Cumulative Duration Of Exposure Research Articles

Importance of specific inhalation challenge in the diagnosis of occupational asthma induced by quaternary ammonium compounds

Importance of specific inhalation challenge in the diagnosis of occupational asthma induced by quaternary ammonium compounds

A Large National Cohort Study of the Association between Bisphosphonates and Osteonecrosis of the Jaw in Patients with Osteoporosis

The purpose of this study was to examine the association between bisphosphonate exposure and osteonecrosis of the jaw (ONJ) in Korean patients with osteoporosis. A nested case-control study was performed using the claims database during 2002 to 2010 provided by the National Health Insurance Service. We identified a cohort of individuals with diagnosis of osteoporosis during 2002 to 2010. Cases and controls were identified during 2004 to 2010, and the date of potential cases of ONJ was defined as the index date. Bisphosphonate exposure was evaluated during 2 y prior to the index date. The association between bisphosphonate exposure and ONJ was tested by performing a conditional logistic regression analysis for matched data, and odds ratios (ORs) with 95% confidence intervals (CIs) were presented. Subjects were classified as nonuser, recent user, past user, or continuous user, depending on the prescription of bisphosphonates in 2 periods (1 to 2 y and 0 to 1 y prior to the index date). Continuous users were defined as patients who were exposed to bisphosphonate in both periods. We also examined the impact of bisphosphonate medication compliance by measuring the cumulative duration of exposure (CDE) on the risk of ONJ. A total of 212 cases with ONJ and 2,120 controls matched by sex, age, income level, and insurance type were identified among 109,787 patients with osteoporosis out of 1,025,340 enrollees in the sample cohort. The odds of having ONJ after adjusting for patient comorbidities significantly increased in continuous users of bisphosphonates (OR, 3.9; 95% CI, 2.4 to 6.2) compared to nonusers. Increased odds of ONJ were observed as CDE increased. The adjusted OR in patients with 1.5 y < CDE ≤ 2 y prior to the index date was 7.8 (95% CI, 4.0 to 15.5) versus nonusers. Our study results support significantly increased occurrences of potential ONJ in patients with osteoporosis who were exposed to bisphosphonates compared to those without exposure.

Exploring the possible association between montelukast and neuropsychiatric events among children with asthma: a matched nested case-control study.

There is conflicting evidence regarding the association between montelukast and neuropsychiatric events (NE). We sought to examine this association among children with asthma. Using a 10% sample of the LifeLink Health Plan Claims data, subjects less than 18 years of age with a primary diagnosis of asthma between 1 January 1998 and 31 December 2009 were identified. A range of case definitions for NE was formulated based on diagnoses of psychiatric disorders and use of psychotropic medications. Using a matched nested case-control design, three controls were matched to each case on age, gender and geographic region, and assigned a matching index date. Exposure to montelukast was measured as any exposure during the year, recency of exposure, cumulative duration of exposure, and cumulative dose. Conditional logistic regression was used to estimate unadjusted and adjusted odds ratio (OR) controlling for potential confounders. Using the broadest case definition, 1920 cases were identified. Subjects exposed to montelukast during the prior year had an unadjusted OR of 1.09 (95%CI [0.96, 1.22]) and adjusted OR of 1.01 (95%CI [0.88, 1.14]) for experiencing NE measured using the broadest definition. A clear dose-response relationship was not observed. Exposure to a moderate chronic cumulative dose of montelukast (481 mg-1050 mg) had a higher odds of being diagnosed with neuropsychiatric disturbances (OR = 1.27; 95%CI [1.03, 1.57]) while exposure to high cumulative doses (>1050 mg) had a lower odds (OR = 0.64; 95%CI [0.50, 0.82]). These data did not detect a consistent significant positive association between montelukast and NE in children with asthma.

Long-term effects of single or multiple neonatal sevoflurane exposures on rat hippocampal ultrastructure.

