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Let f and g be weight k holomorphic cusp forms and let S f ( n ) and S g ( n ) denote the sums of their first n Fourier coefficients. Hafner and Ivić [9] proved asymptotics for ∑ n ≤ X | S f ( n ) | 2 and proved that the Classical Conjecture, that S f ( X ) ≪ X k − 1 2 + 1 4 + ϵ , holds on average over long intervals. In this paper, we introduce and obtain meromorphic continuations for the Dirichlet series D ( s , S f × S g ) = ∑ S f ( n ) S g ( n ) ‾ × n − ( s + k − 1 ) and D ( s , S f × S g ‾ ) = ∑ n S f ( n ) S g ( n ) n − ( s + k − 1 ) . We then prove asymptotics for the smoothed second moment sums ∑ S f ( n ) S g ( n ) ‾ e − n / X , giving a smoothed generalization of [9] . We also attain asymptotics for analogous sums of normalized Fourier coefficients. Our methodology extends to a wide variety of weights and levels, and comparison with [4] indicates very general cancellation between the Rankin–Selberg L -function L ( s , f × g ) and convolution sums of the coefficients of f and g . In forthcoming works, the authors apply the results of this paper to prove the Classical Conjecture on | S f ( n ) | 2 is true on short intervals, and to prove sign change results on { S f ( n ) } n ∈ N . [ABSTRACT FROM AUTHOR]

Let f be a weight k holomorphic cusp form of level one, and let S f ( n ) denote the sum of the first n Fourier coefficients of f . In analogy with Dirichlet's divisor problem, it is conjectured that S f ( X ) ≪ X k − 1 2 + 1 4 + ϵ . Understanding and bounding S f ( X ) has been a very active area of research. The current best bound for individual S f ( X ) is S f ( X ) ≪ X k − 1 2 + 1 3 ( log ⁡ X ) − 0.1185 from Wu [17] . Chandrasekharan and Narasimhan [2] showed that the Classical Conjecture for S f ( X ) holds on average over intervals of length X . Jutila [10] improved this result to show that the Classical Conjecture for S f ( X ) holds on average over short intervals of length X 3 4 + ϵ . Building on the results and analytic information about ∑ | S f ( n ) | 2 n − ( s + k − 1 ) from our recent work [9] , we further improve these results to show that the Classical Conjecture for S f ( X ) holds on average over short intervals of length X 2 3 ( log ⁡ X ) 1 6 . [ABSTRACT FROM AUTHOR]

Background: Although echinocandins are generally well tolerated, there is little information on the frequency with which renal and hepatic adverse effects occur during use of micafungin or other parenteral antifungal (PAF) agents in clinical practice.Methods: MYCOS is a multicentre cohort study of adult and paediatric patients who received micafungin or other PAFs between 2005 and 2012 at seven tertiary care hospitals from six centres in the USA. PAF cohort controls were selected through propensity score (PS) matching to micafungin recipients using clinical characteristics, other treatments, procedures and hospital service where PAF treatment was initiated. Analysis was restricted to patients without chronic liver and kidney conditions at the time of cohort entry. Treatment-emergent hepatic and renal injury was documented by changes in liver enzymes or estimated glomerular filtration rate through 30 days following completion of PAF treatment. Comparisons were quantified using the HR from a proportional hazards analysis.Results: There were 2970 micafungin recipients PS matched to 6726 recipients of comparator PAFs. Balance was achieved in all baseline covariates between treatment groups. There were similar rates of hepatic injury (micafungin, 13 events per 100 patients and other PAF, 12 per 100; HR = 0.99; 95% CI 0.86-1.14) and lower rates of renal injury (micafungin, 63 events per 100 patients and other PAF, 65 per 100; HR = 0.93; 95% CI 0.87-0.99) for micafungin recipients versus PAF comparators.Conclusion: For a wide spectrum of underlying conditions, we observed no increase in liver injury by micafungin and possibly a reduced risk of renal dysfunction in comparison with other PAF medications. [ABSTRACT FROM AUTHOR]

Abstract: The current standard for measuring cognitive workload is the NASA Task-load Index (TLX) questionnaire. Although this measure has a high degree of reliability, diagnosticity, and sensitivity, a reliable physiological measure of cognitive workload could provide a non-invasive, objective measure of workload that could be tracked in real or near real-time without interrupting the task. This study investigated changes in respiratory sinus arrhythmia (RSA) during seven different sub-sections of a proposed selection test for Navy aviation and compared them to changes reported on the NASA-TLX. 201 healthy participants performed the seven tasks of the Navy''s Performance Based Measure. RSA was measured during each task and the NASA-TLX was administered after each task. Multi-level modeling revealed that RSA significantly predicted NASA-TLX scores. A moderate within-subject correlation was also found between RSA and NASA TLX scores. The findings support the potential development of RSA as a real-time measure of cognitive workload. [Copyright &y& Elsevier]

Background: Pre-marketing clinical studies of tegaserod suggested an increased risk of abdominal surgery, particularly cholecystectomy. We sought to quantify the association between tegaserod use and the occurrence of abdominal or pelvic surgery, including cholecystectomy. Methods: This cohort study was conducted within an insured population. Tegaserod initiators and similar persons who did not initiate tegaserod were followed for up to six months for the occurrence of abdominal or pelvic surgery. Surgical procedures were identified from health insurance claims validated by review of medical records. The incidence of confirmed outcomes was compared using both as-matched and as-treated analyses. Results: Among 2,762 tegaserod initiators, there were 94 abdominal or pelvic surgeries (36 gallbladder): among 2,762 comparators there were 134 abdominal or pelvic surgeries (37 gallbladder) (hazard ratio HR] = 0.70, 95% confidence interval [C.I.] = 0.54-0.91 overall, HR = 0.98, 95% C.I. = 0.62-1.55 for gallbladder). Current tegaserod exposure compared to nonexposure was associated with a rate ratio [RR] of 0.68 (95% C.I. = 0.48-0.95) overall, while the RR was 0.99 (95% C.I. = 0.56-1.77) for gallbladder surgery. Conclusions: In this study, tegaserod use was not found to increase the risk of abdominal or pelvic surgery nor the specific subset of gallbladder surgery. [ABSTRACT FROM AUTHOR]

