Comparison of Outcomes Following a Switch From a Brand to an Authorized Versus Independent Generic Drug.

Authorized generics are identical in formulation to brand drugs, manufactured by the brand company but marketed as a generic. Generics, marketed by generic manufacturers, are required to demonstrate pharmaceutical and bioequivalence to the brand drug, but repetition of clinical trials is not required. This retrospective cohort study compared outcomes for generics and authorized generics, which serves as a generic vs. brand proxy that minimizes bias against generics. For the seven drugs studied between 1999 and 2014, 5,234 unique patients were on brand drugs prior to generic entry and 4,900 (93.6%) switched to a generic. During the 12 months following the brand-to-generic switch, patients using generics vs. authorized generics were similar in terms of outpatient visits, urgent care visits, hospitalizations, and medication discontinuation. The likelihood of emergency department (ED) visits was slightly higher for authorized generics compared with generics. These data suggest that generics were clinically no worse than their proxy brand comparators.

Brand vs generic adverse event reporting patterns: An authorized generic-controlled evaluation of cardiovascular medications.

WHAT IS KNOWN AND OBJECTIVE: Some public scepticism exists about generics in terms of whether brand and generic drugs produce identical outcomes. This study explores whether adverse event (AE) reporting patterns are similar between brand and generic drugs, using authorized generics (AGs) as a control for possible generic drug perception biases. METHODS: Events reported to the FDA Adverse Event Reporting System from the years 2004-2015 were analysed. Drugs were classified as brand, AG or generic based on drug and manufacturer names. Reports were included if amlodipine, losartan, metoprolol extended release (ER) or simvastatin were listed as primary or secondary suspect drugs. Disproportionality analyses using the reporting odds ratio (ROR) assessed the relative rate of reporting labelled AEs compared to reporting these AEs with all other drugs. The Breslow-Day test compared RORs across brand, AG and generic. Interrupted time series analysis evaluated the impact of generic entry on reporting trends. RESULTS AND DISCUSSION: Generics accounted for significant percentages of total U.S. reports, but AGs accounted for smaller percentages of reports, including for amlodipine (14.26%), losartan (1.48%), metoprolol ER (0.35%) and simvastatin (0.70%). Whereas the RORs were significantly different for multiple brand vs generic comparisons, the AG vs generic comparisons yielded fewer statistically significant findings. Namely, only the ROR for AG differed from generic for amlodipine with peripheral oedema (P < .01). WHAT IS NEW AND CONCLUSION: Inconsistent reporting patterns were observed more between brand and generic compared with AG and generic. Use of AGs as a control for perception biases against generics is useful, but this approach can be limited by small AG report numbers. Requiring the manufacturer name to be printed on the prescription bottle or packaging could improve the accuracy of assignment for products being reported.

Mutational and biochemical findings in adults with persistent hypophosphatasemia.

A majority of adults with persistently low serum alkaline phosphatase values carry a pathogenic or likely pathogenic variant in the ALPL gene and also have elevated alkaline phosphatase substrate values in serum and urine. These adults may fall within the spectrum of the adult form of hypophosphatasia. INTRODUCTION: The primary objective of this study was to determine what proportion of adults with persistently low serum alkaline phosphatase values (hypophosphatasemia) harbor mutations in the ALPL gene or have elevated alkaline phosphatase (ALP) substrates. Some adults with persistent hypophosphatasemia share clinical and radiographic features with the adult form of hypophosphatasia (HPP). In HPP, ALPL mutations result in persistent hypophosphatasemia and ALP substrate accumulation in plasma (pyridoxal-5-phosphate (PLP)) and urine (phosphoethanolamine (PEA)). METHODS: Biochemical analyses, including serum ALP activity, bone-specific ALP, plasma PLP, and urine PEA, were performed in adults with persistent hypophosphatasemia. Mutational analyses were performed using PCR and Sanger sequencing methods. Gene variants were classified as pathogenic (P), likely pathogenic (LP), variants of uncertain significance (VUS), likely benign (LB), and benign (B). P and LP variants were further grouped as "Positive ALPL variants" and LB and B grouped as "Negative ALPL variants." RESULTS: Fifty subjects completed all mutational and biochemical analyses. Sixteen percent carried only Negative ALPL variants. Of the remaining 42 subjects, 67% were heterozygous for a P variant, 19% for an LP variant, and 14% for a VUS. Biochemical results were highly inter-correlated and consistent with the expected inverse relationship between ALP and its substrates. Subjects harboring Positive ALPL variants showed lower ALP and BSAP and higher PLP and PEA values compared with subjects harboring only Negative ALPL variants. Approximately half of all subjects harboring Positive ALPL variants or ALPL VUS showed elevations in plasma PLP, and three quarters showed elevations in urine PEA. CONCLUSION: Adults with persistent hypophosphatasemia frequently harbor ALPL mutations and have elevated ALP substrates. These adults may fall within the spectrum of the adult form of hypophosphatasia. Clinicians should take note of persistent hypophosphatasemia in their patients and be cautious in prescribing bisphosphonates when present.

