.76% (95% CI 0.62-0.92), respectively, and the OR was 0.69 (95% CI 0.51-0.94). Few serious complications were observed. CONCLUSION: Patients initiating erenumab had similar risk of inpatient constipation within 90 days of treatment initiation versus patients initiating other CGRP mAbs, and lower risk versus patients initiating AEDs. These findings provide context to events observed during post-marketing surveillance.

Trends in COVID-19 patient characteristics in a large electronic health record database in the United States: A cohort study.

BACKGROUND: Electronic health record (EHR) databases provide an opportunity to facilitate characterization and trends in patients with COVID-19. METHODS: Patients with COVID-19 were identified based on an ICD-10 diagnosis code for COVID-19 (U07.1) and/or a positive SARS-CoV-2 viral lab result from January 2020 to November 2020. Patients were characterized in terms of demographics, healthcare utilization, clinical comorbidities, therapies, laboratory results, and procedures/care received, including critical care, intubation/ventilation, and occurrence of death were described, overall and by month. RESULTS: There were 393,773 patients with COVID-19 and 56,996 with a COVID-19 associated hospitalization. A greater percentage of patients hospitalized with COVID-19 relative to all COVID-19 cases were older, male, African American, and lived in the Northeast and South. The most common comorbidities before admission/infection date were hypertension (40.8%), diabetes (29.5%), and obesity (23.8%), and the most common diagnoses during hospitalization were pneumonia (59.6%), acute respiratory failure (44.8%), and dyspnea (28.0%). A total of 85.7% of patients hospitalized with COVID-19 had CRP values > 10 mg/L, 75.5% had fibrinogen values > 400 mg/dL, and 76.8% had D-dimer values > 250 ng/mL. Median values for platelets, CRP, lactate dehydrogenase, D-dimer, and fibrinogen tended to decrease from January-March to November. The use of chloroquine/hydroxychloroquine during hospitalization peaked by March (71.2%) and was used rarely by May (5.1%) and less than 1% afterwards, while the use of remdesivir had increased by May (10.0%) followed by dexamethasone by June (27.7%). All-cause mortality was 3.2% overall and 15.0% among those hospitalized; 21.0% received critical care and 16.0% received intubation/ventilation/ECMO. CONCLUSIONS: This study characterizes US patients with COVID-19 and their management during hospitalization over the first eleven months of this disease pandemic.

Identification of pregnancies and infants within a US commercial healthcare administrative claims database.

PURPOSE: Health care insurance claims databases are becoming a more common data source for studies of medication safety during pregnancy. While pregnancies have historically been identified in such databases by pregnancy outcomes, International Classification of Diseases, 10th revision Clinical Modification (ICD-10-CM) Z3A codes denoting weeks of gestation provide more granular information on pregnancies and pregnancy periods (i.e., start and end dates). The purpose of this study was to develop a process that uses Z3A codes to identify pregnancies, pregnancy periods, and links infants within a commercial health insurance claims database. METHODS: We identified pregnancies, gestation periods, pregnancy outcomes, and linked infants within the US-based Optum Research Database between 2015 and 2020 via a series of algorithms utilizing diagnosis and procedure codes on claims. The diagnosis and procedure codes included ICD-10-CM codes, Current Procedural Terminology (CPT) codes, and Healthcare Common Procedure Coding System (HCPCS) codes. RESULTS: We identified 1 030 874 pregnancies among 841 196 women of reproductive age. Of pregnancies with livebirth outcomes, 84% were successfully linked to infants. The prevalence of pregnancy outcomes (livebirth, stillbirth, ectopic, molar, and abortion) was similar to national estimates. CONCLUSIONS: This process provides an opportunity to study drug safety and care patterns during pregnancy and may be replicated in other claims databases containing ICD-10-CM, CPT, and HCPCS codes. Work is underway to validate and refine the various algorithms.

Predictors of critical care, mechanical ventilation, and mortality among hospitalized patients with COVID-19 in an electronic health record database.

