Generalisability of pharmacoepidemiological studies using restricted prescription data.

BACKGROUND: Linking medication databases to disease registries enables population-based pharmacoepidemiology research. In Ireland, country-wide dispensing data is available only from the means-tested government-medical cards scheme. This restriction may impact generalisability of analyses based on these data. AIM: Gender was previously identified as predictor of card status so we aimed to compare women with and without medical cards at the time of ovarian cancer diagnosis. METHODS: Ovarian cancers diagnosed 2001-2010 were identified from the National Cancer Registry Ireland. Age, region, deprivation, smoking, employment and marital status were evaluated using logistic regression for associations with card status. Cumulative incidence of de novo card receipt post-diagnosis was assessed. RESULTS: 1778 (52 %) of 3396 women with incident ovarian cancer had a card at diagnosis (<70:33 %; 70+:87 %). Within those <70, all variables were significantly associated with card status at diagnosis. 52 % of those without a card at diagnosis received one post-diagnosis. CONCLUSIONS: Although medical card coverage within ovarian cancer patients is similar to the general population, various factors predict card status. Particularly within those under 70, external validity needs to be considered when interpreting pharamcoepidemiological analyses using these data.

A cohort study investigating aspirin use and survival in men with prostate cancer.

BACKGROUND: Aspirin use has been associated with reduced mortality from cancer including prostate cancer in some studies. A number of anti-cancer mechanisms of aspirin have been proposed, including the inhibition of the cyclooxygenase enzymes, through which aspirin mediates both anti-platelet and anti-inflammatory activities. This cohort study examines associations between pre-diagnostic aspirin use (overall and by dose and dosing intensity) and mortality in men with localised prostate cancer. PATIENTS AND METHODS: Men with stage I-III prostate cancer were identified from Irish National Cancer Registry records, which have been linked to national prescribing data from the Irish General Medical Services scheme. Aspirin use in the year preceding prostate cancer diagnosis was identified from this linked prescription-claims data. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for associations between aspirin use and all-cause and prostate cancer-specific mortality. Associations between prescribed dose and dosing intensity were examined. The presence of effect modification by the type of treatment received and tumour characteristics was also assessed. RESULTS: Two thousand nine hundred and thirty-six men with a diagnosis of stage I-III prostate cancer (2001-2006) were identified (aspirin users, n = 1131). The median duration of patient follow-up was 5.5 years. In adjusted analyses, aspirin use was associated with a small, but non-significant, reduced risk of prostate cancer-specific mortality (HR = 0.88, 95% CI 0.67-1.15). In dose-response analyses, stronger associations with prostate cancer-specific mortality were observed in men with higher aspirin dosing intensity (HR = 0.73, 95% CI 0.51-1.05) and in men receiving >75 mg of aspirin (HR = 0.61, 95% CI 0.37-0.99). Analyses of effect modification by treatment type or tumour characteristics were non-significant. CONCLUSIONS: Consistent with prior studies, aspirin use was associated with a non-significant reduced risk of prostate cancer-specific mortality in men with localised prostate cancer. Men receiving higher doses of aspirin had a statistically significant reduced risk of prostate cancer-specific mortality. These findings regarding an aspirin dose require further investigation.

A nested case-control study of adjuvant hormonal therapy persistence and compliance, and early breast cancer recurrence in women with stage I-III breast cancer.