The relationship between childhood BMI and adult serum cholesterol, LDL, and ankle brachial index.

OBJECTIVE: Effects of childhood overweight may persist into adulthood. We assessed the effect of childhood overweight on cardiovascular disease high risk factor levels in the same participants as adults, after controlling for adult body mass index (BMI) status. DESIGN: A subset of participants in an observational study (Heartwatch) were contacted approximately 26-27 years after initial enrollment to participate in a follow-up study on the long-term effects of childhood overweight. During follow-up, BMI, waist:hip circumference (WHC), blood pressure (BP), serum lipids, and ankle brachial index (ABI) were measured; additional BMI measures throughout childhood were obtained as available from the electronic medical record. Primary outcomes were ABI and serum low density lipoprotein (LDL). SETTING: The 1982 Heartwatch study was conducted with children participants living in Marshfield, Wisconsin; follow-up included original participants who were re-contacted and agreed to be enrolled. PARTICIPANTS: Participants were a stratified random sample of eligible participants in the original 1982 Heartwatch study. Of the original 3106 participants, 647 adult participants completed follow-up exams. RESULTS: Among males with 1982 BMI ≥ 85(th) percentile, adult BMI, WHC, (both P ≤ 0.001), ABI (P = 0.001), total cholesterol (P = 0.01), LDL (P = 0.003) and BP (P < 0.02) were higher in 2008-2009 as compared to males with 1982 BMI < 85(th) percentile. Among females, BMI, BP and WHC (all P < 0.001) were higher in 2008-2009. BMI in 1982 and 2008-2009 were correlated [r = 0.56 (males); 0.58 (females), P < 0.001]. 2008-2009 BMI was more strongly correlated with 2008-2009 measures of ABI (r = 0.16, P = 0.006, males) and high LDL [r = 0.18, P = 0.002 (males); r = 0.11, P = 0.046 (females)]. 1982 BMI was not independently associated with ABI or LDL after adjusting for adult BMI. CONCLUSION: In a cohort studying childhood and adult overweight, childhood BMI was associated with health outcomes relating to cardiovascular disease in adulthood. However, childhood BMI was not independently related to LDL-C or ABI levels in adulthood after accounting for adult BMI. Longitudinal measurements of BMI and other health risk factors were not found to improve accuracy of models for high cardiovascular disease risk factor levels.

Characterization of statin dose response in electronic medical records.

Efforts to define the genetic architecture underlying variable statin response have met with limited success, possibly because previous studies were limited to effect based on a single dose. We leveraged electronic medical records (EMRs) to extract potency (ED50) and efficacy (Emax) of statin dose-response curves and tested them for association with 144 preselected variants. Two large biobanks were used to construct dose-response curves for 2,026 and 2,252 subjects on simvastatin and atorvastatin, respectively. Atorvastatin was more efficacious, was more potent, and demonstrated less interindividual variability than simvastatin. A pharmacodynamic variant emerging from randomized trials (PRDM16) was associated with Emax for both. For atorvastatin, Emax was 51.7 mg/dl in subjects homozygous for the minor allele vs. 75.0 mg/dl for those homozygous for the major allele. We also identified several loci associated with ED50. The extraction of rigorously defined traits from EMRs for pharmacogenetic studies represents a promising approach to further understand the genetic factors contributing to drug response.

