Data Linkages for Wildfire Exposures and Human Health Studies: A Scoping Review.

Wildfires are increasing in frequency and intensity, with significant consequences that impact human health. A scoping review was conducted to: (a) understand wildfire-related health effects, (b) identify and describe environmental exposure and health outcome data sources used to research the impacts of wildfire exposures on health, and (c) identify gaps and opportunities to leverage exposure and health data to advance research. A literature search was conducted in PubMed and a sample of 83 articles met inclusion criteria. A majority of studies focused on respiratory and cardiovascular outcomes. Hospital administrative data was the most common health data source, followed by government data sources and health surveys. Wildfire smoke, specifically fine particulate matter (PM2.5), was the most common exposure measure and was predominantly estimated from monitoring networks and satellite data. Health data were not available in real-time, and they lacked spatial and temporal coverage to study health outcomes with longer latency periods. Exposure data were often available in real-time and provided better temporal and spatial coverage but did not capture the complex mixture of hazardous wildfire smoke pollutants nor exposures associated with non-air pathways such as soil, household dust, food, and water. This scoping review of the specific health and exposure data sources used to underpin these studies provides a framework for the research community to understand: (a) the use and value of various environmental and health data sources, and (b) the opportunities for improving data collection, integration, and accessibility to help inform our understanding of wildfires and other environmental exposures.

Gut and intestinal passage time in the Rainbow Skink (Trachylepis margaritifer): implications for stress measures using faecal analysis.

Stress levels in organisms provide a rapid measure for assessing population health. Handling and capture stress, however, cause error in blood measures, so this method is rapidly being replaced by assessing levels of stress metabolites in faeces. This eliminates the source of error because there is a lag period between stress perception and the resultant stress metabolite accumulation within faeces. This lag period is correlated with specific intestinal passage time, a measure that can vary greatly between taxa, particularly amongst ectotherms. Due to two deleterious consequences associated with extended exposure of the metabolites to the intestinal environment, species that exhibit long and variable intestinal passage times are not good candidates for metabolite studies. We measured gut and intestinal passage times in Trachylepis margaritifer to ascertain whether it would be an appropriate candidate for stress metabolite studies. We first tested if barium sulphate in the meal had an effect on gut passage time at three ambient temperatures (25, 27 and 32 °C). Barium sulphate had no effect; however, temperature had a significant effect with an unexpected pattern: gut passage time was fastest at 32 °C but was slower at 27 °C than at 25 °C. We then used X-ray technology and barium sulphate-loaded meals to measure gut and intestinal passage times at 25 and 27 °C. This allowed us to observe which parts of the digestive process were responsible for increased passage times at 27 °C: the faster passage time at 25 °C was due to faster intestinal passage time; there was no difference in gastric emptying time. We assess the species to be a suitable candidate for studies using faeces to measure stress. It is imperative however, that the effect of temperature on passage rates is known and taken into account in such studies.

Pharmacokinetics of rosiglitazone in patients with end-stage renal disease.

The pharmacokinetics and tolerability of a single 8-mg oral dose of rosiglitazone, an anti-diabetic agent, were compared in 10 long-term haemodialysis patients and 10 healthy volunteers. Haemodialysis patients received rosiglitazone 4 h after haemodialysis (non-dialysis day) and 3 h before haemodialysis (dialysis day). Haemodialysis did not influence rosiglitazone pharmacokinetics, and dialytic clearance was low (0.10 1/h). The mean area under the concentration-time curve (AUC(0-infinity)), the maximum observed plasma concentration (Cmax) and the half-life for rosiglitazone were similar in haemodialysis patients (non-dialysis day) and healthy individuals (2192 +/- 598 ng.h/ml versus 2388 +/- 494 ng.h/ml, 338 +/- 114 ng/ml versus 373 +/- 95 ng/ml, and 3.70 +/- 0.75 h versus 3.81 +/- 0.86 h, respectively). AUC(0-infinity) and Cmax were not markedly influenced by haemodialysis. Rosiglitazone dose adjustments are not warranted in patients with type 2 diabetes with end-stage renal failure on haemodialysis.