BACKGROUND: Non-persistence and non-compliance are common in women prescribed hormonal therapy for breast cancer, but little is known about their influence on recurrence. METHODS: A nested case-control study of associations between hormonal therapy non-persistence and non-compliance and the risk of early recurrence in women with stage I-III breast cancer was undertaken. Cases, defined as women with a breast cancer recurrence within 4 years of hormonal therapy initiation, were matched to controls (1 : 5) by tumour stage and age. Conditional logistic regression was used to examine associations between early recurrence and hormonal therapy non-persistence and non-compliance. RESULTS: Ninety-four women with breast cancer recurrence were matched to 458 controls. Women who were non-persistent (≥ 180 days without hormonal therapy) had a significantly increased adjusted recurrence odds ratio (OR) of 2.88 (95%CI 1.11, 7.46) compared with persistent women. There was no significant association between low compliance (OR 1.30; 95% CI 0.74, 2.30) and breast cancer recurrence. CONCLUSION: Hormonal therapy non-persistence is associated with a significantly higher risk of early recurrence in women with stage I-III oestrogen receptor (ER)-positive breast cancer. This finding is consistent with results from randomized studies of hormonal therapy treatment duration and suggests that interventions to target modifiable risk factors for non-persistence are required.

A competing risks prescription refill model of compliance and persistence.

OBJECTIVES: There is evidence to suggest that noncompliant and nonpersistent behaviors have differing risk factors, clinical consequences, and responses to intervention. This has led to calls for these behaviors to be defined and measured separately to characterize medication-taking behavior comprehensively. Current prescription refill models of compliance are, however, unable to appropriately distinguish between noncompliant and nonpersistent behaviors. To address this limitation, a prescription refill model of medication-taking behavior in which noncompliance and nonpersistence are treated as competing risks is presented. METHODS: The proposed competing risks model of compliance and persistence is compared with a selection of widely applied prescription refill models of compliance and persistence using a common cohort of patients prescribed statin therapy. RESULTS: The competing risks model allows the simultaneous measurement of noncompliance and nonpersistence, the partitioning of their individual contributions to medication-taking behavior, and the estimation of noncompliance risk for patients with varying treatment persistence. The results from this model provide information about the relative and overall contributions of noncompliant and nonpersistent behaviors to medication-taking behavior. The methodology also allows an assessment of the differential influence of various risk factors on these behaviors. CONCLUSIONS: The proposed competing risks model differentiates between noncompliant and nonpersistent behaviors using prescription refill data. Results from the model provide insights into the dynamics of noncompliant and nonpersistent behaviors that have not been possible with current prescription refill methodologies.

Lamotrigine monotherapy in children.

The effectiveness of lamotrigine as a monotherapeutic agent for a variety of pediatric epilepsies was reviewed retrospectively. Children were categorized as having focal vs generalized epilepsy and according to whether they were antiepileptic drug naive or drug exposed. Data collected included dosages, side effects, length of follow-up, number of prior drugs, and treatment response. Treatment was considered successful if the patient was seizure free for 6 months or more. Eighty-three children were identified (average age = 8.7 years); 43 had focal epilepsy, 32 had generalized epilepsy, and eight were not classified. Twenty-nine patients were classified as having specific syndromes. Fourteen patients were drug naive. The median follow-up period was 8 months (mean = 8.5). Overall, 45% were seizure free, 44% with focal epilepsy and 36% with generalized epilepsy. All children with juvenile myoclonic epilepsy and benign rolandic epilepsy of childhood were seizure free, although not all had been treated for at least 6 months. One third of drug-naive patients were seizure free. Rash was the most common side effect and was reported in five patients (6%); two patients discontinued the drug. None had Stevens-Johnson syndrome. One quarter of children experienced nonquantifiable improvements, namely increased alertness and improved behavior regardless of seizure control. Lamotrigine is effective as a monotherapeutic agent in children for both focal and generalized epilepsies. Side effects are relatively uncommon. Lamotrigine may be an effective firstline agent.

Tuberculous enteritis: a case report.

Tuberculous enteritis is an unusual diagnosis in the United States. Because this entity is rare and the symptoms are not specific, the physician must have a high index of suspicion. We report the case of a young man with tuberculous involvement of the gastrointestinal tract who required surgical intervention for small bowel obstruction.

Iron and manganese homeostasis in chronic liver disease: relationship to pallidal T1-weighted magnetic resonance signal hyperintensity.