BACKGROUND: There are limited data on risk factors for serious outcomes and death from COVID-19 among patients representative of the U.S. POPULATION: The objective of this study was to determine risk factors for critical care, ventilation, and death among hospitalized patients with COVID-19. METHODS: This was a cohort study using data from Optum's longitudinal COVID-19 electronic health record database derived from a network of healthcare provider organizations across the US. The study included patients with confirmed COVID-19 (presence of ICD-10-CM code U07.1 and/or positive SARS-CoV-2 test) between January 2020 and November 2020. Patient characteristics and clinical variables at start of hospitalization were evaluated for their association with subsequent serious outcomes (critical care, mechanical ventilation, and death) using odds ratios (OR) and 95% confidence intervals (CI) from logistic regression, adjusted for demographic variables. RESULTS: Among 56,996 hospitalized COVID-19 patients (49.5% male and 72.4% ≥ 50 years), 11,967 received critical care, 9136 received mechanical ventilation, and 8526 died. The median duration of hospitalization was 6 days (IQR: 4, 11), and this was longer among patients that experienced an outcome: 11 days (IQR: 6, 19) for critical care, 15 days (IQR: 8, 24) for mechanical ventilation, and 10 days (IQR: 5, 17) for death. Dyspnea and hypoxemia were the most prevalent symptoms and both were associated with serious outcomes in adjusted models. Additionally, temperature, C-reactive protein, ferritin, lactate dehydrogenase, D-dimer, and oxygen saturation measured during hospitalization were predictors of serious outcomes as were several in-hospital diagnoses. The strongest associations were observed for acute respiratory failure (critical care: OR, 6.30; 95% CI, 5.99-6.63; ventilation: OR, 8.55; 95% CI, 8.02-9.11; death: OR, 3.36; 95% CI, 3.17-3.55) and sepsis (critical care: OR, 4.59; 95% CI, 4.39-4.81; ventilation: OR, 5.26; 95% CI, 5.00-5.53; death: OR, 4.14; 95% CI, 3.92-4.38). Treatment with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers during hospitalization were inversely associated with death (OR, 0.57; 95% CI, 0.54-0.61). CONCLUSIONS: We identified several clinical characteristics associated with receipt of critical care, mechanical ventilation, and death among COVID-19 patients. Future studies into the mechanisms that lead to severe COVID-19 disease are warranted.

Long-term safety of extended levonorgestrel-containing oral contraceptives in the United States.

OBJECTIVES: To compare the safety profile of Seasonique, a 91-day levonorgestrel-containing combined oral contraceptive (COCLNG), to 28-day COCLNG regarding the risk of venous thromboembolism (VTE) and arterial thromboembolism (ATE). STUDY DESIGN: A new user cohort study was conducted in a US health care database from 2006 to 2017. Each 91-day COCLNG treatment episode in females was matched to up to four 28-day COCLNG treatment episodes by propensity score. We identified VTE cases in either (1) an inpatient setting with ICD-9 and ICD-10 diagnosis codes of PE and/or DVT in the primary position, or (2) an outpatient setting with ICD-9 or ICD-10 diagnosis codes of DVT in conjunction with an anticoagulant medication dispensing or alteplase (thrombolytic) during the 30-day period following the date of DVT diagnosis. VTE was validated using medical records. We assessed the study endpoints in the two cohorts using incidence rates and Cox proportional hazards models adjusted for potential confounders. RESULTS: Of the 25,593 treatment episodes in 91-day COCLNG and 76,586 treatment episodes in 28-day COCLNG, 35 and 68 patients had VTEs, respectively, corresponding to a hazard ratio (HR) of 1.40 (95% confidence interval [CI], 0.90-2.19). The VTE algorithm had a positive predictive value of 76.4% (95% CI, 66.2%-84.8%). ATEs were recorded in 13 and 28 episodes, respectively, with a corresponding HR of 1.21 (95% CI, 0.58-2.53). CONCLUSIONS: These results do not indicate a significant difference between 91-day COCLNG and 28-day COCLNG in terms of VTE or ATE risk. IMPLICATIONS: Compared to use of 28-day COCLNG, use of 91-day extended COCLNG was not associated with a significant difference in risk of venous and arterial thromboembolism.

Assessment of a Claims-Based ICD-9 and ICD-10 Medication-Related Osteonecrosis of the Jaw Algorithm in the United States.