Lack of effect of rosiglitazone on the pharmacokinetics of oral contraceptives in healthy female volunteers.

The effect of rosiglitazone (Avandia [BRL 49653C]) on the pharmacokinetics of ethinylestradiol and norethindrone was evaluated after repeat dosing of rosiglitazone with an oral contraceptive (OC; Ortho-Novum 1/35 containing norethindrone 1 mg and ethinylestradiol 0.035 mg) in a randomized, double-blind, placebo-controlled crossover study. Thirty-four healthy female volunteers received oral rosiglitazone (RSG) 8 mg + OC or matched placebo (P) + OC daily on days 1 to 14 of a 28-day OC dosing cycle; the alternate regimen was administered during a second cycle. Ethinylestradiol and norethindrone pharmacokinetics were determined from plasma concentrations on day 14. Lack of pharmacokinetic effect was prospectively defined as 90% CI for the point estimate (PE) of the ratio (RSG + OC):(P + OC) contained within a 20% equivalence range for both ethinylestradiol and norethindrone (analyzed by ANOVA). For RSG + OC and P + OC, respectively, mean ethinylestradiol AUC(0-24) was 1126 and 1208 pg.h/mL (PE: 0.92; 90% CI: 0.88-0.97), and mean norethindrone AUC(0-24) was 178 and 171 ng.h/mL (PE: 1.04; 90% CI: 1.00-1.07). Thus, rosiglitazone had no significant effects on the pharmacokinetics of ethinylestradiol or norethindrone. Coadministration of rosiglitazone with OCs does not induce metabolism of these synthetic sex steroids and is not expected to impair the efficacy of OCs or hormone replacement therapy.

The effect of acarbose on the pharmacokinetics of rosiglitazone.

OBJECTIVES: To investigate whether treatment with acarbose alters the pharmacokinetics (PK) of coadministered rosiglitazone. METHODS: Sixteen healthy volunteers (24-59-years old) received a single 8-mg dose of rosiglitazone on day 1, followed by 7 days of repeat dosing with acarbose [100 mg three times daily (t.i.d.) with meals]. On the last day of acarbose t.i.d. dosing (day 8), a single dose of rosiglitazone was given with the morning dose of acarbose. PK profiles following rosiglitazone dosing on days 1 and 8 were compared, and point estimates (PE) and associated 95% confidence intervals (CI) were calculated. RESULTS: Rosiglitazone absorption [as measured with peak plasma concentration (Cmax) and time to peak concentration (Tmax)] was unaffected by acarbose. The area under the concentration-time curve from time zero to infinity [AUC(0-infinity)] was on average 12% lower (95% CI-21%, -2%) during rosiglitazone + acarbose coadministration and was accompanied by an approximate 1-h (23%) reduction in terminal elimination half-life t1/2 (4.9 h versus 3.8 h). This small decrease in AUC(0-infinity) appears to be due to an alteration in systemic clearance of rosiglitazone and not changes in absorption. These observed changes in AUC(0-infinity) and t1/2 are not likely to be clinically relevant. Coadministration of rosiglitazone and acarbose was well tolerated. CONCLUSION: Acarbose administered at therapeutic doses has a small, but clinically insignificant, effect on rosiglitazone pharmacokinetics.

Absorption, disposition, and metabolism of rosiglitazone, a potent thiazolidinedione insulin sensitizer, in humans.