The hyperintense signal in the globus pallidus of cirrhotic patients on T1-weighted magnetic resonance (MR) imaging has been postulated to arise from deposition of paramagnetic manganese2+ (Mn). Intestinal absorption of both iron and Mn are increased in iron deficiency; iron deficiency may therefore increase susceptibility to Mn neurotoxicity. To investigate the relationships between MR signal abnormalities and Mn and Fe status, 21 patients with chronic liver disease were enrolled (alcoholic liver disease, 5; primary biliary cirrhosis, 9; primary sclerosing cholangitis, 3; hepatitis B virus, 2; hepatitis C virus, 1; alpha1-antitrypsin deficiency, 1). Signal hyperintensity in the pallidum on axial T1 weighted images (repetition time/evolution time: 500 ms/15 ms) was observed in 13 of 21 subjects: four patients had mild hyperintensity, three moderate, and six exhibited marked hyperintensity. Erythrocyte Mn concentrations were positively correlated with the degree of the MR hyperintensity (Kendall's tau-b=0.52, P<0.005). The log of erythrocyte Mn concentration was also inversely correlated with all measures of iron status: hemoglobin (Pearson's R=-0.73, P<0.0005); hematocrit (R=-0.62, P<0.005); serum Fe concentrations (R=-0.65, P<0.005); and TIBC saturation (R=-0.62, P<0.005). These findings confirm the association of Mn with the development of pallidal hyperintensity in patients with liver disease. We further found that iron deficiency is an exacerbating factor, probably because of increased intestinal absorption of Mn. We therefore recommend that patients with chronic liver disease avoid Mn supplements without concurrent iron supplementation.

Optic nerve enlargement in Krabbe's disease.

We report imaging and gross pathologic findings from two cases of Krabbe disease in which there was marked enlargement of the intracranial optic nerves. Numerous globoid cells were observed in the optic nerves at autopsy in one case. Krabbe disease should be included in the differential diagnosis of children with enlargement of the optic nerves.

Infantile spasms: a proposal for a staged evaluation.

The purpose of this study was to determine whether a staged, algorithmic evaluation of infantile spasms could be developed to minimize patient discomfort, treatment delay, and overall costs. A retrospective chart review of patients diagnosed with infantile spasms at the authors' institution during a 10-year period was performed, with 29 patients identified; 28 charts were reviewed. By history and physical examination, 21 were classified as symptomatic and seven as cryptogenic. Of the 21 symptomatic patients, 13 had a known etiology at presentation; with further testing the specific etiology was determined in two more. Two in the cryptogenic group were reclassified on the basis of neuroimaging findings. Evaluations included neuroimaging (27, 15 abnormal), cerebrospinal fluid studies (nine, all normal), comprehensive metabolic studies (17, all normal), chromosomal analysis (11, two abnormal), and ophthalmologic evaluation (27, six abnormal). The average cost of the studies per patient was $5,076 at the authors' institution. Etiologic yield was increased by 20% with neuroimaging. The other investigations either confirmed a known etiology or were noncontributory. On the basis of these findings, the authors propose an algorithm for a more focused evaluation of infantile spasms. Using the algorithm, the authors suggest directly proceeding to therapy in patients with specific etiologies determined by history and examination. Further evaluation should start with neuroimaging. Subsequent evaluations should be on the basis of those results. The authors estimate a potential 60-90% reduction in total costs if this algorithm is applied.

A review of the newer antiepileptic drugs and the ketogenic diet.

Since 1994, three new antiepileptic drugs, felbamate, lamotrigene, and gabapentin, have been released for the treatment of epilepsy. The present paper provides an overview of these three drugs and reviews their potential uses in pediatric epilepsy even though felbamate is the only one with an approved use in children. Topiramate and vigabatrin, which are under investigation, are briefly reviewed. In addition, a discussion of the ketogenic diet is included because of its recent publicity. Patient examples included provide clinical illustrations for the reader.

