Varenicline for smoking cessation: nausea severity and variation in nicotinic receptor genes.

This study evaluated association between common and rare sequence variants in 10 nicotinic acetylcholine receptor subunit genes and the severity of nausea 21 days after initiating the standard, Food and Drug Administration-approved varenicline regimen for smoking cessation. A total of 397 participants from a randomized clinical effectiveness trial with complete clinical and DNA resequencing data were included in the analysis (mean age=49.2 years; 68.0% female). Evidence for significant association between common sequence variants in CHRNB2 and nausea severity was obtained after adjusting for age, gender and correlated tests (all P(ACT)<0.05). Individuals with the minor allele of CHRNB2 variants experienced less nausea than did those without the minor allele, consistent with previously reported findings for CHRNB2 and the occurrence of nausea and dizziness as a consequence of first smoking attempt in adolescents, and with the known neurophysiology of nausea. As nausea is the most common reason for discontinuance of varenicline, further pharmacogenetic investigations are warranted.

Value of antimicrobials in the prevention and treatment of tuberculosis in the United States.

OBJECTIVE: To estimate the economic value of antimicrobials for the prevention and treatment of tuberculosis in the United States from 1954 through 1997. DESIGN: Published sources were used to estimate the burden of illness (direct medical costs, reductions in quality of life, and years of life lost) from active tuberculosis (TB) cases diagnosed between 1954 and 1997. Published literature concerning the pre-antimicrobial incidence rate and treatment of TB were extrapolated to estimate the burden of illness that would have occurred in the absence of antimicrobials. RESULTS: Between 1954 and 1997, the use of antimicrobials reduced the number of newly diagnosed cases of active TB by 32% (relative to the number that would have occurred in the absence of antimicrobials), the number of mortalities by 81%, the number of life-years lost by 87%, and the cost of medical treatment by 76%. The total financial burden of illness over this time period (including the value of lost life-years) was reduced from $894 billion (in 1997 dollars) to $128 billion. CONCLUSION: TB antimicrobials had a substantial health impact in the US from 1954 to 1997. This quantitative assessment of the economic impact of innovative biopharmaceutical products demonstrates the importance of continuing medical innovation.

In vitro investigation of host resistance to Toxoplasma gondii infection in microglia of BALB/c and CBA/Ca mice.

Toxoplasmic encephalitis (TE) is a life-threatening disease of immunocompromised individuals and has increased in prevalence as a consequence of AIDS. TE has been modeled in inbred mice, with CBA/Ca mice being susceptible and BALB/c mice resistant to the development of TE. To better understand the innate mechanisms in the brain that play a role in resistance to TE, nitric oxide (NO)-dependent and NO-independent mechanisms were examined in microglia from BALB/c and CBA/Ca mice and correlated with the ability of these cells to inhibit Toxoplasma gondii replication. These parameters were measured 48 h after stimulation with lipopolysaccharide (LPS) gamma interferon (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), or combinations of these inducers in T. gondii-infected microglia isolated from newborn mice. CBA/Ca microglia consistently produced less NO than did BALB/c microglia after stimulation with LPS or with IFN-gamma plus TNF-alpha, and they inhibited T. gondii replication significantly less than did BALB/c microglia. Cells of both strains treated with IFN-gamma alone significantly inhibited uracil incorporation by T. gondii, and N(G)-monomethyl-L-arginine (NMMA) treatment did not reverse this effect. In cells treated with IFN-gamma in combination with other inducers, NMMA treatment resulted in only partial recovery of T. gondii replication. This IFN-gamma-dependent inhibition of replication was not due to generation of reactive oxygen species or to increased tryptophan degradation. These data suggest that NO production and an IFN-gamma-dependent mechanism contribute to the inhibition of T. gondii replication after in vitro stimulation with IFN-gamma plus TNF-alpha or with LPS. Differences in NO production but not in IFN-gamma-dependent inhibition of T. gondii replication were observed between CBA/Ca and BALB/c microglia.

Direct medical cost of chronic obstructive pulmonary disease in the U.S.A.

The aim of this study was to estimate the direct medical costs of chronic obstructive pulmonary disease (COPD) in the United States using a public-payor perspective. Cost estimates were derived separately for 10 components of care using national survey databases and valued using Medicare and Medicaid reimbursement rates. COPD affects 15 million people in the U.S.A. and the total annual U.S. payment for care is $6.6 billion. Approximately one-third ($2.3 billion) is due to the cost of long-term oxygen therapy, one-quarter is attributed to hospitalizations and inpatient physician services ($1.9 billion), and one-seventh ($942 million) is due to nursing home stays. Other annual costs are outpatient physician visits ($480 million), prescription medications ($462 million), home healthcare ($309 million), emergency department visits ($148 million), outpatient diagnostic procedures ($55 million) and hospice care ($28 million). The cost of COPD is therefore considerable. The significant expenditure for long-term oxygen therapy indicates that disease severity is a major driver of costs. However, the cost of hospitalizations, nursing home stays, emergency department and physician visits are not insignificant.

A comparison of three approaches for attributing hospitalizations to specific diseases in cost analyses.