Acute hypophosphatasemia.

UNLABELLED: The temporal evolution of a low serum alkaline phosphatase value may relate to its cause. Precipitous lowering of serum alkaline phosphatase below the lower range of normal is uncommon and may indicate severe physiologic stress and increased short-term mortality. INTRODUCTION: The differential diagnosis of a low serum alkaline phosphatase (ALP) value (hypophosphatasemia) is wide ranging, anecdotal, and unfamiliar. The temporal evolution of hypophosphatasemia may relate to its cause. The purpose of this study is to report conditions and circumstances associated with precipitous lowering of serum ALP below the lower range of normal. METHODS: Marshfield Clinic IRB approved use of their electronic medical record to search for subjects with at least two serum ALP values ≤ 40 U/L (normal 40-125 U/L). When the temporal evolution of the qualifying ALP values indicated a precipitous lowering from usually normal serum ALP values, the subject was deemed to have acute hypophosphatasemia. Thirty years of laboratory data and 10 years of clinical narrative were analyzed. Associated diagnoses, clinical circumstances, and short-term mortality were recorded. RESULTS: A total of 458,767 subjects had 2,584,051 serum ALP values, and 5,190 (1.1 %) subjects had at least two serum values ≤ 40 U/L. A detailed review of 1,276 subjects selected on the basis of their lowest ALP value and age identified 190 subjects with acute hypophosphatasemia. Acute hypophosphatasemia was recorded during periods of major trauma/surgery, multisystem failure, acute anemia, blood product transfusions (often massive), apheresis, hypomagnesemia, and acute caloric restriction. Twenty-eight subjects (15 %) died within 35 days of their nadir serum ALP. CONCLUSION: Acute hypophosphatasemia is associated with profound illness or physiologic stress and followed by increased short-term mortality. The temporal evolution of hypophosphatasemia may relate to its cause.

The utility of BMD Z-score diagnostic thresholds for secondary causes of osteoporosis.

UNLABELLED: This very large dual X-ray absorptiometry (DXA) cohort confirmed a significant, inverse relationship between bone mineral density (BMD) Z-scores and the presence of secondary causes of osteoporosis but receiver operating characteristic (ROC) curves indicate that Z-score diagnostic thresholds (such as -2.0) discriminate poorly between the presence and absence of secondary causes of osteoporosis. INTRODUCTION: BMD Z-score diagnostic thresholds have been proposed to detect secondary causes of osteoporosis. To determine the sensitivity and diagnostic utility of such thresholds, we analyzed comprehensive BMD and personal health information data from a large, multispecialty group practice. METHODS: Adult subjects were assigned their lowest axial BMD Z-score and ICD-9 diagnosis codes for secondary causes of osteoporosis when cited at least twice in their electronic medical record. Multiple logistic regression was used to model the prevalence of matching ICD-9 codes as a function of Z-score. ROC curves were used to investigate various Z-score cut points for sensitivity and specificity. RESULTS: Eighteen thousand six hundred seventy-four subjects were analyzed. Secondary causes of osteoporosis were identified in 31% of men and 16% of women. The frequency of secondary causes varied with age and between genders and varied inversely with Z-score. No inflection point was observed in this relationship to suggest a useful clinical decision threshold. The difference in mean Z-score of those with and without a secondary cause of osteoporosis was biologically slight (±0.3). Low Z-score diagnostic thresholds were insensitive to the presence of secondary causes of osteoporosis and provided relatively poor predictive value. CONCLUSIONS: This DXA cohort confirmed a significant inverse relationship between Z-score and the presence of secondary causes of osteoporosis but diagnostic Z-score thresholds discriminate poorly between the presence and absence of secondary causes of osteoporosis. If only patients with very low Z-scores are evaluated for secondary causes of osteoporosis the diagnostic specificity may be high but most cases will be missed.

Integration of genetic, clinical, and INR data to refine warfarin dosing.