The clinical phenotype of succinic semialdehyde dehydrogenase deficiency (4-hydroxybutyric aciduria): case reports of 23 new patients.

OBJECTIVES: To further define the clinical spectrum of the disease for pediatric and metabolic specialists, and to suggest that the general pediatrician and pediatric neurologist consider succinic semialdehyde dehydrogenase (SSADH) deficiency in the differential diagnosis of patients with (idiopathic) mental retardation and emphasize the need for accurate, quantitative organic acid analysis in such patients. PATIENTS: The clinical features of 23 patients (20 families) with SSADH deficiency (4-hydroxybutyric acid-uria) are presented. The age at diagnosis ranged from 3 months to 25 years in the 11 male and 12 female patients; consanguinity was noted in 39% of families. OUTCOME MEASUREMENTS: The following abnormalities were observed (frequency in 23 patients): motor delay, including fine-motor skills, 78%; language delay, 78%; hypotonia, 74%; mental delay, 74%; seizures, 48%; decreased or absent reflexes, 39%; ataxia, 30%; behavioral problems, 30%; hyperkinesis, 30%; neonatal problems, 26%; and electroencephalographic abnormalities, 26%. Associated findings included psychoses, cranial magnetic resonance or computed tomographic abnormalities, and ocular problems in 22% or less of patients. Therapy with vigabatrin proved beneficial to varying degrees in 35% of the patients. Normal early development was noted in 30% of patients. CONCLUSIONS: Our data imply that two groups of patients with SSADH deficiency exist, differentiated by the course of early development. Our recommendation would be that accurate, quantitative organic acid analysis in an appropriate specialist laboratory be requested for any patients presenting with two or more features of mental, motor, or language delay and hypotonia of unknown cause. Such analyses are the only definitive way to diagnose SSADH deficiency; the diagnosis can be confirmed by determination of enzyme activity in white cells from whole blood. We think that increased use of organic acid determination will lead to increased diagnosis of SSADH deficiency and a more accurate representation of disease frequency. As additional patients are identified, we should have a better understanding of both the metabolic and clinical profiles of SSADH deficiency.

Focal status epilepticus and hemiparesis in an 8-year-old boy.

An afebrile child with focal status epilepticus and an altered mental status presents a diagnostic and therapeutic challenge. Traditional morphological neuroimaging may be of limited value in the evaluation of such patients, and one may have to rely more upon functional neuroimaging studies. Recent advances in the understanding of the pathogenesis and the role of functional neuroimaging studies in the evaluation of focal status epilepticus are discussed.

Visual display delay effects on pilot performance.

BACKGROUND: The Helmet Integrated Display Sight System (HIDSS), originally proposed for the RAH-66 Comanche, displays sensor data from FLIR and image intensifiers, as well as flight instrument and targeting data. All these data will be processed through onboard computers before being displayed on miniature CRT's. In addition to processing delays, delays also are arising from the helmet tracker and from sensor slewing that may increase the total visual display delay to as much as 250 ms. METHODS: Because display lag is one of the most important limitations affecting the ability of an aviator to use a display, we investigated the effects of 0, 67, 133, 267, 400, and 533 ms visual display delays on the flight performance of 10 volunteer U.S. Army aviators in a full motion flight simulator. RESULTS: There were few performance decrements at 67, 133, or 267 ms delays as compared with the 0 ms delay condition. Significant performance decrements consistently were observed at 400 and 533 ms delays. CONCLUSIONS: Given the anticipated visual display delays for the proposed system, flight performance, as measured within the range of flight conditions and profiles examined, should not be affected significantly, although the aviators will experience an increase in workload to compensate for the delay effects. During low level flight, they will face additional risk due to their proximity to obstacles and a resulting decrease in their time to react and avoid collisions. Given the high accident rates, further research to investigate training strategies to offset delay effects clearly is necessary.

Effect of hypoxia/ischemia on bicuculline-induced seizures in immature rats: behavioral and electrocortical phenomena.