Abstract: Physiological compliance (PC) refers to the correlation between physiological measures of team members over time. The goals of this study were to examine ways of measuring PC in heart rate variability (HRV) data and the relationship between PC and team performance. Teams were tasked with entering both real and simulated rooms and “shooting” individuals with a weapon and identifying individuals without a weapon. The linear correlation and directional agreement PC methods were shown to be the most sensitive to differences in performance, with greater PC being associated with better performance. The correlation method when applied to a measure of respiratory sinus arrhythmia (RSA) revealed a significant difference between high and low performers (t[8]=−2.31, p =0.03) and the directional agreement applied to inter-beat-intervals and RSA revealed trend-level differences (t[4.62]=−1.86, p =0.06 and t[8]=−1.68, p =0.07). These results suggest that PC may have merit for predicting team performance. [Copyright &y& Elsevier]

Abstract: Background: The oral contraceptive ethinyl estradiol 0.03 mg/drospirenone 3 mg (EE/DRSP) contains a progestin component that possesses potassium-sparing diuretic activity similar to spironolactone. We sought to determine whether EE/DRSP use might lead to adverse effects possibly attributable to hyperkalemia. Study Design: This was a matched cohort study in which we identified oral contraceptive (OC) initiators between July 2001 and June 2004 within a large, US health plan. We matched EE/DRSP initiators to other OC initiators in a 1:2 ratio on the basis of a prediction model (propensity score) of EE/DRSP initiation that incorporated dozens of characteristics. We identified insurance claims mentioning hyperkalemia, related clinical outcomes (electrolyte disturbances, arrhythmia, syncope, myocardial infarction) and verified the underlying condition through medical record review. Results: There were 22,429 EE/DRSP initiators matched to 44,858 other OC initiators, with an average follow-up of 7.6 months. A composite clinical surrogate hyperkalemia end point occurred with equal frequency in the compared groups [118 cases in EE/DRSP and 260 in comparators; rate ratio (RR) 0.9, 95% confidence interval (CI) 0.7–1.1]. The individual hyperkalemia surrogate end points exhibited similar results. One EE/DRSP initiator and four comparators were diagnosed specifically with hyperkalemia (RR 0.5, 95% CI 0.0–4.9). The results were not different when we accounted for changes in OC use during follow-up. Conclusion: EE/DRSP initiators are no more likely than other OC initiators to experience hyperkalemia or related clinical outcomes which could be caused by hyperkalemia during follow-up. [Copyright &y& Elsevier]

Background: Aprotinin (Trasylol) is used to mitigate bleeding during coronary-artery bypass grafting (CABG). Accumulating evidence suggests that this practice increases mortality. Methods: Using electronic administrative records of the Premier Perspective Comparative Database, we studied hospitalized patients with operating-room charges for the use of aprotinin (33,517 patients) or aminocaproic acid (44,682 patients) on the day CABG was performed. We tabulated the numbers of patients with a hospital-discharge status of death and performed three types of analyses: a multivariable logistic-regression analysis (primary analysis); propensity-score matching in the highly selected subcohort of patients who received full amounts of the study drug, who underwent CABG by surgeons who performed 50 or more CABG surgeries during the study period, and for whom information on 10 additional covariates was available because the surgery occurred on hospital day 3 or later; and an instrumental-variable analysis of data from patients whose surgeons showed a strong preference for one of the two study drugs. Results: In all, 1512 of the 33,517 aprotinin recipients (4.5%) and 1101 of the 44,682 aminocaproic acid recipients (2.5%) died. After adjustment for 41 characteristics of patients and hospitals, the estimated risk of death was 64% higher in the aprotinin group than in the aminocaproic acid group (relative risk, 1.64; 95% confidence interval [CI], 1.50 to 1.78). In the first 7 days after surgery, the adjusted relative risk of in-hospital death in the aprotinin group was 1.78 (95% CI, 1.56 to 2.02). The relative risk in a propensity-score–matched analysis was 1.32 (95% CI, 1.08 to 1.63). In the instrumental-variable analysis, the use of aprotinin was found to be associated with an excess risk of death of 1.59 per 100 patients (95% CI, 0.14 to 3.04). Postoperative revascularization and dialysis were more frequent among recipients of aprotinin than among recipients of aminocaproic acid. Conclusions: Patients who received aprotinin alone on the day of CABG surgery had a higher mortality than patients who received aminocaproic acid alone. Characteristics of neither the patients nor the surgeons explain the difference, which persisted through several approaches to control confounding. N Engl J Med 2008;358:771-83. [ABSTRACT FROM AUTHOR]

The article reports on the results of a study of the risk of thromboembolism in women taking ethinylestradiol/drospirenone and other oral contraceptives. A description of the experimental setup and measurement method is given. The study concluded that ethinylestradiol/drospirenone initiators and initiators of other oral contraceptives are similarly likely to experience thromboembolism.

Purpose: To estimate the rate of new-onset afebrile provoked and unprovoked seizure in a general pediatric population and subgroups of patients with and without psychiatric diagnoses other than attention deficit hyperactivity disorder (ADHD). Methods: A retrospective cohort study of 133,440 pediatric patients, between the ages of 6 and 17 years, and without history of seizure or prior use of anticonvulsant medications, with follow-up during 2003. The data source for this study was Ingenix's research database containing pharmacy and medical claims for members of a large US-based managed care organization. The main outcome measure was new-onset nonfebrile seizure. Incidence rates of seizure and 95% confidence intervals (CI) were calculated and expressed as rates per 100,000 person-years. Results: There were 132 new-onset provoked and unprovoked seizures in 78,423 person-years of follow-up among the general pediatric population sample. The incidence rate of seizure among the general pediatric population was 168 per 100,000 p-y (95% CI 141–200). The incidence rate of seizure among patients without psychiatric diagnoses was 149 per 100,000 p-y (95% CI 122–180). The incidence rate of seizure among patients with psychiatric diagnoses other than ADHD was 513 per 100,000 p-y (95% CI 273–878). There were increases in the incidence rates of seizure in all of the seizure risk factor groups, but this was more pronounced among males ages 6–12 with psychiatric diagnoses. Conclusions: The results of this study are consistent with previous reports showing that pediatric patients with psychiatric disorders have a higher incidence rate of seizure than the general pediatric population. [ABSTRACT FROM AUTHOR]

The article studies the association of venous thromboembolism, myocardial infarction, and stroke among transdermal contraceptive system users. The researchers attempt to estimate the incidence of these conditions among transdermal contraceptive system users compared with users of norgestimate-containing oral contraceptives with ethinyl estradiol.