Rosiglitazone is a potent peroxisome proliferator-activated receptor gamma agonist that decreases hyperglycemia by reducing insulin resistance in patients with type 2 diabetes mellitus. The disposition of (14)C-labeled rosiglitazone was determined after oral and i.v. dosing of rosiglitazone solution, and the disposition of nonradiolabeled rosiglitazone was determined after oral dosing of tablets in this open-label, three-part, semirandomized, crossover study. The absorption of rosiglitazone was rapid and essentially complete, with absolute bioavailability estimated to be approximately 99% after oral tablet dosing and approximately 95% after oral solution dosing, and clearance was primarily metabolic. The time to maximal concentration of radioactivity and the elimination half-life for two metabolites in plasma were significantly longer than for rosiglitazone itself (4-6 h versus 0. 5-1 h, and ca. 5 days versus 3-7 h). Radioactivity was excreted primarily via the urine ( approximately 65%) and was excreted similarly after oral and i.v. dosing. The major routes of metabolism were N-demethylation and hydroxylation with subsequent conjugation, of which neither was affected by the route of drug administration. The major metabolites, those of intermediate importance, and nearly all of the trace metabolites in humans have been identified previously in preclinical studies. Rosiglitazone was well tolerated in all formulations.

Rosiglitazone does not affect the steady-state pharmacokinetics of digoxin.

Rosiglitazone is a potent insulin-sensitizing oral hypoglycemic agent of the thiazolidinedione class that works through activation of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) nuclear receptor and improves glycemic control in patients with non-insulin-dependent diabetes mellitus. The potential for a drug-drug interaction with oral digoxin was investigated. Subjects received both of the study regimens in a random sequence: digoxin 0.375 mg plus matching placebo for rosiglitazone orally each morning for 14 days or digoxin 0.375 mg plus 8 mg rosiglitazone orally each morning for 14 days. There was a 14-day washout period between sessions. Blood and urine were collected over 24 hours beginning on the morning of day 14 for measurement of digoxin concentrations. An equivalence statistical approach was used, with rosiglitazone considered to have no effect on the pharmacokinetics of digoxin if the 90% confidence interval (CI) for the ratio of digoxin plus rosiglitazone relative to digoxin plus placebo was completely contained within the range (0.80, 1.25) for the primary end points, AUC(0-24), and C24. Digoxin AUC(0-24) and C24 values were similar for digoxin 0.375 mg plus matching placebo (18.5 ng.h/mL and 0.579 ng/mL, respectively) and digoxin 0.375 mg plus rosiglitazone (19.1 ng.h/mL and 0.594 ng/mL, respectively). Point estimates were 1.05 (90% CI: 1.01, 1.10) for AUC(0-24) and 1.04 (90% CI: 0.98, 1.11) for C24. Oral and renal clearance were also similar between regimens. Digoxin alone or in combination with rosiglitazone was safe and well tolerated. The most common adverse experience was headache. Coadministration of digoxin with rosiglitazone had no significant effect on the safety or steady-state pharmacokinetics of digoxin.

Rosiglitazone has no clinically significant effect on nifedipine pharmacokinetics.

To examine the effects of repeat oral dosing of rosiglitazone on the pharmacokinetics of nifedipine, a prototype CYP3A4 substrate, a randomized, open-label, crossover study was performed with two treatment phases separated by a washout period of at least 14 days. Twenty-eight healthy male volunteers received either a single 20 mg oral nifedipine dose or rosiglitazone 8 mg orally once daily for 14 days with a single 20 mg oral nifedipine dose administered on day 14. Plasma nifedipine concentrations were determined over the 24-hour period following administration of the nifedipine doses. Lack of effect was defined as the demonstration that the 90% CI was contained entirely within a symmetrical 30% range either side of unity on the loge-scale. Following rosiglitazone + nifedipine administration, the area under the nifedipine concentration-time curve from time zero to infinity (AUC(0-infinity)) was 13% lower than that after administration of nifedipine alone. This difference in nifedipine AUC(0-infinity) was not deemed to be clinically significant since the 90% CI was contained within the protocol-defined 30% range (point estimate for ratio of geometric means 0.87; 90% CI: 0.79, 0.96). Rosiglitazone had no marked effect on nifedipine peak plasma concentration (point estimate: 0.99; 90% CI: 0.73, 1.34) or time to peak concentration compared with nifedipine alone. Rosiglitazone coadministration produced a small decrease in the mean nifedipine half-life (point estimate: -0.77; 90% CI: mean difference -1.29 h, -0.25 h). Both treatment regimens were well tolerated and associated with a favorable safety profile. Rosiglitazone, at the highest dose used in clinical studies, produced a small, clinically insignificant decrease in nifedipine exposure. The very small effect on nifedipine pharmacokinetics suggests that rosiglitazone is an extremely weak inducer of CYP3A4, a characteristic that distinguishes rosiglitazone from troglitazone.