Well-characterized genes that affect warfarin metabolism (cytochrome P450 (CYP) 2C9) and sensitivity (vitamin K epoxide reductase complex 1 (VKORC1)) explain one-third of the variability in therapeutic dose before the international normalized ratio (INR) is measured. To determine genotypic relevance after INR becomes available, we derived clinical and pharmacogenetic refinement algorithms on the basis of INR values (on day 4 or 5 of therapy), clinical factors, and genotype. After adjusting for INR, CYP2C9 and VKORC1 genotypes remained significant predictors (P < 0.001) of warfarin dose. The clinical algorithm had an R(2) of 48% (median absolute error (MAE): 7.0 mg/week) and the pharmacogenetic algorithm had an R(2) of 63% (MAE: 5.5 mg/week) in the derivation set (N = 969). In independent validation sets, the R(2) was 26-43% with the clinical algorithm and 42-58% when genotype was added (P = 0.002). After several days of therapy, a pharmacogenetic algorithm estimates the therapeutic warfarin dose more accurately than one using clinical factors and INR response alone.

Forces required to operate controls on farm tractors: implications for young operators.

Farm tractors account for the majority of fatal injuries to adolescents working in agriculture and therefore remain a leading occupational priority. The question of whether these injuries occur because adolescents are assigned tractor jobs beyond their physical capabilities has not been answered. The purpose of this study was to estimate the activation forces required to operate controls on 40 tractors in common use in the US and compare them with existing estimates of physical strength for children of varying ages and with recommended ergonomic force limits for repeatedly engaging controls. Activation forces for steering, brakes and clutch were measured on each tractor. The main study finding was that the activation forces required to operate tractors typically exceeded the physical abilities of most children aged 13 to 17 years. This raises serious questions about the ability of children to safely operate tractors in common use on US farms. This study provides an ergonomic approach for evaluating the potential mismatch between young people's strength capabilities and forces required in operating farm tractors. This approach could be used in similar situations where adolescents may operate vehicles (e.g. all-terrain vehicles), machinery or other mechanical devices requiring activation of levers and controls. Study findings potentially inform the establishment of occupational policies surrounding tractor operation by young people.

Evaluation of a policy to reduce youth tractor crashes on public roads.

OBJECTIVE: Evaluate the effectiveness of a United States state law, Wisconsin Act 455, in reducing highway tractor crashes involving youth operators. DESIGN: Policy outcome evaluation involving review of a retrospective case series. SETTING: Youth highway tractor crashes from Wisconsin for the years 1994-2003 that resulted in a fatality, injury, and/or property damage. SUBJECTS: One hundred and forty six tractor crash cases involving operators younger than 16 years. METHODS: Describe and model the tractor crash patterns before and after enactment of the law, and examine the relation between the contributing circumstances identified in the crash reports and the content covered in the mandated tractor certification course. RESULTS: There was neither a significant change in the number of youth tractor crashes after the law was passed, nor any reduction in the proportion of crashes where the youth operator was designated at fault. The tractor certification course did not cover the major factors contributing to youth tractor crashes on public roads. CONCLUSIONS: No significant effect of the law was detected and crash rates at the end of the study period were similar to those before Wisconsin Act 455. The authors'findings should not be construed to suggest that public policy, in general, is an ineffective strategy for the prevention of pediatric agricultural injuries. Negotiating a balance in public policy debates will be a challenge, but it is clear that future policy initiatives need to identify and implement the right policy for the right problem.

Motivation and satisfaction among polyclinic volunteers at the 2002 Winter Olympic and Paralympic Games.