Abstract: Purpose: Yasmin-28 [ethinyl estradiol 0.03 mg/drospirenone 3 mg (EE/DRSP)] contains drospirenone, a progestin component that possesses antimineralocorticoid activity with a potassium-sparing diuretic effect similar to that in spironolactone. Product labeling recommends potassium monitoring in the first month of use for women concurrently receiving medication that may increase serum potassium. Methods: We evaluated compliance with this recommendation by measuring monitoring around the date of oral contraceptive (OC) initiation in women who received EE/DRSP while being treated with medications predisposing to hyperkalemia and in similar women who received other OCs. Because preliminary analyses indicated incomplete compliance, we surveyed physicians who prescribed EE/DRSP to women receiving drugs predisposing to hyperkalemia on their knowledge and attitudes with regard to the recommendation. We conducted this study using data from the Ingenix Research Datamart, which includes insurance claims for reimbursement for medical services and prescription medications for approximately 8,000,000 members of a large nationally dispersed health plan. We used claims for pharmacy dispensings of prescription medications to identify all women aged 10–59 years old who initiated EE/DRSP or other OCs during the first 3 years of EE/DRSP availability (July 2001 to June 2004). The frequency of potassium monitoring was measured by identifying claims for serum potassium tests. We conducted a telephone survey of 58 physicians who had prescribed EE/DRSP up to June 2003 to women who received concomitant hyperkalemic drugs. Results: Although potassium monitoring was generally more frequent among EE/DRSP initiators receiving concomitant hyperkalemic drugs than among other OC initiators receiving similar medications, only 40% of 466 EE/DRSP initiators with concurrent hyperkalemic treatment had potassium tests. More than 98% of surveyed physicians were aware of the potassium-sparing property of EE/DRSP. Compared with physicians whose patients had potassium tests, physicians of patients without such tests were more likely to disagree with the recommendation for users of angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, heparin and nonsteroidal anti-inflammatory drugs. Patient barriers and health plan restrictions were other factors possibly contributing to noncompliance. Conclusion: This study demonstrates incomplete physician compliance with a labeling recommendation of potassium monitoring for initiators of EE/DRSP receiving concomitant therapy predisposing to hyperkalemia. The limited compliance was likely due to a combination of selective physician acceptance of the recommendations and specific patient and health plan barriers to testing. [Copyright &y& Elsevier]

Study Objective. To measure the association among prescription copayment, drug adherence, and subsequent health outcomes among patients with chronic heart failure (CHF). Design. Retrospective cohort study. Data Source. Database of a large, national health insurance plan. Patients. Patients with CHF receiving commercial and Medicare supplemental benefits. Measurements and Main Results. We estimated adherence to therapy with β-blockers or angiotensin-converting enzyme (ACE) inhibitors in 2002 by using the medication possession ratio, an estimate of the proportion of days a patient was exposed to a drug while taking a drug regimen. For 2003, we measured the annualized total cost of health care and identified hospitalizations with a diagnostic code for CHF. We used a two-stage regression approach to model the association among copayment, adherence, and patient outcomes. For patients taking ACE inhibitors, a $10 increase in copayment was associated with a 2.6% decrease in the medication possession ratio (95% confidence interval [CI] 2.0-3.1%). This change in adherence was associated with a predicted 0.8% decrease in medical costs (95% CI -4.2-2.5%) but a predicted 6.1% increase in the risk of hospitalization for CHF (95% C1 0.5-12.0%). Among patients taking β-blockers, a $10 increase in copayment was associated with a 1.8% decrease in the medication possession ratio (95% C1 1.4-2.2%). This change in adherence was associated with a predicted 2.8% decrease in medical costs (95% Cl -5.9-0.1%) and a predicted 8.7% increase in the risk of hospitalization for CHF (95% CI 3.8-13.8%). Conclusion. Among patients with CHF, higher drug copayments were associated with poorer adherence. The change was relatively small and did not affect predicted total health care costs, but it was sufficient to increase the predicted risk of hospitalization for CHF. [ABSTRACT FROM AUTHOR]

Objective: To examine nonvertebral fracture risk in relation to inhaled corticosteroid (ICS) exposure among adults with respiratory disease. Design and patients: Nested case-control study within a cohort of 89,877 UnitedHealthcare members aged ≥ 40 years with physician insurance claims for COPD or asthma, enrolled for ≥ 1 year from January 1, 1997 to June 30, 2001. Methods: Cases (n = 1,722) represented patients with a first treated nonvertebral fracture (the index date is the first fracture claim). Control subjects (n = 17,220) were randomly selected from the person-time and assigned a random index date. ICS exposure was ascertained 1 month, 3 months, 6 months, and 12 months before the index date, with estimated cumulative dose through 0 to 6 months, 7 to 12 months, and 0 to 12 months. Covariates included demographics, oral corticosteroid and other medication exposure, comorbidities, and indicators of respiratory disease severity. Odds ratios (ORs) adjusted for all covariates were estimated by logistic regression. Results: No increased fracture risk with ICS exposure as a class or with fluticasone propionate alone was detected. ORs for exposure in the preceding 30 days were 1.05 (95% confidence interval [CI], 0.89 to 1.24), 1.13 (95% CI, 0.90 to 1.40), and 0.97 (95% CI, 0.78 to 1.21) for all ICS, fluticasone propionate, and other ICS, respectively. No dose-response effect was present. Among patients with COPD only (n = 6,932), no increased risk was found for recent ICS exposure (OR, 0.86; 95% CI, 0.59 to 1.25). Conclusions: Concern about nonvertebral fracture risk should not strongly influence the decision to use recommended doses of ICS for adult patients with asthma or COPD in managed-care settings in the United States. This study could not evaluate very-high ICS dose, long-term ICS exposure, or vertebral fracture risk. [ABSTRACT FROM AUTHOR]