Neonatal exposure to general anesthetics may pose significant neurocognitive risk. Human epidemiological studies demonstrate higher rates of learning disability among children with multiple, but not single, exposures to anesthesia. The authors employ a rat model to provide a histological correlate for these population-based observations. The authors examined long-term differences in hippocampal synaptic density, mitochondrial density, and dendritic spine morphology. Twenty male rat pups (n = 5/condition) were exposed to 2.5% sevoflurane under one of four conditions: single 2-h exposure on postnatal day 7 (P7); single 6-h exposure on P7; repeated 2-h exposures on P7, P10, and P13 for a cumulative 6 h of general anesthetics; or control exposure to 30% oxygen on P7, P10, and P13. Repeated exposure to general anesthetics resulted in greater synaptic loss relative to a single 2-h exposure (P < 0.001). The magnitude of synaptic loss induced by three 2-h exposures (1.977 ± 0.040 μm [mean ± SEM]) was more profound than that of a single 6-h exposure (2.280 ± 0.045 μm, P = 0.022). Repeated exposures did not alter the distribution of postsynaptic density length, indicating a uniform pattern of loss across spine types. In contrast, mitochondrial toxicity was best predicted by the cumulative duration of exposure. Relative to control (0.595 ± 0.017), both repeated 2-h exposures (0.479 ± 0.015) and a single 6-h exposure (0.488 ± 0.013) were associated with equivalent reductions in the fraction of presynaptic terminals containing mitochondria (P < 0.001). This suggests a "threshold effect" for general anesthetic-induced neurotoxicity, whereby even brief exposures induce long-lasting alterations in neuronal circuitry and sensitize surviving synapses to subsequent loss.

Sunlight exposure during leisure activities and risk of prostate cancer in Montréal, Canada, 2005-2009.

BackgroundProstate cancer (PCa) is the leading cause of cancer in men in many developed countries, but no modifiable risk factors have been identified. A handful of analytical studies have suggested a possible etiological role for sunlight exposure. We report here on the association between leisure-time sunlight exposure during adulthood and PCa risk in the context of a population-based case–control study.MethodsIn all, 1,904 PCa cases were ascertained across Montreal French hospitals between 2005 and 2009. Concurrently, 1,962 population controls, frequency matched to cases by age (±5 years), were selected from the electoral list for French-speakers in Greater Montreal. Interviews elicited the frequency of engagement in any leisure activity during adulthood. This was used to derive cumulative sunlight exposure indices: a cumulative number of leisure activities events entailing sunlight exposure and a cumulative duration of sunlight exposure during leisure activities. Unconditional logistic regression was conducted to yield odds ratios (OR) and 95% confidence intervals (CI) for estimating the association between sunlight exposure indices and PCa risk, adjusting for age, ancestry, family history of PCa, PCa screening, education, solar protection, body mass index and physical activity.ResultsCompared with men in the upper quartile category for the number of sunlight exposure events, men never exposed during leisure time had an OR of 1.32 (95% CI: 0.82-2.14). ORs were 1.11, 0.91 and 1.00 for the first to the third quartiles of exposure, respectively. Similar results were observed for cumulative duration of exposure to sunlight, and by PCa aggressiveness.ConclusionThese findings provide little evidence of an association between sunlight exposure during leisure-time and PCa risk. Men with no sunlight exposure appeared at somewhat higher risks but none of the estimates achieved statistical significance.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2458-14-756) contains supplementary material, which is available to authorized users.

Using fractional polynomials to model the effect of cumulative duration of exposure on outcomes: applications to cohort and nested case‐control designs

PurposeDetermining the nature of the relationship between cumulative duration of exposure to an agent and the hazard of an adverse outcome is an important issue in environmental and occupational epidemiology, public health and clinical medicine. The Cox proportional hazards regression model can incorporate time-dependent covariates. An important class of continuous time-dependent covariates is that denoting cumulative duration of exposure.MethodsWe used fractional polynomial methods to describe the association between cumulative duration of exposure and adverse outcomes. We applied these methods in a cohort study to examine the relationship between cumulative duration of use of the antiarrhythmic drug amiodarone and the risk of thyroid dysfunction. We also used these methods with a conditional logistic regression model in a nested case-control study to examine the relationship between cumulative duration of use of bisphosphonate medication and the risk of atypical femur fracture.ResultsUsing a cohort design and a Cox proportional hazards model, we found a non-linear relationship between cumulative duration of use of the antiarrhythmic drug amiodarone and the risk of thyroid dysfunction. The risk initially increased rapidly with increasing cumulative use. However, as cumulative duration of use increased, the rate of increase in risk attenuated and eventually levelled off. Using a nested case-control design and a conditional logistic regression model, we found evidence of a linear relationship between duration of use of bisphosphonate medication and risk of atypical femur fractures.ConclusionsFractional polynomials allow one to model the relationship between cumulative duration of medication use and adverse outcomes.

Association Between Metformin Use and Mortality in Patients With Prostate Cancer: Explained by Confounding by Indication?