The relation between hypoxia/ischemia and subsequent alterations in seizure susceptibility in developing brain remains unclear. We assessed the behavioral and electrocorticographic (ECoG) effects of hypoxic/ischemic brain damage on bicuculline (BIC)-induced seizures in 7-day postnatal rats, and determined maturational changes in seizure susceptibility, behavior and ECoG activity. Rat pups were subjected to unilateral common carotid artery ligation, followed by exposure to 8% O2 at 37 degrees C for 2 h, an insult that produces brain damage in the cerebral hemisphere ipsilateral to carotid artery occlusion. The experimental group consisted of rat pups previously subjected to hypoxia/ischemia; control littermates received neither arterial ligation nor systemic hypoxia. Experimental animals received 4, 5, or 6 mg/kg BIC subcutaneously (s.c.) at 2 and 24 h, and at 3, 7, and 21 days of recovery from hypoxia/ischemia. Two animals at each interval of recovery, 1 each from the experimental and control groups, were used for ECoG monitoring. After BIC injection, animal behavior was observed for 2 h. Behaviors and seizures were classified in five categories based on severity, duration, and character: 1, mild irritability; 2, few clonic seizures and agitation; 3, few tonic-clonic seizures with swimming movements; 4, frequent tonic-clonic seizures with apneic episodes; 5, continuous tonic-clonic seizures and death. Rat pups previously subjected to hypoxia/ischemia had lesser seizure susceptibility than controls at 2-h recovery (p < 0.05) and greater susceptibility than controls at 24 h (p < 0.05). Tonic seizures were prominent at 2 and 24 h in both the experimental and control groups, whereas lesion-sided circling was prominent only in the hypoxic/ischemic rat pups.(ABSTRACT TRUNCATED AT 250 WORDS)

MRI abnormalities in Behr syndrome.

The etiology of Behr syndrome remains uncertain. A 6-year-old girl with a progressive syndrome of optic atrophy, ataxia, myoclonic epilepsy, urinary incontinence, and pyramidal tract degeneration suggestive of Behr syndrome is described. Diffuse, symmetric white matter abnormalities were demonstrated by magnetic resonance imaging suggesting that Behr syndrome may represent a disorder of white matter associated with an unknown biochemical abnormality.

Dystonia, hyperintense basal ganglia, and high whole blood manganese levels in Alagille's syndrome.

Hyperintensity of the globus pallidus on T1-weighted magnetic resonance imaging (MRI) has been reported in patients with chronic liver disease. This abnormality has been associated with the severity of liver disease and tremor, but its cause is unknown. Similar MRI signal abnormalities have been reported in experimental models of manganese neurotoxicity. This case report describes a child with Alagille's syndrome and end-stage liver disease who developed dystonia and tremor associated with an elevated whole blood manganese level and symmetric hyperintense globus pallidi and subthalamic nuclei on T1-weighted but not T2-weighted MRI. Liver transplantation was performed; 2 months later, neurological function was improved, manganese levels were normal, and the MRI signal abnormality had completely resolved. This child had neurological findings described in manganese neurotoxicity with compatible laboratory and radiological findings. Manganese is excreted by the liver in bile, and toxicity may have resulted from the inadequacy of this mechanism, subsequently corrected by liver transplantation.

Symptomatic manganese neurotoxicity in a patient with chronic liver disease: correlation of clinical symptoms with MRI findings.

Hyperintense symmetric pallidal lesions have been described in chronic hepatic failure. Similar lesions are reported in experimental models of manganese neurotoxicity. We describe an 8-year-old girl with chronic hepatic failure and dystonia in association with an elevated whole blood manganese level and symmetric hyperintense pallidal lesions on magnetic resonance imaging. After hepatic transplantation, her symptoms and signs resolved with normalization of magnetic resonance imaging and the whole blood manganese suggesting that in chronic hepatic failure, the pallidal lesions may be secondary to manganese deposition.