Background It remains unclear whether benzodiazepine use increases hip fracture incidence. We studied this relationship in a large cohort, controlling for multiple potential confounders. Methods We analyzed 42 months of New Jersey Medicaid health care claims data for all enrollees. Each eligible person-day was assigned to categories of benzodiazepine exposure and categories of other predictors, based on prior and current medication dispensing and diagnosis information. Hip fractures were identified based on hospital claims with primary discharge diagnosis International Classification of Diseases, Ninth Revision (ICD-9) codes 820.xx. Results Cohort members (n = 125 203) contributed 194 071 person-years and had 2312 eligible hip fractures. After adjustment for age, sex, race, Medicaid nursing home residence, exposure to other psychoactive medications, including antiparkinsonian medications, diagnoses of epilepsy and dementia, and hospitalization in the previous 6 months, the incidence rate of hip fracture was significantly higher compared with no benzodiazepine use for exposure to any benzodiazepine (incidence rate ratio [IRR], 1.24; 95% confidence interval [CI], 1.06-1.44), to a short half-life, high-potency benzodiazepine (IRR, 1.27; 95% CI, 1.01-1.59), during the first 2 weeks after starting a benzodiazepine (IRR, 2.05; 95% CI, 1.28-3.28), during the second 2 weeks after starting a benzodiazepine (IRR, 1.88; 95% CI, 1.15-3.07), and for continued use (IRR, 1.18; 95% CI, 1.03-1.35). Conclusions The incidence of hip fracture appears to be associated with benzodiazepine use. Contrary to several previous studies, short half-life benzodiazepines are not safer than long half-life benzodiazepines. Hip fracture risk is highest during the first 2 weeks after starting a benzodiazepine and declines thereafter. [ABSTRACT FROM AUTHOR]

Objective.—To estimate rates of vascular events in relation to dispensing of triptans and ergot alkaloids among migraineurs, and to compare these rates with those of nonmigraineurs. Context. —It has been speculated that the use of triptans or ergot alkaloid drugs might increase risk of ischemic events through vasoconstriction. Design.—A retrospective cohort study of 130,411 migraineurs and 130,411 age-, sex-, and health plan-matched nonmigraineurs who were members of UnitedHealthcare during 1995 through 1999. The data source for this study was Ingenix's research database containing pharmacy and medical claims for UnitedHealthcare members, and the National Death Index. Main Outcome Measures .—Incidence of cardiovascular and cerebrovascular events and mortality. Results.—Migraineurs and nonmigraineurs had identical rates of myocardial infarction: 1.4 per 1000 person-years. Migraineurs were 67% more likely to suffer a stroke than nonmigraineurs (adjusted relative risk [RR] 1.67, 95% confidence interval [CI] 1.31–2.13), and had higher rates of unstable angina and transient ischemic attacks. There was no increase in risk of myocardial infarction with current (adjusted RR 0.80, 95% CI 0.58–1.11) or recent (adjusted RR 1.15, 95% CI 0.71–1.87) triptan use. Neither current (adjusted RR 0.90, 95% CI 0.64–1.26) nor recent (adjusted RR 0.84, 95% CI 0.46–1.55) triptan use was associated with risk of stroke. Current users of ergot alkaloids were somewhat more likely to have a stroke than other migraineurs (adjusted RR 1.49, 95% CI 0.93–2.41), but there was no dose-response relationship. Conclusions.—Use of triptans is not associated with increased risk of any ischemic events, including myocardial infarction and stroke, or mortality. Consistent with previous studies, migraineurs in general have an elevated risk of stroke, but not myocardial infarction, compared with nonmigraineurs. [ABSTRACT FROM AUTHOR]

OBJECTIVE: In November 2000, alosetron HCl (Lotronex®), a treatment for irritable bowel syndrome (IBS), was removed from the U.S. market in part because of the occurrence of colon ischemia in treated patients. Since the relation between colon ischemia and IBS is poorly understood, we evaluated the incidence of colon ischemia among people with and without IBS.METHODS: Using medical claims data from a large health care organization in the United States, we identified 87,449 people with an IBS diagnosis between January 1995 and December 1999. We calculated age- and sex-specific incidence rates in the general population and in IBS patients.RESULTS: There were 740 cases of colon ischemia during 8.5 million person-years of observation in 5.4 million persons. The crude incidence rate was 42.8 cases per 100,000 person-years for IBS patients. By comparison, the incidence rate was 7.2 per 100,000 person-years in the general population. After adjustment for age, sex, and calendar year, the incidence of colon ischemia in people with IBS was 3.4 times higher than in persons without (95% CI 2.6–4.5).CONCLUSIONS: Rates of colon ischemia among patients carrying a diagnosis of IBS are substantially higher than in the general population. Colon ischemia, though unusual in IBS patients, may nonetheless constitute a distinct part of the IBS natural history. Alternatively, it may be a consequence of therapy, or a manifestation of other bowel pathology that is sometimes confused with IBS. [ABSTRACT FROM AUTHOR]

: ObjectiveAlosetron hydrochloride (Lotronex), a potent selective 5-hydroxytryptamine3 receptor antagonist, was approved in February, 2000 in the United States for the treatment of diarrhea-predominant irritable bowel syndrome (IBS) in women. Marketing was suspended in November, 2000, after reports of colonic ischemia and serious complications of constipation. We sought to compare the incidence of colonic ischemia, hospitalized complications of constipation, and bowel surgery among alosetron users and a cohort of patients with IBS who did not use alosetron.: MethodsWe sought outcomes of colonic ischemia, hospitalized complications of constipation, and bowel surgery in 3,631 Lotronex users and 2,480 comparison IBS subjects using diagnoses, procedures, and drugs recorded in the UnitedHealthcare insurance claims database, and validated these by chart review. The initial assessment was to last for 3 yr beginning with the start of alosetron treatment and was to include 10,000 Lotronex users; however, the observation period ended by December 31, 2000, after suspension of marketing.: ResultsThere were 3631 alosetron users among members of UnitedHealthcare from March through December, 2000, and we identified 2480 comparison IBS-only patients; follow-up time averaged about 5 months in both groups. There were no instances of colonic ischemia in either cohort. Thirty instances of bowel surgery occurred, giving rates of 10.2/1000 person-yr in the alosetron cohort and 11.8/1000 person-yr in the IBS/no alosetron cohort. There were three cases of hospitalized complications of constipation. The incidence rates were essentially the same in alosetron users (1.24/1000 person-yr) and in IBS patients with no alosetron use (0.92/1000 person-yr).: ConclusionsAlosetron users did not differ from IBS patients not using alosetron in the incidence of bowel surgery or hospitalized complications of constipation; there were no cases of colonic ischemia. The statistical upper limit of colonic ischemia rates in alosetron users was 2.28/1000 person-yr. Because of the market withdrawal, the size of the cohort and the duration of follow-up were smaller than originally planned; consequently, the statements about the safety of alosetron were necessarily limited. On June 7, 2002, the Food and Drug Administration approved alosetron for reintroduction in the U.S. market for women with severe diarrhea-related IBS. [Copyright &y& Elsevier]