The effect of low-dose cimetidine (200 mg twice daily) on the pharmacokinetics of theophylline.

The potential for nonprescription cimetidine (200 mg twice daily) to affect the pharmacokinetics of sustained-release (SR) theophylline was assessed in 26 male subjects, 13 smokers and 13 nonsmokers. This was a concentration-controlled drug interaction study in which the subjects were administered a dose of SR theophylline every 12 hours to provide a mean steady-state concentration between 8 and 15 micrograms/ml. To determine individual theophylline dose, a test dose of aminophylline was administered, and baseline theophylline pharmacokinetics were determined. Subjects remained on SR theophylline for 23 days and were treated in the following sequence: run-in phase (4 days), treatment 1 (7 days), washout (5 days), and treatment 2 (7 days). During the treatment phases, subjects received cimetidine (200 mg at approximately 08:00 and 12:00) or placebo for 7 days in a randomized crossover fashion. Theophylline pharmacokinetics were determined on days 1, 4, and 7 of both treatment phases. A large day-to-day variability in the oral clearance of theophylline was evident for the theophylline-placebo treatment and the theophylline-cimetidine treatment. Nonprescription strength cimetidine resulted in a mean 5% decrease in theophylline oral clearance on day 1 and a mean 12% decrease on days 4 and 7 combined. There were no significant differences in the cimetidine-theophylline interaction between smokers and nonsmokers. Oral clearance during the nighttime dosing interval was 13% greater than the daytime oral clearance for nonsmokers and 22% greater for smokers, showing a greater circadian rhythm for smokers. In summary, nonprescription doses of cimetidine (400 mg/day) have the potential to produce small changes in theophylline concentrations during steady-state dosing with SR theophylline; however, this effect appears less than changes that occur as a consequence of theophylline's intrasubject variability.

Safety and pharmacokinetics of an intramuscular monoclonal antibody (SB 209763) against respiratory syncytial virus (RSV) in infants and young children at risk for severe RSV disease.

We conducted a multicenter, double-blind, placebo-controlled, randomized trial of a humanized monoclonal antibody against a respiratory syncytial virus (RSV) fusion protein (SB 209763) to evaluate its safety, pharmacokinetics, and fusion inhibition and neutralization titers. Forty-three infants who were either delivered prematurely (

Effect of age and gender on the pharmacokinetics of eprosartan.

AIMS: To compare the pharmacokinetics of eprosartan between young (18-45 years) and elderly (65 years) men and between young men and young, premenopausal women (18-45 years). METHODS: Twenty-four subjects (eight subjects/group) received a single 200 mg eprosartan oral dose followed by serial blood sampling over 24 h. RESULTS: Eprosartan was safe and well tolerated. There were no apparent differences in the pharmacokinetics of eprosartan between young females and young males or in the plasma protein binding of eprosartan (98%) for the three groups. On average, AUC (0,infinity) and Cmax values were approximately 2-fold higher in elderly men than young men [AUC (0,infinity) 95% CI: 1.22, 4.34; Cmax 95% CI: 0.98, 4.001. Similarly, unbound AUC (0,infinity) and Cmax values were, on average, approximately 2-fold higher in elderly men than young men [unbound AUC (0,infinity) 95% CI: 1.29, 4.44; unbound Cmax 95% CI: 1.02, 4.12]. tmax was delayed in the elderly men compared with young men, with a median difference of 2.5 h (95% CI: 1.00, 3.01 h). CONCLUSIONS: No gender differences were observed in the pharmacokinetics of eprosartan. There were approximately two fold higher AUC and Cmax values for eprosartan observed in elderly men as compared with young men, most likely due to increased bioavailability of eprosartan in the elderly. Based on the excellent safety profile in the elderly in Phase III clinical trials (doses up to 1200 mg eprosartan) eprosartan can be safely administered to elderly hypertensive patients without an initial dose adjustment. Subsequently, the dose of eprosartan, as for other antihypertensive agents, may be individualized based on tolerability/response.