BACKGROUND: The Olympic and Paralympic Games rely heavily on volunteers to provide many essential services, including medical care of athletes. OBJECTIVE: This preliminary investigation sought to characterise the motivational influences and factors responsible for the satisfaction of Olympic and Paralympic healthcare volunteers. METHODS: The 2002 Winter Games polyclinic healthcare volunteers were asked to complete a questionnaire designed to elicit information about their motives for volunteering and the factors that contributed to their satisfaction with their volunteer experience. RESULTS: There was no significant difference in the motivation or satisfaction summary scores based on event worked. There was a strong positive correlation between motivation and satisfaction. Physician respondents had a lower mean motivation score than did non-physician volunteers. CONCLUSIONS: There were no significant motivational differences between Olympic and Paralympic volunteers, but there were several differences noted between physician and non-physician volunteers. The 2002 polyclinic volunteers appear to have been motivated by a complex process best described as "enlightened self interest," and all were generally well satisfied with their experience. These results may assist organisers of future Games in selecting appropriately motivated volunteer personnel and creating rewarding work environments for them.

Pediatric farm injuries involving non-working children injured by a farm work hazard: five priorities for primary prevention.

OBJECTIVES: To describe pediatric farm injuries experienced by children who were not engaged in farm work, but were injured by a farm work hazard and to identify priorities for primary prevention. DESIGN: Secondary analysis of data from a novel evaluation of an injury control resource using a retrospective case series. DATA SOURCES: Fatal, hospitalized, and restricted activity farm injuries from Canada and the United States. SUBJECTS: Three hundred and seventy known non-work childhood injuries from a larger case series of 934 injury events covering the full spectrum of pediatric farm injuries. METHODS: Recurrent injury patterns were described by child demographics, external cause of injury, and associated child activities. Factors contributing to pediatric farm injury were described. New priorities for primary prevention were identified. RESULTS: The children involved were mainly resident members of farm families and 233/370 (63.0%) of the children were under the age of 7 years. Leading mechanisms of injury varied by data source but included: bystander and passenger runovers (fatalities); drowning (fatalities); machinery entanglements (hospitalizations); falls from heights (hospitalizations); and animal trauma (hospitalizations, restricted activity injuries). Common activities leading to injury included playing in the worksite (all data sources); being a bystander to or extra rider on farm machinery (all data sources); recreational horseback riding (restricted activity injuries). Five priorities for prevention programs are proposed. CONCLUSIONS: Substantial proportions of pediatric farm injuries are experienced by children who are not engaged in farm work. These injuries occur because farm children are often exposed to an occupational worksite with known hazards. Study findings could lead to more refined and focused pediatric farm injury prevention initiatives.

Evaluation of the North American Guidelines for Children's Agricultural Tasks using a case series of injuries.

OBJECTIVE: To evaluate the potential for the North American Guidelines for Children's Agricultural Tasks (NAGCAT) to prevent the occurrence of pediatric farm injuries. This evaluation focuses upon farm injuries experienced when children were engaged in farm work. DESIGN: Novel outcome evaluation involving primary review of three retrospective case series. SETTING: Fatal, hospitalized, and restricted activity injuries from the United States and Canada. SUBJECTS: Nine hundred and thirty four pediatric farm injury cases. METHODS: The applicability of NAGCAT to each case was rated. For injuries where NAGCAT were applicable, recurrent injury patterns were described and the potential for NAGCAT to prevent their occurrence was assessed. RESULTS: A total of 283 (30.3%) cases involved children engaged in farm work. There was an applicable NAGCAT guideline in 64.9% of the work related cases. Leading individual guidelines applicable to the injury events were: (1) working with large animals; (2) driving a farm tractor; and (3) farm work with an all-terrain vehicle. In the judgment of the research team, 59.6% of these injuries were totally preventable if the principles espoused by NAGCAT had been applied. CONCLUSIONS: NAGCAT are a set of consensus guidelines aimed at the prevention of pediatric farm injuries. The findings suggest that NAGCAT, if applied, would be efficacious in preventing many of the most serious injuries experienced by children engaged in farm work. However, work related injuries represent only a modest portion of pediatric farm injuries. This new information assists in the refinement of NAGCAT as an injury control resource and puts its potential efficacy into context.

Self reported injury patterns among competitive curlers in the United States: a preliminary investigation into the epidemiology of curling injuries.