Background The aim of this study was to investigate predictors of Quality of Life in a group of severely mentally ill substance abusers. These patients took part in a multi-centre study aimed at improving cooperation between psychiatric and social services in Sweden during the years 1995 to 1998. Methods Two hundred and eighty-eight patients, 62.4% men, were included in the study. The criteria to enter the study were to have a diagnosis of severe mental illness and a diagnosis of substance dependence according to the DSMIII-R criteria. Quality of Life (QoL) was measured by a global assessment, Cantril's ladder (1965). Initially and after 18 months the following measurements were also used: Addiction Severity Index (ASI), Symptom Check List 90 (SCL-90) and The Clinical Rating Scale (CRS) for Alcohol Use (AUS) and Drug Use (DUS). Results Initially those who were older and those who had an apartment of their own or who lived in sheltered living had a higher QoL than the others. Those belonging to the borderline personality disorder subgroup had a lower QoL than those belonging to other psychiatric diagnostic subgroups. At follow-up QoL had improved significantly. Improvement in QoL was related to improvements in physical health, legal and family problems, psychiatric symptoms and a reduction of alcohol and drug problems (ASI), global functioning (GAF) and psychological problems (SCL-90). A multiple stepwise regression analysis showed that improvement in QoL primarily was predicted by improvements in psychiatric symptoms. Number of months without alcohol and drugs were positively associated with improvement in QoL. As a whole, at follow-up the QoL is still not high. Conclusions In this group of severely mentally ill substance abusers, improvement in QoL was primarily predicted by improve- ments in psychiatric symptoms. Further, less alcohol and drug abuse seems to augment the subjective feeling of QoL. [ABSTRACT FROM AUTHOR]

Background: Complications of influenza are a major cause of morbidity and mortality during the influenza season. Clinical trials of zanamivir have reported a reduced incidence of influenza complications among high-risk patients.Objectives: This retrospective study sought to determine whether the use of zanamivir lowers the risk of acute influenza complications in a broader population, based on an analysis of claims data from a large managed care organization.Methods: Medical and pharmacy health insurance claims data from October 1, 1999, through April 30, 2000, were compiled for UnitedHealthcare members in 19 states. All patients with a diagnosis of influenza (International Classification of Diseases, Ninth Revision, Clinical Modification diagnostic code 487.xx) associated with a physician visit were identified. From these, all patients were selected who had received zanamivir on the same day as the diagnosis of influenza. The propensity score matching technique was used to identify a comparison group with similar health service utilization and comorbidities who received a diagnosis of influenza but no antiviral therapy. Follow-up started the day after the influenza diagnosis and continued for 21 days.Results: From the 43,741 patients originally identified, 2341 were selected who received a simultaneous diagnosis of influenza and a prescription for zanamivir. The untreated comparator group numbered 2337. Fewer zanamivir patients than untreated patients were hospitalized for complications, and the absolute risks were low (0.6% and 1.0%, respectively; risk ratio [RR], 0.58; 95% CI, 0.30–1.12). Zanamivir-treated patients had an excess of outpatient visits (16.9% vs 14.5%; RR, 1.16; 95% CI, 1.02–1.33) and antibiotic use (16.3% vs 14.8%; RR, 1.10; 95% CI, 0.97–1.26), although the RRs were modest.Conclusions: In the setting of a large managed care plan, patterns of influenza complications were similar in zanamivir-treated and untreated patients with a diagnosis of influenza. The results of this study are in contrast to those of published clinical trials reporting a reduction in the risk of influenza complications in zanamivir-treated patients. [Copyright &y& Elsevier]

Background: Inhaled zanamivir is indicated for treatment of uncomplicated acute illness due to influenza A and B viruses in patients aged ≥12 years who have been symptomatic for no more than 2 days.Objective: The primary objective of this study was to estimate the incidence of adverse respiratory events among zanamivir-treated patients under conditions of usual care.Methods: The Ingenix research database includes insurance claims for all dispensations, inpatient and outpatient services, and procedures including the associated diagnoses and costs for a subset of all enrolled UnitedHealthcare members. We identified all persons with a dispensation of zanamivir recorded between October 1, 1999, and April 30, 2000. We captured medical and pharmaceutical claims data for the 6 months before the dispensation to obtain information about comorbidities, overall health status, and respiratory events. Medical and hospital record abstraction and clinical review served to confirm inpatient/emergency department (ED) events. We also examined the records of an ∼ 10% random sample of patients treated for a potential respiratory event in an outpatient/physician office visit during the 10-day follow-up period. Respiratory events not sufficiently severe to result in medical care were not captured in this study.Results: A total of 5498 eligible zanamivir dispensations contributed by 5450 patients (2911 females, 2539 males; mean age, 38.8 years), with 40 confirmed inpatient/ED respiratory events, were included in the study. Of these 40 events, 31 were pneumonia, bronchitis, or exacerbations of existing chronic respiratory disease; none required intubation or ventilation. No events occurred on the dispensation date. The overall risk for an inpatient/ED respiratory event was 0.7 per 100 episodes (95% CI, 0.5–1.0). Seven events of wheezing or shortness of breath were not an obvious extension of the original influenza-like illness or of a complicating bronchitis (risk = 0.13 per 100 episodes; 95% CI, 0.06–0.26).Conclusions: No immediate or severe bronchoconstrictive responses occurred among 5498 zanamivir dispensations. The overall risk for any respiratory event was low, and none was sufficiently severe to suggest respiratory failure. [Copyright &y& Elsevier]