Response of spinal cord blood flow to the nitric oxide inhibitor nitroarginine.

OBJECTIVE: The extent to which nitric oxide (NO) is involved in the modulation of spinal cord blood flow (SCBF) in the uninjured and injured cord is unknown. To elucidate these questions, the following experiments in anesthetized rats were conducted. METHODS: Because NO is an unstable free radical with a half-life of seconds, its role can be understood through the study of the NO synthase inhibitor L-NG-nitroarginine (L-NOARG). L-NOARG was administered intravenously for 30 minutes at a dose of 100 or 500 micrograms/kg/min in 12 and 10 uninjured animals, respectively. SCBF fluctuations at C7-T1 were measured using laser doppler flowmetry. In a second set of 12 rats, L-NOARG (500 micrograms/kg/min) was administered 10 minutes before spinal cord injury using a modified aneurysm clip at C7-T1 and continued for 30 minutes thereafter. RESULTS: In the uninjured animals, L-NOARG was associated with a dose-dependent increase in mean arterial pressure of 20 to 80% above baseline (P = 0.0001), together with a dose-related decrease in SCBF (P = 0.0373). In the injured animals, L-NOARG was associated with a 48% increase in mean arterial pressure. With L-NOARG, the changes in SCBF from baseline after injury were similar to those of noninjured controls (n = 25) and significantly less than injury controls (n = 18) or those receiving phenylephrine (n = 8). CONCLUSION: NO synthase inhibitors, by reducing available NO, cause systemic vasoconstriction and a decrease in SCBF in the uninjured spinal cord. In the injured spinal cord, the administration of L-NOARG results in a redistribution of blood flow with an augmentation in posttraumatic SCBF at the injury site.

Reduction of paraphimosis with hyaluronidase.

The use of hyaluronidase facilitates reduction of paraphimosis. It acts by dispersing extracellular edema, permitting easy reduction of the foreskin. Its use is applicable both in the hospital and outpatient setting. Hyaluronidase is widely available and keeps well if refrigerated. It is effective for children and adults.

Preservation of continence after posterior sagittal surgery.

PURPOSE: An animal study was performed to evaluate the effect of posterior sagittal pararectal mobilization on anorectal sphincter function. MATERIALS AND METHODS: We initially divided 11 juvenile pigs into 3 groups: group 1-anesthesia alone (3), group 2-posterior sagittal incision alone (4) and group 3-posterior sagittal incision with unilateral pararectal dissection (4). Two animals in group 1 subsequently underwent posterior sagittal incision with circumferential pararectal dissection (group 4). The anal canal was preserved intact in all animals. Anorectal sphincter manometry was performed preoperatively, and 2, 4, 8 and 12 weeks postoperatively. Electromyography was performed 12 weeks postoperatively. Anorectal sphincter muscle complexes were harvested for histological examination. RESULTS: All animals had postoperative bowel continence. Postoperatively manometry revealed no difference from preoperative measurements in all study groups (p = 0.90). Electromyography and histological examination of the anorectal sphincters were normal in all but 2 animals. Denervation injury and histological atrophy were detected after repair of inadvertent enterotomy in 1 animal following unilateral pararectal dissection, and polyphasic motor unit potentials implying reinnervation were detected in another after circumferential pararectal mobilization. CONCLUSIONS: These results indicate that posterior sagittal incision and unilateral pararectal mobilization cause no permanent injury to the anorectal sphincter. However circumferential pararectal dissection or repair of a rectal injury may cause measurable changes in sphincter function.