OBJECTIVES: Calculations of healthcare costs rarely disclose the specific approach used to allocate the cost of hospitalizations by diagnosis. However, the type of approach used can have a major impact on the findings in the case of significant comorbidities. The present analyses compared three approaches for attributing Medicare DRG reimbursements (which were used as surrogates for average costs) for hospitalization by diagnosis. METHODS: Medical resource utilization data from the National Hospital Discharge Survey were analyzed using each of three allocation approaches: a) attributing 100% of the cost of hospitalization to the disease when it was the first-listed diagnosis; b) attributing a portion of the cost of hospitalization to the disease, depending on its position in the list of diagnoses and the relevance of any comorbidities; and c) an incremental analysis of cost based upon the hospitalization experiences of an age and gender matched cohort. These three approaches were applied to the cost of hospitalization for chronic obstructive pulmonary disease (COPD). RESULTS: The first approach projected 206,098 hospitalizations at $3,449 per hospitalization for a projected U.S. annual total of $711 million. The second approach projected 681,547 hospitalizations at $3,205 per hospitalization for a projected U.S. annual total of $2.2 billion. The third approach also projected 681,547 hospitalizations, but at $2,361 per hospitalization, for a projected U.S. annual total of $1.6 billion. CONCLUSIONS: Expanding from the example on COPD, the limitations of each approach are described and their applications to other conditions are presented.

The direct cost of rheumatoid arthritis.

OBJECTIVES: This analysis estimated the direct cost of rheumatoid arthritis (RA) from a societal perspective. METHODS: Primary and secondary data sets were used to determine the rate of medical resource utilization. National average Medicare or Medicaid reimbursement rates were used to value direct costs (in 1994 dollars). RESULTS: Persons with RA have, on average, dollar 1702 in direct costs for treating RA annually. More than half of the total cost is for medications. Nursing home care accounts for nearly one fifth of the cost and hospitalizations and ambulatory care (combined) comprise another fifth of the total cost. Travel to medical appointments and medical supplies make up the remaining 10%. The projected annual US direct costs are dollar 3.6 billion for treating RA. CONCLUSIONS: The health care utilization in persons with RA is frequent and includes a number of components leading to high annual direct cost.

Major costs associated with pressure sores.

Cost drivers in the treatment of full-thickness pressure sores were identified from the literature, Medicare data tapes and interviews with health-care providers. The following were identified as cost drivers in pressure sore treatment: nursing time related to wound care; nursing time devoted to patient position changes; dressing products; patient support devices; antibiotics; room charges for nursing home care; doctor visits for nursing home and home care patients; surgical debridement for nursing home and home care patients; hospital admissions for medical treatment for pressure sores; admissions for surgical treatment for pressure sores; and additional costs for hospital stays when patients who are admitted for other diagnoses develop sores. These cost drivers may be useful to health-care providers in developing cost-effective strategies for treating and preventing pressure sores.

Ambulatory monitoring of heart rate and blood pressure during the first week after smoking cessation.

To investigate the timecourse of cardiovascular changes immediately after smoking cessation, 16 subjects wore ambulatory monitors on alternate days during a 1-week residential smoking cessation program. Heart rate was significantly elevated at the time of cessation, then declined steadily until 6 h after cessation, when it reached the level of subsequent nonsmoking days. Systolic and diastolic blood pressures were elevated to a lesser degree for the same period after cessation. The timing of the decline in heart rate and blood pressure was coincident with the timing of an increase in withdrawal symptoms and has implications for laboratory and epidemiologic studies.

Effect of smoking cessation and relapse on cardiovascular levels and reactivity.

This study was designed to investigate the effect of smoking cessation on heart rate, blood pressure, and finger temperature absolute levels and reactivity to a range of laboratory challenges. The 148 quitters (mean age = 43.3 years, mean amount smoked = 24.9 cigarettes per day, mean years smoked = 25.2) completed three assessments: an average of 4 +/- 2.8 days before cessation (Exam 1), an average of 2 +/- 1.0 days after cessation (Exam 2), and an average of 20 +/- 5.5 days after cessation (Exam 3). A nonsmoking group (n = 39) was similarly assessed three times to control for effects related to repeated testing. Comparison of group changes from Exam 1 to Exam 2 indicated that smoking cessation produced a significant decrease in heart rate during rest and during all stressors (mean = -8.9 bpm). Those quitters who remained abstinent or smoked occasionally showed minimal changes in heart rate from Exam 2 to Exam 3, but those quitters who returned to their previous smoking level showed a significant increase in heart rate from Exam 2 to Exam 3. None of the indices of cardiovascular reactivity changed across exams, and neither did absolute levels of blood pressure or finger temperature at rest or during stressors. The possible mechanisms producing a selective heart rate decline after smoking cessation in the absence of pressor or vasodilation effects are discussed.

Cardiovascular reactivity as a predictor of relapse in male and female smokers.

This study examined the role of psychophysiological reactivity to general stressors measured before smoking cessation as a predictor of relapse in individuals who quit for a minimum of 12 hr and were then followed for a 12-month interval. The study group consisted of 132 (56.9%) female and 100 (43.1%) male participants in a formal smoking cessation program. The reactivity measures were taken while the Ss were still smoking. Heart rate and blood pressure measurements were taken while Ss were resting, performing mental arithmetic, and delivering a speech and after Ss had been standing for 2 min. In the sample as a whole and for women, a higher level of systolic blood pressure reactivity to the cognitive challenge was associated with a shorter time to relapse (p < .05). In men, greater systolic blood pressure decline to standing was significantly associated with a shorter time to relapse (p < .05).

A variance formula for gene mutation studies using agar plates.

Previous attempts to derive a formula for the variance of the estimated mutant fraction have assumed (without providing justification) that variance components due to treatment, growth and dilution, and plating, are additive. We have derived a variance formula that does not depend on this assumption. Our formula also includes variability attributable to imprecise counting of cells to be plated in the non-selective conditions.

A confidence interval for mutant frequency in assays using microtiter wells.

Previous attempts to derive a confidence interval for the estimated mutant fraction in assays using microtiter wells have not considered the variance introduced by the early growth and dilution steps. We derive a confidence interval that includes these sources of variability.