PURPOSE: Medication-related osteonecrosis of jaw (MRONJ) is associated with certain drug therapies. Pharmacoepidemiologic studies often rely on electronic healthcare data to assess adverse events following drug exposure. Few studies have developed and validated claims-based MRONJ identification algorithms. This study assessed the performance of claims-based MRONJ algorithms by chart review of potential cases among postmenopausal (PM) women and women with postmenopausal osteoporosis (PMO). METHODS: Among PM and PMO women sourced from a large US commercial health insurance database affiliated with Optum, potential cases were identified by International Classification of Diseases, 9th and 10th Revisions (ICD-9, ICD-10) diagnosis codes; 200 were selected for chart retrieval, with the goal of obtaining 100 charts in each coding era. Procured charts were redacted and then reviewed by an oral surgeon who determined case status. Positive predictive values (PPV) and 95% confidence intervals (CI) were calculated overall, by cohorts, and coding eras. Baseline characteristics were assessed. Two potential algorithm refinements were explored: using a restricted set of ICD codes; requiring antibiotic use after MRONJ diagnosis. RESULTS: A total of 1273 potential cases were identified. Of the 200 potential cases selected, 104 (52%) were procured, and six cases were confirmed (PPV 5.8%, 95% CI 2.2, 12.1). Baseline characteristics were largely similar across all strata. Potential algorithm refinements yielded marginal PPV improvement. CONCLUSION: This study identified a small number of confirmed cases, and the resulting PPVs were low, but consistent with reported studies. Potential algorithm refinements yielded minimal improvements. To our knowledge, this study is the first to report on the identification of MRONJ using ICD-10 codes in the US.

Predictive values of diagnostic codes for identifying serious hypocalcemia and dermatologic adverse events among women with postmenopausal osteoporosis in a commercial health plan database.

BACKGROUND: Post-marketing safety studies of medicines often rely on administrative claims databases to identify adverse outcomes following drug exposure. Valid ascertainment of outcomes is essential for accurate results. We aim to quantify the validity of diagnostic codes for serious hypocalcemia and dermatologic adverse events from insurance claims data among women with postmenopausal osteoporosis (PMO). METHODS: We identified potential cases of serious hypocalcemia and dermatologic events through ICD-9 diagnosis codes among women with PMO within claims from a large US healthcare insurer (June 2005-May 2010). A physician adjudicated potential hypocalcemic and dermatologic events identified from the primary position on emergency department (ED) or inpatient claims through medical record review. Positive predictive values (PPVs) and 95% confidence intervals (CIs) quantified the fraction of potential cases that were confirmed. RESULTS: Among 165,729 patients with PMO, medical charts were obtained for 40 of 55 (73%) potential hypocalcemia cases; 16 were confirmed (PPV 40%, 95% CI 25-57%). The PPV was higher for ED than inpatient claims (82 vs. 24%). Among 265 potential dermatologic events (primarily urticaria or rash), we obtained 184 (69%) charts and confirmed 128 (PPV 70%, 95% CI 62-76%). The PPV was higher for ED than inpatient claims (77 vs. 39%). CONCLUSION: Diagnostic codes for hypocalcemia and dermatologic events may be sufficient to identify events giving rise to emergency care, but are less accurate for identifying events within hospitalizations.

Evidence of herd immunity and sustained impact of rotavirus vaccination on the reduction of rotavirus-related medical encounters among infants from 2006 through 2011 in the United States.

BACKGROUND: Rotavirus (RV) is the leading cause of severe acute gastroenteritis among young children. Since the US licensure of the pentavalent RV vaccine (RV5) and the monovalent RV vaccine (RV1), a decline of RV activity has been observed. OBJECTIVE: To describe patterns of RV-related health care utilization among infants receiving RV vaccines (RVVs). METHODS: A large national health insurance claims database was used to identify infants born from January 2002 through July 2011. From this cohort, infants were divided into three groups: (1) those who received a RVV, (2) those receiving a diphtheria, tetanus, and acellular pertussis (DTaP) vaccine before the introduction of RVV (February 2006), and (3) those receiving DTaP without a concurrent RVV during the period of RVV availability. Study outcomes were rotavirus gastroenteritis (RGE) and acute gastroenteritis. Longitudinal, seasonal RGE incidence patterns among the RVV cohort (n = 140,952) were compared with the referent DTaP-vaccine cohort (n = 131,529). RESULTS: More than 91% of administered RVV were RV5. Mean peak incidence of RV medical encounters in RV-vaccinated infants was 95-96% lower than among DTaP-vaccinated infants who did not receive RVV. RGE incidence among the non-RV-vaccinated DTaP recipients in the RVV-available period (110 per 100,000 infants) was lower than among DTaP recipients in the pre-RVV period (151 per 100,000 infants). The highest RGE incidence in the 2007-2011 period was among older non-RV-vaccinated infants. CONCLUSIONS: Analysis of a national medical claims database indicates a sustained and substantial decrease in the seasonal RV medical claims pattern after the introduction of RVV. This analysis also reveals evidence of herd immunity, although unvaccinated infants continue to be at risk and contribute to smaller seasonal peaks in RV disease activity.

