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.

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 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.

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.

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.

Glomerular function in Pima Indians with noninsulin-dependent diabetes mellitus of recent onset.

Differential solute clearances were used to characterize glomerular function in 20 Pima Indians with noninsulin-dependent diabetes mellitus (NIDDM) of less than 3 yr duration. 28 Pima Indians with normal glucose tolerance served as controls. In the diabetic group, the glomerular filtration rate (GFR, iothalamate clearance) exceeded the control value by 15% (140 +/- 6 vs. 122 +/- 5 ml/min, P less than 0.01). A corresponding 12% increase in renal plasma flow (RPF) was not statistically significant and did not account fully for the observed hyperfiltration, suggesting a concomitant elevation of the ultrafiltration pressure or coefficient. The median albumin excretion ratio in NIDDM exceeded control by almost twofold (10.1 vs. 5.8 mg/g creatinine), a trend which just failed to achieve statistical significance (P = 0.06). Fractional clearances of dextrans of broad size distribution were also elevated in diabetic subjects, significantly so for larger dextrans of between 48 and 60 A radius. A theoretical analysis of dextran transport through a heteroporous membrane revealed glomerular pores in NIDDM to be uniformly shifted towards pores of larger size than in controls. We conclude that an impairment of barrier size selectivity combined with high GFR elevates the filtered protein load in NIDDM of recent onset. We propose that enhanced transglomerular trafficking of protein may predispose to sclerosis of glomeruli in those Pima Indians with NIDDM who ultimately develop diabetic nephropathy.

Restriction of P-element insertions at the Notch locus of Drosophila melanogaster.

P elements move about the Drosophila melanogaster genome in a nonrandom fashion, preferring some chromosomal targets for insertion over others (J. C. J. Eeken, F. H. Sobels, V. Hyland, and A. P. Schalet, Mutat. Res. 150:261-275, 1985; W. R. Engels, Annu. Rev. Genet. 17:315-344, 1983; M. D. Golubovsky, Y. N. Ivanov, and M. M. Green, Proc. Natl. Acad. Sci. USA 74:2973-2975, 1977; M. J. Simmons and J. K. Lim, Proc. Natl. Acad. Sci. USA 77:6042-6046, 1980). Some of this specificity may be due to recognition of a particular DNA sequence in the target DNA; derivatives of an 8-base-pair consensus sequence are occupied by these transposable elements at many different chromosomal locations (K. O'Hare and G. M. Rubin, Cell 34:25-36, 1983). An additional level of specificity of P-element insertions is described in this paper. Of 14 mutations induced in the complex locus Notch by hybrid dysgenesis, 13 involved P-element insertions at or near the transcription start site of the gene. This clustering was not seen in other transposable element-induced mutations of Notch. DNA sequences homologous to the previously described consensus target for P-element insertion are not preferentially located in this region of the locus. The choice of a chromosomal site for integration appears to be based on more subtle variations in chromosome structure that are probably associated with activation or expression of the target gene.

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.

The value of urine screening for glucose at each prenatal visit.

OBJECTIVE: To determine whether chemical (dipstick) urinalysis for glucose at each prenatal visit predicts gestational outcomes such as gestational diabetes, abruptio placentae, preterm delivery, fetal heart rate abnormality, cesarean delivery for dystocia, fetal macrosomia, and shoulder dystocia. METHODS: We retrospectively evaluated each of the 3217 women who were delivered at St. Joseph's Hospital between July 1, 1990, and September 1, 1993, and who had received all prenatal care at Marshfield Clinic. Study subjects had complete urinalyses at the first prenatal visit, blood glucose diabetes screening at 24-28 weeks, and dipstick urinalysis for glucose at each prenatal visit. Women were excluded because of preexisting diabetes, multiple gestation, glucosuria at the first prenatal visit, or failure to complete the recommended blood screening at 24-28 weeks. The remaining 2965 women were grouped according to whether their dipstick urine tests were positive for glucose. Then the two groups were compared with regard to relevant pregnancy outcomes. RESULTS: Women with glucosuria in the first two trimesters had a significantly higher incidence of gestational diabetes (12.8 versus 2.9%, P = .003). For women without evidence of gestational diabetes, there were no clinically important differences in the measured pregnancy outcomes between the two groups. CONCLUSION: Routine dipstick urinalysis for glucose can identify gravidas at increased risk for gestational diabetes, possibly allowing certain women with gestational diabetes to be diagnosed earlier than 24-28 weeks. However, most glucosuria testing is performed after a patient has completed routine blood screening for gestational diabetes. This third-trimester testing is not predictive of any clinically important pregnancy outcome.

