Pharmacogenomic biomarkers do not predict response to drotrecogin alfa in patients with severe sepsis.

PURPOSE: To explore potential design for pharmacogenomics trials in sepsis, we investigate the interaction between pharmacogenomic biomarkers and response to drotrecogin alfa (activated) (DrotAA). This trial was designed to validate whether previously identified improved response polymorphisms (IRPs A and B) were associated with an improved response to DrotAA in severe sepsis. METHODS: Patients with severe sepsis at high risk of death, who received DrotAA or not, with DNA available were included and matched to controls adjusting for age, APACHE II or SAPS II, organ dysfunction, ventilation, medical/surgical status, infection site, and propensity score (probability that a patient would have received DrotAA given their baseline characteristics). Independent genotyping and two-phase data transfer mitigated bias. The primary analysis compared the effect of DrotAA in IRP+ and IRP- groups on in-hospital 28-day mortality. Secondary endpoints included time to death in hospital; intensive care unit (ICU)-, hospital-, and ventilator-free days; and overall DrotAA treatment effect on mortality. RESULTS: Six hundred and ninety-two patients treated with DrotAA were successfully matched to 1935 patients not treated with DrotAA. Genotyping was successful for 639 (DrotAA) and 1684 (nonDrotAA) matched patients. The primary hypothesis of a genotype-by-treatment interaction (assessed by conditional logistic regression analysis) was not significant (P = 0.30 IRP A; P = 0.78 IRP B), and there was no significant genotype by treatment interaction for any secondary endpoint. CONCLUSIONS: Neither IRP A nor IRP B predicted differential response to DrotAA on in-hospital 28-day mortality. ClinicalTrials.gov registration NCT01486524.

Hypoglycaemia in sulphonylurea-treated subjects with type 2 diabetes undergoing Ramadan fasting: a five-country observational study.

OBJECTIVES: To determine the incidence of hypoglycaemia during Ramadan in Muslim subjects with type 2 diabetes treated with a sulphonylurea. METHODS: In an observational study, eligible subjects were Muslims with type 2 diabetes (age ≥18 years) who were treated with glimepiride, gliclazide, or glibenclamide with or without metformin and who expressed their intention to fast during Ramadan in 2009. Subjects were recruited by clinicians in India, Malaysia, Israel, the United Arab Emirates (UAE), and Saudi Arabia. Each day during Ramadan, patients completed diary cards, which collected information regarding hypoglycaemic symptoms and complications, time from last meal and from last medication, self-monitored blood glucose measurements, and need for assistance. The overall incidence of symptomatic hypoglycaemia recorded during Ramadan was the primary endpoint of interest. RESULTS: Of the enrolled subjects (N = 1397), 1378 returned their diary cards at study end and were included in the analysis. Overall, 89% of subjects who expressed their intention to fast prior to Ramadan reported that they observed the fast during Ramadan. A total of 271 subjects (19.7%) experienced one or more symptomatic hypoglycaemic events during Ramadan, with incidences of 25.6%, 16.8%, and 14.0% observed in subjects treated with glibenclamide, glimepiride, and gliclazide, respectively. By country, the highest incidence of hypoglycaemia was reported by subjects from Israel (40%) followed by those from Malaysia (24%), the UAE (18%), India (13%), and Saudi Arabia (10%). The overall incidence of severe hypoglycaemic events (i.e., events requiring medical or non-medical assistance) was 6.7%, with the highest incidence occurring in the glibenclamide group. LIMITATIONS: This was an observational study and as such subjects were not randomised to treatments. While baseline measures appeared comparable, it is possible that differences in measured and unmeasured patient characteristics (e.g., measures of glycaemic control) could partially explain these results. Lastly, no inferential testing was performed on the comparisons between sulphonylurea types and/or countries. CONCLUSIONS: In this five-country observational study, nearly 20% of sulphonylurea-treated Muslim subjects with type 2 diabetes experienced symptomatic hypoglycaemia while fasting during Ramadan, with variations across sulphonylureas and countries.

The relation between disease severity and cost of caring for patients with Alzheimer disease in Canada.

OBJECTIVES: to characterize the cost of caring for an outpatient in Canada with Alzheimer disease (AD) based on disease severity, and to describe how costs change with increases in disease severity. METHOD: community-dwelling patients with mild-to-moderate AD were enrolled in a 3-year, naturalistic, observational study. Assessments included cognition (Mini Mental Status Examination), global ratings (Global Deterioration Scale [GDS]), and daily function (Functional Autonomy Measurement System) as part of the Canadian Outcomes Study in Dementia. Direct (medical and nonmedical) and indirect costs were collected using resource use questionnaires. Costs at baseline were compared with costs at follow-up and correlated with disease severity. RESULTS: total costs associated with treating AD were significantly higher with greater disease severity. The mean total cost to treat patients with very mild AD (GDS = 2) was $367 per month, compared with $4063 per month for patients with severe or very severe AD (GDS = 6). From baseline to follow-up, the greatest changes in cost were observed in the group of patients with the most severe AD as measured by all scales. The largest component of total cost was indirect costs at most severity levels, though medication costs contributed the most in patients with very mild AD. Significant independent contributors to cost were being female, having more impaired activities of daily living, and exhibiting more neuropsychiatric symptoms. CONCLUSIONS: costs for treating a patient with AD were strongly associated with disease severity, even though none of the patients were institutionalized. Delaying the progression of AD may reduce indirect costs and burden to caregivers.

The contribution of neuropsychiatric symptoms to the cost of dementia care.

OBJECTIVE: To estimate the contribution of behavioral and psychological symptoms of dementia (BPSD) to the costs of care. METHOD: A one-year prospective study of resource utilization recorded monthly by 500 caregivers of community dwelling patients with dementia. The effect of behavior on total, direct and indirect costs of care was examined. RESULTS: The total cost of care was $1,298 per month and there was a significant independent relationship between costs and BPSD. The incremental cost of a one point increase in Neuropsychiatric Inventory score was $30 per month (95% CI: $19-$41). CONCLUSION: BPSD contribute significantly to the overall costs of dementia care. Interventions targeted at BPSD may help to reduce the staggering societal costs of this illness.

A cohort study of thyroid cancer and other thyroid diseases after the Chornobyl accident: objectives, design and methods.

The thyroid gland in children is one of the organs that is most sensitive to external exposure to X and gamma rays. However, data on the risk of thyroid cancer in children after exposure to radioactive iodines are sparse. The Chornobyl accident in Ukraine in 1986 led to the exposure of large populations to radioactive iodines, particularly (131)I. This paper describes an ongoing cohort study being conducted in Belarus and Ukraine that includes 25,161 subjects under the age of 18 years in 1986 who are being screened for thyroid diseases every 2 years. Individual thyroid doses are being estimated for all study subjects based on measurement of the radioactivity of the thyroid gland made in 1986 together with a radioecological model and interview data. Approximately 100 histologically confirmed thyroid cancers were detected as a consequence of the first round of screening. The data will enable fitting appropriate dose-response models, which are important in both radiation epidemiology and public health for prediction of risks from exposure to radioactive iodines from medical sources and any future nuclear accidents. Plans are to continue to follow-up the cohort for at least three screening cycles, which will lead to more precise estimates of risk.