Modifying roles of glutathione S-transferase polymorphisms on the association between cumulative lead exposure and cognitive function.

BACKGROUND: Glutathione-S-transferase gene (GST) polymorphisms can result in variable ability of these enzymes to remove electrophilic substrates. We investigated whether the GSTP1 Val105 and GSTM1 deletion polymorphisms modify the lead-cognitive function association. METHODS: We used repeated measures analysis to compare the association between cumulative lead biomarkers-bone lead measured using K-shell X-Ray Fluorescence-and Mini-Mental State Exam (MMSE) score by GST variants, adjusted for covariates, among Normative Aging Study participants, a Boston-based prospective cohort of men. We had complete data for 698 men (providing 1292 observations) for GSTM1 analyses and 595 men (providing 1142 observations) for GSTP1 analyses. RESULTS: A 15µg/g higher tibia lead concentration (interquartile range of tibia lead) was associated with a 0.24 point decrement in MMSE score among GSTP1 Val105 variant carriers, which was significantly stronger than the association among men with only wild-type alleles (p=0.01). The association among GSTP1 Val105 carriers was comparable to that of 3 years of age in baseline MMSE scores. The association between tibia lead and MMSE score appeared progressively steeper in participants with increasingly more GSTP1 Val105 alleles. A modest association between tibia lead and lower MMSE score was seen among participants with the GSTM1 deletion polymorphism. Neither of the glutathione S-transferase variants was independently associated with cognitive function, nor with lead biomarker measures. The results pertaining to patella lead were similar to those observed for tibia lead. CONCLUSION: Our results suggest that the GSTP1 Val105 polymorphism confers excess susceptibility to the cognitive effects of cumulative lead exposure.

Effectiveness of an incomplete RotaTeq (RV5) vaccination regimen in preventing rotavirus gastroenteritis in the United States.

BACKGROUND: Effectiveness of the pentavalent rotavirus vaccine (RV5) after administration of the complete (3 dose) regimen has been demonstrated in a real-world setting. This study assessed the effectiveness of RV5 following partial completion of the 3-dose regimen. METHODS: Using a large national health insurance claims database, 2 cohorts of infants (those who received RV5 and a concurrent group who received diphtheria-tetanus-acellular pertussis, but not RV5) were followed through the 2007 and 2008 rotavirus seasons (January 1 to May 31) to identify cases of rotavirus gastroenteritis and all-cause gastroenteritis resulting in medical care encounters. Vaccine effectiveness following the first and the second RV5 doses was estimated by quantifying reductions in hospitalizations, emergency department (ED) and physician office visits. RESULTS: A first RV5 dose was received by 42,306 infants whereas 28,417 infants in the concurrent comparison group received a first diphtheria-tetanus-acellular pertussis dose; 43,704 infants received a second RV5 dose, and 31,810 infants received a second diphtheria-tetanus-acellular pertussis dose. One dose of RV5 was associated with 88% effectiveness against rotavirus gastroenteritis hospitalizations and ED visits and 44% effectiveness against all-cause gastroenteritis hospitalizations and ED visits. A 2-dose regimen of RV5 was associated with 94% effectiveness against rotavirus gastroenteritis hospitalizations and ED visits and 40% effectiveness against all-cause gastroenteritis hospitalizations and ED visits. CONCLUSION: The RV5 vaccine exhibits effectiveness against rotavirus gastroenteritis even before completing the full 3-dose regimen. These results are of particular relevance when considering the benefits of a partially completed rotavirus vaccine series.

Postmarketing evaluation of the short-term safety of the pentavalent rotavirus vaccine.