A causal relation between drug benefit policy change and the increase in adverse outcomes can be tested by comparing the experience of a group of patients affected by the policy vs. the (counterfactual) experience of the same patients if the policy had not been implemented. Because counterfactual experiences cannot be observed, it must be assumed that the counterfactual is correctly described by extrapolating from the same population''s previous experience. The null hypothesis of no policy effect can be empirically tested using quasi-experimental longitudinal designs with repeated measures. If compliance to a policy is low, results may be biased towards the null, but a subgroup analysis of compliers may be biased by nonignorable treatment selection. Using the example of reference drug pricing in British Columbia we discuss assumptions for causal interpretations of such analyses, and provide supplementary analyses to assess and improve the validity of findings. Results from nonrandomized comparisons of subgroups defined by their compliance to a policy change should generally be interpreted cautiously, and several biases should be explored. [Copyright &y& Elsevier]

Background: Increasing copayments for higher-priced prescription medications has been suggested as a means to help finance drug coverage for elderly patients, but evaluations of the impact of such policies are rare. The objective of this study was to analyze the effect of reference-based pricing of angiotensin-converting enzyme (ACE) inhibitors on drug utilization, cost savings and potential substitution with other medication classes.Methods: We analyzed 36 months of claims data from British Columbia for 2 years before and 1 year after implementation of reference-based pricing (in January 1997). The 119,074 patients were community-living Pharmacare beneficiaries 65 years of age or older who used ACE inhibitors during the study period. The main outcomes were changes over time in use of ACE inhibitors, use of antihypertensive drugs and expenditures for antihypertensive drugs, as well as predictors of medication switching related to reference-based pricing.Results: We observed a sharp decline (29%) in the use of higher-priced cost-shared ACE inhibitors immediately after implementation of the policy (p < 0.001). After a transition period, the post-implementation utilization rate for all ACE inhibitors was 11% lower than projected from pre-implementation data. However, overall utilization of antihypertensives was unchanged (p = 0.40). The policy saved $6.7 million in pharmaceutical expenditures during its first 12 months. Patients with heart failure or diabetes mellitus who were taking a cost-shared ACE inhibitor were more likely to remain on the same medication after implementation of reference-based pricing (OR 1.12 [95% confidence interval, CI, 1.06-1.19] and 1.28 [95% CI 1.20-1.36] respectively). Patients with low-income status were more likely than those with high-income status to stop all antihypertensive therapy (OR 1.65 [95% CI 1.43-1.89]), which reflects a general trend toward discontinuation of therapy among these patients even before implementation of reference-based pricing.Interpretation: Reference-based pricing in British Columbia achieved a sustained reduction in drug expenditures, and no changes in overall use of antihypertensive therapy were observed. Further research is needed on the overall health and economic effects of such policies. [ABSTRACT FROM AUTHOR]

Background Increasing copayments for higher-priced prescription medications has been suggested as a means to help finance drug coverage for elderly patients, but evaluations of the impact of such policies are rare. The objective of this study was to analyze the effect of reference-based pricing of angiotensin- converting enzyme (ACE) inhibitors on drug utilization, cost savings and potential substitution with other medication classes. Methods We analyzed 36 months of claims data from British Columbia for 2 years before and 1 year after implementation of reference-based pricing (in January 1997). The 119 074 patients were community-living Pharmacare beneficiaries 65 years of age or older who used ACE inhibitors during the study period. The main outcomes were changes over time in use of ACE inhibitors, use of antihypertensive drugs and expenditures for antihypertensive drugs, as well as predictors of medication switching related to reference-based pricing. Results We observed a sharp decline (29%) in the use of higher-priced cost-shared ACE inhibitors immediately after implementation of the policy ( >p < 0.001). After a transition period, the post-implementation utilization rate for all ACE inhibitors was 11% lower than projected from pre-implementation data. However, overall utilization of antihypertensives was unchanged ( >p = 0.40). The policy saved $6.7 million in pharmaceutical expenditures during its first 12 months. Patients with heart failure or diabetes mellitus who were taking a cost-shared ACE inhibitor were more likely to remain on the same medication after implementation of reference-based pricing (OR 1.12 [95% confidence interval, CI, 1.06-1.19] and 1.28 [95% CI 1.20-1.36] respectively). Patients with low-income status were more likely than those with high-income status to stop all antihypertensive therapy (OR 1.65 [95% CI 1.43-1.89]), which reflects a general trend toward discontinuation of therapy among these patients even before implementation... [ABSTRACT FROM AUTHOR]

Objective. To quantify resource utilization and costs incurred for patients who received transdermal fentanyl as their first long-acting analgesic for non-malignant pain, and to compare these with utilization and costs for similar patients dispensed other long-acting oral opioids. Design. A retrospective matched cohort study using medical claims data from a large New England Insurer. Patients. We identified 478 patients without cancer who received transdermal fentanyl during 1995-1998. We selected patients who had no previous long-acting opioid dispensings and were enrolled during the 180 days before and 30 days following the initial dispensing. We used propensity scores to identify a matched comparison group of 478 long-acting oral opioid users. Results. Transdermal fentanyl and matched long-acting oral opioid users incurred identical median costs for outpatient medical services and prescriptions during 2 years of follow-up. A larger proportion of transdermal fentanyl patients were still taking their initial opioid analgesic at the end of the 2-year follow-up than were patients initially taking other long-acting opioids. Use of short-acting opioids tapered off more slowly among transdermal fentanyl patients than among long-acting opioid patients. In the first 6 months, the transdermal fentanyl patients had more hospital discharges than the long-acting oral opioid patients, but this difference appeared to reflect preexisting conditions. Conclusions. Users of fentanyl transdermal system and other long-acting opioids experienced essentially identical evolution of health services utilization and costs over a 2-year period. The choice of long-acting opioid analgesia does not appear to be a determinant of future medical costs. [ABSTRACT FROM AUTHOR]

Refractory ceramic fiber (RCF) is an energy-efficient, high-temperature insulation, used principally in industrial furnaces, heaters, and reactors. Prior to the 1980s, there were few publications dealing with the potential health effects of this material. However, with the advent of higher energy costs and the need for thermally efficient high-temperature insulating materials, production of RCF grew rapidly, as did interest in its potential health effects. This article provides a comprehensive and integrated review of the toxicology (in vitro and in vivo), epidemiology, and risk analysis literature of RCF. Based on the available literature, we conclude that an occupational exposure of 0.5 fibers per cubic centimeter (cm[sup 3]) [8-h time-weighted average (8-h TWA)] results in an occupational health risk no greater than 9.1 x 10[sup -5]. [ABSTRACT FROM AUTHOR]

A response by Alberto Ascherio, Shumin M. Zhang and Alexander M. Walker to a letter to the editor about their article "Hepatitis B Vaccination and the Risk of Multiple Sclerosis" in the February 1, 2001 issue is presented.