OBJECTIVE: To investigate the injury patterns among competitive curlers. METHODS: Participants at two curling championship events were asked to complete injury history questionnaires. RESULTS: 76 curlers (39%) participated; 79% of these reported curling related musculoskeletal pain, most commonly involving the knee (54%), back (33%), and shoulder (20%). Sweeping and delivering the stone were most likely to provoke symptoms. Time loss injuries were estimated to occur at a rate of 2 per 1000 athlete exposures. CONCLUSIONS: Curling appears to be a relatively safe winter sport. Prospective studies are needed to confirm these preliminary findings and to further define the risk factors for curling related injuries.

Operational characteristics of tractors driven by children on farms in the United States and Canada.

Farm tractors are an important source of traumatic injury for children on farms. There is, however, no documentation about the age and size of tractors that children are operating and little information about the frequency with which rollover protective structures (ROPS) are used. This study described tractors that children on farms in the U.S. and Canada were operating by age, horsepower, and the presence of ROPS, according to the age and gender of the farm children involved. As a sub-analysis of data compiled during a randomized controlled trial, a descriptive analysis was completed on work exposure data collected by telephone interview. Of the 1,113 children involved in the trial, 522 (47%) were reported to perform at least one job that involved the operation of a farm tractor, and 408 (36.7%) were operating tractors of at least 20 horsepower. The majority of these children were male. There was a wide range of ages and sizes of tractors operated. However, the majority of tractors were between 20 and 70 horsepower and manufactured after 1970. Nearly one-half of the tractors were equipped with ROPS, and these tended to be newer and larger tractors. This analysis provides new data about the broad range of tractors driven by farm children in the U.S. and Canada. The findings point to a need to re-examine the reliance on a single voluntary standard to mitigate the hazard of tractor rollovers and the need for an enhanced safety policy requiring all tractors operated by children be equipped with ROPS.

Assignment of work involving farm tractors to children on North American farms.

BACKGROUND: Children are at high risk for tractor-related injury. The North American Guidelines for Children's Agricultural Tasks (NAGCAT) provide recommendations for the assignment of tractor work. This analysis describes tractor-related jobs assigned to farm children and compares them to NAGCAT. METHODS: A descriptive analysis was conducted of baseline data collected by telephone interview during a randomized, controlled trial. RESULTS: The study population consisted of 1,138 children who worked on 498 North American farms. A total of 2,389 farm jobs were reported and 456 (19.1%) involved operation of farm tractors. Leading types of tractor jobs were identified. Modest, yet important, percentages of children were assigned tractor work before the minimum ages recommended by NAGCAT. CONCLUSIONS: Children on farms are involved in tractor work at a young age and some are involved in jobs that they are unlikely to have the developmental abilities to perform. NAGCAT is a new parental resource that can be applied to these work situations.

Preoperative computed tomography scans for parotid tumor evaluation.

OBJECTIVE: We sought to determine whether an advantage is obtained in the routine use of computed tomography (CT) scans in preoperative assessments of parotid tumors. METHODS: A prospective study of 32 consecutive cases of patients who underwent evaluation for parotidectomies was performed. Twenty-nine received preoperative CT scans. The scans were systematically reviewed to see if they correlated with the clinical findings. Specifically, we compared clinical and CT assessments of tumor size, location, density, and malignancy. Further comparisons were performed based on postoperative tissue pathology. RESULTS: In our series of patients, routine preoperative CT scans resulted in the discovery of details not revealed on clinical examination: some masses were found to be extra-parotid rather than primary parotid tumors, some tumors deemed to be deep were superficial, tumor density was more clearly identified, and certain pathology correlates were clarified. Most importantly, there were instances of detection of additional tumors in the same lobe, and in one instance in the opposite lobe, that were not otherwise noticed. CONCLUSIONS: To reduce errors of omission in the treatment of suspected parotid tumors, it would seem appropriate to consider the inclusion of CT scans for the routine preoperative evaluation of all parotid masses.

Agricultural work activities reported for children and youth on 498 North American farms.