BACKGROUND: A pentavalent rotavirus vaccine (RV5) demonstrated efficacy and safety in a large clinical trial before US licensure in 2006. The primary objective of this observational study was to assess the occurrence of intussusception (IS) among infants who received RV5 in routine use. Secondary objectives assessed the occurrence of Kawasaki disease (KD) and general safety. METHODS: We identified and followed infants with a health insurance claim for RV5 during the first 2 years of RV5 availability. Concurrent and historical cohorts receiving diphtheria-tetanus-acellular pertussis (DTaP) vaccine were used as comparators; the historical DTaP cohort informed sequential monitoring boundaries for IS and KD. Medical records from potential IS and KD cases were reviewed to confirm outcomes. General safety was evaluated across a wide range of outcomes using prespecified criteria. Incidence rates for outcomes along with relative risks and 95% confidence intervals (CIs) were estimated. RESULTS: The 85,397 RV5 and 62,820 DTaP recipients contributed 17,433 and 12,339 person-years, resulting in 6 and 5 confirmed cases of IS, respectively, within 30 days following any dose. The relative risk of IS was 0.8 (95% confidence interval: 0.22-3.52). The number of IS or KD cases did not cross the monitoring boundaries. The general safety evaluation did not identify any specific diagnoses or patterns of diagnoses that might suggest other safety concerns. CONCLUSION: RV5 was not associated with an increased risk of IS, KD, or any other recognized health outcome.

Effectiveness of the pentavalent rotavirus vaccine in preventing gastroenteritis in the United States.

OBJECTIVE: In clinical trials, the pentavalent rotavirus vaccine (RV5) was efficacious in preventing severe rotavirus gastroenteritis (RGE) and related health care encounters. We assessed the vaccine effectiveness (VE) of RV5 among US infants during the first 2 rotavirus seasons after vaccine licensure. METHODS: Using a large, national, health insurance claim database, we monitored 2 cohorts of infants (infants who received 3 doses of RV5 and a concurrent group of infants who received 3 doses of diphtheria-tetanus-acellular pertussis vaccine but did not receive RV5) through the 2007 and 2008 rotavirus seasons (January 1 to May 31), to identify cases of RGE and all-cause acute gastroenteritis (AGE) resulting in medical care encounters. We estimated the VE in reducing hospitalizations, emergency department (ED) and physician office visits, and health care resource utilization, as measured by days and costs of hospitalizations and ED visits. RESULTS: A total of 33 140 RV5-vaccinated infants and 26 167 infants in the concurrent diphtheria-tetanus-acellular pertussis vaccine cohort were included in the analysis. The VE against RGE (hospitalization and ED) was 100% (95% confidence interval [CI]: 87%-100%), whereas the VE against AGE was 59% (95% CI: 47%-68%). In the outpatient setting, the VE against RGE and AGE was 96% (95% CI: 76%-100%) and 28% (95% CI: 22%-33%), respectively. There was a complete (100%) reduction in RGE hospitalization and ED visit days and a 100% reduction in costs. RV5 was associated with a 66% decrease in AGE-related hospitalization and ED visit days and a 74% reduction in costs. CONCLUSIONS: In this first nationwide study evaluating VE under conditions of routine use, RV5 was highly effective in preventing RGE and AGE and in reducing health care resource utilization. Further research is needed to assess VE with an incomplete rotavirus vaccination regimen.

Modifying effects of the HFE polymorphisms on the association between lead burden and cognitive decline.

BACKGROUND: As iron and lead promote oxidative damage, and hemochromatosis (HFE) gene polymorphisms increase body iron burden, HFE variant alleles may modify the lead burden and cognitive decline relationship. OBJECTIVE: Our goal was to assess the modifying effects of HFE variants on the lead burden and cognitive decline relation in older adults. METHODS: We measured tibia and patella lead using K-X-ray fluorescence (1991-1999) among participants of the Normative Aging Study, a longitudinal study of community-dwelling men from greater Boston. We assessed cognitive function with the Mini-Mental State Examination (MMSE) twice (1993-1998 and 1995-2000) and genotyped participants for HFE polymorphisms. We estimated the adjusted mean differences in lead-associated annual cognitive decline across HFE genotype groups (n = 358). RESULTS: Higher tibia lead was associated with steeper cognitive decline among participants with at least one HFE variant allele compared with men with only wild-type alleles (p interaction = 0.03), such that a 15 microg/g increase in tibia lead was associated with a 0.2 point annual decrement in MMSE score among HFE variant allele carriers. This difference in scores among men with at least one variant allele was comparable to the difference in baseline MMSE scores that we observed among men who were 4 years apart in age. Moreover, the deleterious association between tibia lead and cognitive decline appeared progressively worse in participants with increasingly more copies of HFE variant alleles (p-trend = 0.008). Results for patella lead were similar. CONCLUSION: Our findings suggest that HFE polymorphisms greatly enhance susceptibility to lead-related cognitive impairment in a pattern consistent with allelelic dose.