Background: Multivitamin supplementation in pregnant women may reduce the risks of cardiovascular defects, oral clefts, and urinary tract defects in their infants. We evaluated whether the folic acid component of multivitamins is responsible for the reduction in risk by examining the associations between maternal use of folic acid antagonists and these congenital malformations. Methods: We assessed exposure to folic acid antagonists that act as dihydrofolate reductase inhibitors and to certain antiepileptic drugs in 3870 infants with cardiovascular defects, 1962 infants with oral clefts, and 1100 infants with urinary tract defects and also in 8387 control infants with malformations the risk of which is not reduced after vitamin supplementation. Mothers were interviewed within six months after delivery about their medication use during pregnancy. Results: The relative risks of cardiovascular defects and oral clefts in infants whose mothers were exposed to dihydrofolate reductase inhibitors during the second or third month after the last menstrual period, as compared with infants whose mothers had no such exposure, were 3.4 (95 percent confidence interval, 1.8 to 6.4) and 2.6 (95 percent confidence interval, 1.1 to 6.1), respectively. The relative risks of cardiovascular defects, oral clefts, and urinary tract defects after maternal exposure to antiepileptic drugs were 2.2 (95 percent confidence interval, 1.4 to 3.5), 2.5 (95 percent confidence interval, 1.5 to 4.2), and 2.5 (95 percent confidence interval, 1.2 to 5.0), respectively. Use of multivitamin supplements containing folic acid diminished the adverse effects of dihydrofolate reductase inhibitors, but not that of antiepileptic drugs. Conclusions: Folic acid antagonists, which include such common drugs as trimethoprim, triamterene, carbamazepine, phenytoin, phenobarbital, and primidone, may increase the risk not only of neural-tube defects, but also of cardiovascular defects, oral clefts, and urinary tract defects. The folic acid component of multivitamins may reduce the risks of these defects. (N Engl J Med 2000;343:1608-14.) [ABSTRACT FROM AUTHOR]

The African population in South Africa is undergoing relatively rapid transition in lifestyle, with increasing proneness to western diseases. At the Medical University of Southern Africa (MEDUNSA), the majority of the African students come from homes where mainly cereal‐based diets are eaten. They are now exposed to ‘western’ foods. To throw light on the subsequent changes, between 1989 and 1993, 383 third year students underwent a practical course on nutritional assessment, which included determinations of anthropometry, 3 days’ estimated dietary intake record, and serum lipid analysis. Results indicated that their dietary risk levels for western diseases were now approaching the high levels prevailing in white populations. While the likelihood of influencing African students to meaningfully conform to a ‘prudent’ diet and lifestyle is remote, every endeavour must be made to fully inform them of the benefits likely to follow. [ABSTRACT FROM PUBLISHER]

Abstract: In a case-control study spanning five years' experience at Group Health Cooperative of Puget Sound, we could demonstrate no plausible association between the use of spermicides, oral contraceptives, Bendectin, or antibiotics prior to conception and the occurrence of 73 nontraumatic stillbirths. [ABSTRACT FROM AUTHOR]

Presents commentaries on issues related to pediatric care and health. Contraindications of birth control pills; Information on the billings method of contraception in adolescents; Age of onset of lactose intolerance in children; Blood pressure of children in the United States.

The article cites a study which presents findings on the relationship of childhood firesetting and DSM-III diagnosis in a representative sample of child psychiatric out-patients. The subjects for this diagnostic study were selected from 204 child psychiatric out-patients. For the purposes of this study, two comparison groups were used. The first group was the 32 firesetters and the second group consisted of 32 controls chosen from 172 non-firesetters. The study findings point to a significant association between firesetting and the DSM-III diagnosis of conduct disorder in children who were being seen in a child psychiatric out patient setting.

Focuses on a study conducted by the Framingham Heart Study using cohort analysis to determine whether obesity is the possible cause of knee osteoarthritis. Description of osteoarthritis; Difference in risks of getting osteoarthritis for both obese women and men; Observance of an association between antecedent obesity and both symptomatic and asymptomatic radiographic osteoarthritis.

Mentions a synthesis meeting on osteoporosis to be held in Milan, Italy in October 2000. How women are affected by osteoporosis; Clinical synthesis meetings being different from consensus meetings; Publication of papers from a joint clinical synthesis meeting on hormone replacement therapy in the `Journal of Epidemiology and Biostatistics.'