Creatinine filtration, secretion and excretion during progressive renal disease. Modification of Diet in Renal Disease (MDRD) Study Group.

The Modification of Diet in Renal Disease (MDRD) Study is a multicenter, randomized, controlled trial to determine acceptance, safety, and efficacy of low protein and phosphorus diets in patients with progressive renal disease. During the feasibility phase, 96 patients aged 18 to 75 years, with previously declining reciprocal serum creatinine concentration (1/PCr) and current glomerular filtration rate (GFR) from 7.5 to 80 ml/min/1.73 m2, were randomly assigned four study diets. After randomization, 91 patients were followed for a mean duration of 14.1 months. GFR, 1/PCr and creatinine clearance (CCr) were measured every three months. In an earlier report, we demonstrated relatively weak correlations of rates of change in GFR and 1/PCr during the feasibility phase; the proportion of variability in 1/PCr slopes that was explained by variability in GFR slopes (r2) was only 0.49 to 0.55. In this study, we examined the relationship of GFR and 1/PCr to other determinants of the serum creatinine concentration, including filtration (GFCr), secretion (TSCr), and total renal excretion (UCrV) of creatinine. Our results show that these parameters varied widely among individuals and changed over time. These findings may explain, in part, the relatively weak correlations. These results strengthen our previous suggestion that the rate of change in 1/PCr may not be an accurate index of the rate of change in GFR and raise questions about the validity of conclusions from other studies in which the efficacy of dietary modification in retarding the progression of renal disease was based principally on measurements of 1/PCr.

Does patient-controlled analgesia achieve better control of pain and fewer adverse effects than intramuscular analgesia? A prospective randomized trial.

OBJECTIVE: To compare three analgesic regimens in patients undergoing colon resection: patient-controlled morphine sulfate analgesia (PCA), intramuscular (IM) morphine, and IM ketorolac tromethamine. DESIGN: Prospective randomized case series. SETTING: Rural, private teaching hospital. PATIENTS: All patients (307) scheduled to undergo a major colon resection between January 1, 1992, and December 31, 1993, were eligible to participate. Of these, 10 (3%) were missed in the screening process, 132 (43%) declined participation, 73 (24%) were excluded, and 92 (30%) were enrolled and randomly assigned to a treatment group. INTERVENTIONS: Ninety-two patients were enrolled in the study. Two patients never received the medication to which they were assigned, owing to administrative error; their data was not analyzed. Of the remaining patients, 31 were randomized to the PCA morphine group, 31 were randomized to the IM morphine group, and 28 were randomized to the IM ketorolac group. The randomly assigned drug was first administered in the post-anesthesia care unit. On arrival on the postoperative ward, the patient was asked to rate his or her pain using both a numerical rating scale and a visual analog scale at 30 minutes; 1, 2, 3, 4, and 6 hours after arrival on the ward; and every 4 hours throughout the first 5 postoperative days. The Mini-Mental State Examination (MMSE) was administered the day before surgery and then daily for the first 5 postoperative days. The first day the patient passed flatus after surgery was also recorded. MAIN OUTCOME MEASURES: The end points analyzed were adverse effects, duration of postoperative ileus, degree of pain control, length of hospitalization, and development of postoperative confusion as measured on serial MMSEs. RESULTS: Only two patients, both in the PCA group, reported adverse effects; neither required a change in analgesia group. Significantly more patients assigned to IM ketorolac broke protocol and required alternative analgesia than did patients in the morphine groups (32% ketorolac vs 16% IM morphine and 0% PCA). The ketorolac group had a significantly shorter duration of ileus than either morphine group (P<.0l). The ketorolac group also had significantly lower pain scores (P<.04) and less postoperative confusion than the morphine groups (P<.03), although these results are limited by missing values. The ketorolac group had a significantly shorter length of stay than either morphine group (P<.01), while there was no significant difference between the morphine groups (P=.75). CONCLUSIONS: While it appears that ketorolac provides a better postoperative course than either IM or PCA morphine in terms of pain control, postoperative confusion, length of stay, and duration of ileus, 18% of our patients assigned to ketorolac required additional analgesia, and there was a strong patient preference for PCA. Most patients should probably be managed with PCA narcotics, but the addition of ketorolac might reduce narcotic dose and resultant adverse effects. Those patients particularly prone to adverse effects should receive primarily ketorolac.