Excretion of tolbutamide metabolites in young and old subjects.

Tolbutamide (1 g/70 kg) was administered as a single intravenous dose to 31 healthy, non-smoking, drug-free males between 23 and 87 years old and the total amounts of hydroxy and carboxytolbutamide excreted in 24 h were measured. There was a significant decrease in the urinary recovery of both metabolites with age. The reason for these findings is not known at the present time and may be associated with the decrease in creatinine clearance observed in these subjects or other changes in the pharmacokinetics of tolbutamide which are currently being investigated.

A systematic approach to examining the patient with nail disease.

The majority of patients who present to the clinician for podiatric care do so because of complaints involving the nail and its surrounding structures. All too often the clinician's examination of the nail is incomplete and in many instances completely overlooked. The authors present a systematic approach to the examination of the patient who presents with nail pathology.

Managing data quality through automation.

Traditional definitions of data quality deal primarily with individual data sets and the data collection process. Today's standards for ensuring data quality have not changed with respect to the desired results, but have simply been expanded to take advantage of modern technology. Computers are used to acquire, review, store, analyze, and report data. Because each of these steps can be automated, the need for human intervention and manual review is minimized. As a result, the potential for invalid data to reach the data analysis stage has increased significantly. To reduce this potential, efforts must be devoted to developing automated procedures that cover every conceivable validation possibility. Relationships between data and data sets must be well defined [1], and data base support that facilitates ready access to the data for the purpose of analysis must be provided. For small data sets, automation may therefore be impractical; but for large, interrelated data sets, automation is highly desirable. Computer automation has therefore expanded the traditional concept of ensuring data quality to include a complex array of interrelated tasks that must be properly managed to achieve the desired results.

Physical-chemical compatibility of cromolyn sodium nebulizer solution--bronchodilator inhalant solution admixtures.

Cromolyn sodium nebulizer solution, 1%, is physically and chemically compatible (stable) for up to 60 minutes when mixed in vitro with metaproterenol, isoproterenol, isoetharine, epinephrine, terbutaline, and acetylcysteine inhalant solutions, respectively. Similarly, cromolyn does not adversely affect the stability of the individual bronchodilator/mucolytic drugs in the admixtures. Adding a bronchodilator/mucolytic agent to a cromolyn nebulizer solution should not negatively influence the in vivo efficacy or safety of either active ingredient.

Automated differential cell counting on a sector of the normal human hippocampus: the influence of age.

The neurons and the glia of the human hippocampus are notoriously vulnerable in various pathological conditions including those linked to ageing. There may even be differences between the young and the old in the absence of manifest disease. Using an image analyser, systematic measurements of cell numbers in the region of the Sommer (Hl) sector of the human hippocampus have been made on post-mortem tissue from thirty-seven female and forty-nine male subjects aged between 15 and 96 years. In fifteen male and fifteen female subjects both hemispheres were available for analysis so that measurements were made on a total of 116 hemispheres. For each specimen the fresh volume of the hemisphere was measured and corrections subsequently made for changes in size which occurred during fixation, processing, mounting and staining. After all the correction factors had been applied the number of nucleolated neurons was found to fall by about 3.6% per decade (P less than 0.0001). There was no significant age-related change in the number of glia. Marked individual variations were found.

Rapid GC method for quantitation of nifedipine in serum using electron capture detection.

For studying the pharmacokinetics of nifedipine after single doses, a rapid, specific, reliable gas chromatographic assay procedure for nifedipine in serum is developed. Using a single-step solvent extraction or a bonded-phase column extraction and electron capture detection, an assay sensitivity of 10 to 25 ng/ml can be achieved using 0.25 ml of serum. The assay quantitates intact nifedipine and separates it reproducibly from its nitro- and nitrosopyridine derivatives.