Children are at high risk for agricultural injury, yet there is little documentation about the range of farm work that children perform or the ages at which children experience these work exposures. The purpose of this study was to identify the scope of agricultural jobs performed by farm children and to describe variations in work involvement within demographic subgroups. A descriptive analysis was conducted of baseline data collected by telephone interview during a multi-site randomized controlled trial. The study population consisted of 1,138 children from 498 North American farms. A total of 2,389 jobs were reported for the 1,138 children. The leading categories of work were animal care, crop management, and tractor with implement operation. Regional differences were observed, consistent with variations in commodities. Substantial proportions of children were assigned to farm work even in the youngest age group of 7-9 years. Males were differentially assigned to tractor with implement operations, while females were more often assigned to animal care. This study provides one of the first systematic accounts of farm work performed by North American children. This analysis of work exposures provides information from which known prevention priorities can be reinforced and new opportunities for prevention identified.

Prospective study of seizures in the elderly in the Marshfield Epidemiologic Study Area (MESA).

PURPOSE: To assess the incidence, etiology, antiepileptic drug (AED) use, and quality of life in patients having their first seizure at age 50 years or older. METHODS: All patients in the Marshfield Epidemiologic Study Area (MESA) aged 50 years or older having their first seizure between July 1, 1996, and June 30, 1998, were identified through the diagnostic coding system. Patients were followed up for 12 months for recurrent seizures. Etiologies, drug treatments, magnetic resonance imaging (MRI), computed tomography (CT), or EEG results and medication adverse effects were recorded. Those patients who reached 1-year follow-up received a quality of life (QOLIE-31) survey. RESULTS: Forty-eight patients having a first seizure were identified (162 of 100,000). Twelve patients had had recurrent seizures, and 36 had a single seizure at the time of study entry. Fourteen of these 36 had had an abnormal MRI, CT, or EEG. The remaining 22 had a single seizure and normal imaging and EEG. Six of these had one or more subsequent seizures, and all six were in the group with normal tests. Etiologies included vascular, neoplasm, trauma, dementia, metabolic, and unknown. Seventy-five percent of the patients achieved seizure control with phenytoin, carbamazepine, and/or valproate. Twenty-seven percent experienced adverse side effects. None had been given second-generation AEDs as an initial treatment. Thirty-one patients received the QOLIE-31 survey; 20 did not complete the survey for various reasons. The mean QOLIE-31 scores for those completing the survey were significantly higher than those of the reference cohort. CONCLUSIONS: The incidence of first seizure in MESA is high in the elderly and increases with advancing age. As in other studies, vascular causes accounted for the largest etiology. Use of new AEDs was uncommon. There was a high incidence of untoward side effects related to the traditional AEDs. High morbidity and mortality unrelated to seizures limits follow-up analysis in the elderly. Quality-of-life analysis via QOLIE questionnaires is problematic in this population.

The antiestrogen ICI 182,780 abolishes developmental injury for murine embryos exposed in vitro to o,p'-DDT(1).

Previously, we reported that in vitro exposure of murine embryos to 0.1 microg/ml o,p'-DDT (an estrogenic pesticide) significantly reduced development to blastocyst and mean cell number per embryo, and increased percent cell death by 96 h of culture. The objective of the present study was to determine if developmental injury induced by o,p'-DDT resulted from estrogenic, antiestrogenic, or unrelated adverse biologic mechanisms. Toward this objective, pronuclear embryos from CD-1 mice were cultured 96 h in medium supplemented with 0.1% ethanol (control) or 0.1 microg/ml o,p'-DDT, 17beta-estradiol, or ICI 182,780 dissolved in ethanol as single agents or as paired mixtures. As single agents, development to blastocyst and mean cell numbers were significantly reduced and percent apoptosis was significantly increased for embryos cultured in the presence of o,p'-DDT or ICI 182,780. Development to blastocyst was significantly reduced for embryos cultured in the presence of 17beta-estradiol. Beneficial interaction occurred when the receptor antagonist ICI 182,780 was combined with either receptor agonist (o,p'-DDT or 17beta-estradiol). In contrast, interaction was not significant when the two agonists were combined. The results indicate that developmental injury due to the estrogenic pesticide o,p'-DDT was abolished by the addition of the receptor antagonist ICI 182,780 and not by the receptor agonist 17beta-estradiol. The findings underscore the utility of the model for uncovering mechanisms of developmental injury.