Neglected aspects of the quality of life.

Health status indexes have focused on physical function such as the activities of daily living, perhaps because the National Health Survey provides data of this sort or because it is the object of rehabilitation programs. In an attempt to elicit values concerning loss of function, 150 health workers were asked to assign weights from zero to 10 for 50 abilities or functions. Serious methodological problems were encountered in finding terms describing functional loss that were simple and meaningful to a wide range of workers. In addition, an open-ended request was made to identify other functions not included in the list. The largest average values were assigned to ability to use one's mental abilities, to see, to think clearly, to love and be loved in return, to make decisions for oneself, to live at home, to walk, to maintain contact with family and friends, and to talk. Some of the functional loss implied in these responses may not be amenable to cure or rehabilitation but may be preventable and thus needs to be included in outcome measures.

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.

Developmental alterations in murine embryos exposed in vitro to an estrogenic pesticide, o,p'-DDT.

Culturing pronuclear embryos from CD-1 mice with o,p'-DDT and p,p'-DDT was examined as a means for directly evaluating toxicant risk and for increasing the speed of screening developmental toxicants. Pronuclear (2PN) embryos from CD-1 mice were cultured 96 h in modified Earle's balanced salt solution containing 0.1% (v/v) ethanol (control) or 10-fold dilutions of 17/beta-estradiol, o,p'-DDT, or p,p'-DDT. Compared to control treatment, 96 h incubation of 2PN embryos with 0.1 gg/mL o,p'-DDT significantly reduced embryo development to blastocyst and mean cell number, and increased the percentage of cells undergoing apoptosis. The effects of o,p'-DDT on developmental parameters were dose-responsive. Embryo sexing by multiplex polymerase chain reaction indicated that both sexes were susceptible to toxicant injury with comparable reduction in development to blastocyst (27% and 24%, respectively) in the presence of o,p'-DDT. Results of this study suggest that in vitro exposure of preimplantation embryos to xenobiotics may provide a useful tool for rapidly screening developmental toxicants.

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.

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.

Effect of interval between booster vaccination and time of breeding on protection against campylobacteriosis (vibriosis) in cattle.

Thirteen heifers (group A) given a booster vaccination with Campylobacter fetus 4 1/2 months before breeding to bulls infected with the homologous strain had a pregnancy rate of 54%, compared with a pregnancy rate of 92% for 12 heifers (group B) given a booster vaccination 10 days before the 63-day breeding period began. None of 7 nonvaccinated heifers became pregnant, and all remained infected for at least 136 days. All three groups of heifers were bred by the same infected bulls. Nine of the heifers in group A, but none of the heifers in group B, became infected during the first estrus. Blood serum agglutination titers peaked 2 weeks after the first vaccination but decreased to prevaccination titers 6 weeks later. Titers more than double those produced by one vaccination peaked between 2 and 3 weeks after booster vaccination but in most heifers had decreased to low titers 7 weeks later. When the breeding period began, the median antibody titer was 640 for heifers in group A and 10, 240 for heifers in group B. Indications of an anamnestic response due to natural challenge were not found in any of the 9 infected heifers in group A when serum titers were determined 27 and 34 days after breeding began. Therefore, it appears that in many heifers and cows, only the antibodies produced by booster vaccination will be available to provide protection. Inasmuch as vaccinal antibody titers decrease rapidly, it was concluded that booster vaccinations should be given approximately 10 days before breeding so that titers will be high during the breeding period.

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.

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.