Background: Transcatheter implantation of the Rashkind PDA occluder is an alternative to conventional surgical closure of isolated patent ductus arteriosus. Neither the clinical outcomes nor the costs of these procedures have been formally compared. Methods: We performed a retrospective cohort study to evaluate the clinical outcomes within a seven-month period for comparable patients with patent ductus arteriosus who underwent either placement of an occluder or surgical closure. The patients were treated between 1982 and 1987 at 14 major North American centers where patent ductus arteriosus was closed predominantly by a surgical procedure or by the occluder technique. To estimate inpatient and follow-up costs, we multiplied the observed use of resources by 1989 unit costs based on hospital-accounting and physician-reimbursement data. Results: On the basis of cardiac auscultation at follow-up, the initial procedure resulted in closure of the ductus arteriosus in 77.3 percent of 185 patients in whom the occluder was implanted (95 percent confidence interval, 70.6 to 83.1 percent) and 99.8 percent of 446 surgical patients (95 percent confidence interval, 98.8 to 100.0 percent). Second procedures increased the percentage of successful closures to 87.6 percent (95 percent confidence interval, 81.9 to 92.0 percent) and 100.0 percent (95 percent confidence interval, 99.3 to 100.0 percent) for patients in the occluder and surgical groups, respectively. There were no deaths. Major complications occurred in 2.7 percent of the patients in whom the occluder was implanted (95 percent confidence interval, 0.9 to 6.2 percent) and 0.2 percent of the patients who underwent surgery (95 percent confidence interval, 0.0 to 1.2 percent); moderate complications in 16.8 percent (95 percent confidence interval, 11.7 to 22.9 percent) and 15.0 percent (95 percent confidence interval, 11.8 to 18.7 percent), respectively; and minor complications in 11.4 percent (95 percent confidence interval, 7.2 to 16.8 percent) and 24.9 percent (95 percent confidence interval, 20.9 to 29.2 percent). Including the cost of follow-up care, the mean estimated cost per case treated surgically was $8,838 (in 1989 U.S. dollars), as compared with $11,466 per case treated with the occluder technique. Sensitivity analyses based on our data identified no plausible situations in which the costs of surgery and of implantation of the occluder would be equal. Conclusions: The more effective and less costly surgical procedure was superior to transcatheter placement of the occluder for closure of isolated patent ductus arteriosus. Consequently, our results do not support the widespread dissemination of the occluder procedure for the management of this common congenital lesion. (N Engl J Med 1993;329:1517-23.) [ABSTRACT FROM AUTHOR]

Purpose: The present study describes the patterns and predictors of treatment persistence and adherence among patients who are diagnosed with glaucoma or as glaucoma suspects (based on claims codes). Design: A retrospective cohort study using health insurance claims data. Methods: Newly treated individuals with diagnosed glaucoma (n = 3623) and suspect glaucoma (n = 1677) were obtained from healthcare claims data in the Ingenix Research Database. For each of these two diagnostic groups, we calculated the duration of continuous treatment with the initially prescribed medication (persistence) and the prevalence of use of the initial medication at various time points (adherence). Four drug classes were included: β-blockers, α-agonists, carbonic anhydrase inhibitors, and prostaglandin analogs. Results: Nearly one half of the individuals who had filled a glaucoma prescription discontinued all topical ocular hypotensive therapy within six months, and just 37% of these individuals recently had refilled their initial medication at three years after the first dispensing. Prostaglandins were associated with better persistence than any other drug class, which was indicated by hazard ratios for discontinuation of prostaglandins compared with β-blockers of 0.40 (95% confidence interval, 0.35–0.44) for diagnosed patients and 0.44 (95% confidence interval, 0.37–0.52) for patients with suspect glaucoma. Prostaglandins showed a similar advantage in adherence. Furthermore, patients with diagnosed glaucoma were more likely to adhere to therapy than patients with suspect glaucoma (relative risk = 1.11; 95% confidence interval, 1.05–1.18). Conclusion: Persistence and adherence were substantially better with prostaglandins than with other drug classes, and patients with diagnosed open-angle glaucoma were more likely to adhere to treatment than suspected glaucoma. [Copyright &y& Elsevier]

Background: Reports of multiple sclerosis developing after hepatitis B vaccination have led to the concern that this vaccine might be a cause of multiple sclerosis in previously healthy subjects. Methods: We conducted a nested case–control study in two large cohorts of nurses in the United States, those in the Nurses' Health Study (which has followed 121,700 women since 1976) and those in the Nurses' Health Study II (which has followed 116,671 women since 1989). For each woman with multiple sclerosis, we selected as controls five healthy women and one woman with breast cancer. Information about hepatitis B vaccination was obtained by means of a mailed questionnaire and was confirmed by means of vaccination certificates. The analyses included 192 women with multiple sclerosis and 645 matched controls (534 healthy controls and 111 with breast cancer) and were conducted with the use of conditional logistic regression. Results: The multivariate relative risk of multiple sclerosis associated with exposure to the hepatitis B vaccine at any time before the onset of the disease was 0.9 (95 percent confidence interval, 0.5 to 1.6). The relative risk associated with hepatitis B vaccination within two years before the onset of the disease was 0.7 (95 percent confidence interval, 0.3 to 1.8). The results were similar in analyses restricted to women with multiple sclerosis that began after the introduction of the recombinant hepatitis B vaccine. There was also no association between the number of doses of vaccine received and the risk of multiple sclerosis. Conclusions: These results indicate no association between hepatitis B vaccination and the development of multiple sclerosis. (N Engl J Med 2001;344:327-32.) [ABSTRACT FROM AUTHOR]

Background: We sought to quantify the impact of patient characteristics on complications and health care costs associated with influenza and influenza-like illness (ILI) in a nonelderly population.Methods: Patients with medical reimbursement claims for influenza in the 1996-1997 season were identified from the automated database of a large private New England Insurer (NEI). Influenza care during the 21- day follow-up period was characterized according to age, gender, vaccine status, co-morbidities, prior influenza/ILI episodes, treatments, and recent health care costs and related diagnoses.Results: There were 6,241 patients. Approximately 20% had preexisting chronic lung disease. Overall, 23% had health care services for possible complications, among which respiratory diagnoses were the most common (13%). Two percent of the influenza/ILI episodes involved hospitalization, with a median stay of five days. Factors most strongly predictive of hospitalizations and complications were preexisting malignancy (hospitalizations OR = 3.7 and complications OR = 2.4), chronic heart disease (OR = 3.2 and OR = 1.8), diabetes (OR = 2.2 and OR = 1.7) and recent illnesses that would have counted as complications had they occurred during an influenza/ILI episode (hospitalizations OR = 3.2 and complications OR = 1.5). The same factors affected influenza-related costs and total costs of care as dramatically as they affected complication rates.Conclusions: Influenza/ILI-related costs are driven by the characteristics that predict complications of influenza. Patients with chronic illness and those with recent acute respiratory events are the most likely to experience complications and hospitalizations. [ABSTRACT FROM AUTHOR]

Announces a conference being developed on women's health by `The Lancet,' the European Institute of Oncology, and the Harvard School of Public Health with assistance from the United Kingdom Medical Research Council and the Italian Istituto Superiore di Sanita. Subject being hormone-replacement therapy; The meeting to focus on issues, such as menopausal symptoms and cardiovascular disease in women.