TO THE EDITOR: Margel et al 1 recently reported on a populationbased retrospective cohort study that used a unique large database to investigate patients with prostate cancer diagnosed with incident diabetes. Increased cumulative duration of metformin exposure after prostate cancer diagnosis was associated with decreases in both all-cause and prostate cancer–specific mortality among men with diabetes. The study showed that prostate cancer–specific mortality even decreased by 24% for each additional 6 months of metformin use after the diagnosis of prostate cancer. Although the approach used in this study did circumvent numerous potential limitations and biases, 2 on the basis of the authors’ conclusions and study design, we have a few comments and requests for clarification. With regard to their statistical analyses, the effects of cumulative duration of exposure to metformin on mortality were assessed by using a Cox proportional hazards model in which drug exposures after prostate cancer diagnosis were modeled as time-dependent covariates. The comparison was not exclusively between users who had different durations of exposure, but also between users and nonusers of the drug. This means that in the time-dependent model, patients not using metformin were included in the analysis as 0 for cumulative use of metformin. Modeling the line for this specific hazard ratio (HR) of cumulative metformin use could be expected to be greatly influenced by events in the nonusers, given that patients using and not using metformin might differ in their previous susceptibility to dying as a result of cancer. As a consequence, these results might be affected by confounding by indication, which could not be avoided by the inclusion of cumulative drug exposure exclusively, as supposed in this analysis. It can be shown algebraically that with the inclusion of an ever-never termformetforminuseinthemodel,theHRofthecumulativeeffectterm

Su1131 Incidence Rate of Lymphoma by the Cumulative Duration of Exposure to Thiopurines: A Nationwide Retrospective Cohort From the Veterans’ Affairs Healthcare System

Su1131 Incidence Rate of Lymphoma by the Cumulative Duration of Exposure to Thiopurines: A Nationwide Retrospective Cohort From the Veterans’ Affairs Healthcare System

P468 Incidence rate of lymphoma by the cumulative duration of exposure to thiopurines: a nationwide retrospective cohort from the Veterans Affairs healthcare system

P468 Incidence rate of lymphoma by the cumulative duration of exposure to thiopurines: a nationwide retrospective cohort from the Veterans Affairs healthcare system

Abnormal Liver Stiffness Assessed Using Transient Elastography (Fibroscan®) in HIV-Infected Patients without HBV/HCV Coinfection Receiving Combined Antiretroviral Treatment

Background and AimsLiver stiffness measurement (LSM) using transient elastography (Fibroscan®) can identify individuals with potential underlying liver disease. We evaluated the prevalence of abnormal LSM values as assessed using LSM and its predictors in HIV-infected asymptomatic patients receiving combined antiretroviral treatment (cART) without HBV/HCV coinfection.MethodsWe prospectively recruited 93 patients who had consistently been undergoing cART for more than 12 months at Severance Hospital in Seoul, Republic of Korea, from June to December 2010. LSM values >5.3 kPa were defined as abnormal.ResultsThirty-nine (41.9%) had abnormal LSM values. On multivariate correlation analysis, the cumulative duration of boosted and unboosted protease inhibitors (PIs) were the independent factors which showed a negative and positive correlation to LSM values, respectively (β = –0.234, P = 0.023 and β = 0.430, P<0.001). In multivariate logistic regression analysis, the cumulative exposure duration of boosted-PIs and γ-glutamyltranspeptidase levels were selected as the independent predictors which showed a negative and positive correlation with abnormal LSM values, respectively (odds ratio [OR], 0.941; 95% confidence interval [CI], 0.889–0.997; P = 0.039 and OR, 1.032; 95% CI, 1.004–1.060; P = 0.023).ConclusionThe high percentage of HIV-infected asymptomatic patients receiving cART without HBV/HCV coinfection had abnormal LSM values. The cumulative exposure duration of boosted-PIs and γ-GT level were independent predictors which showed a negative and positive correlation with abnormal LSM values, respectively.

Hepatic steatosis in HIV-HCV coinfected patients receiving antiretroviral therapy is associated with HCV-related factors but not antiretrovirals

BackgroundIn HIV and hepatitis C virus (HCV) coinfected patients, the role of antiretroviral therapy (ART) on hepatic steatosis (HS) remains controversial.MethodsHIV/HCV coinfected patients receiving ART and previously untreated for HCV who underwent a liver biopsy were included. Cumulative duration of exposure to each antiretroviral was recorded up to liver biopsy date. Logistic regression analyses evaluated factors associated with steatosis and its severity.Results184 patients were included: median age 41years, 84% male, 89% Caucasian, 61% with a past history of intravenous drug use. HCV genotypes were 1 (55%), 2 (6%), 3 (26%), and 4 (13%). Median HCV-RNA was 6.18 log10 IU/ml. HIV-RNA was undetectable (<400 copies/ml) in 67% of patients. Median CD4 count was 321/mm3. All patients had been exposed to nucleoside reverse transcriptase inhibitors (median cumulative exposure 56months); 126 received protease inhibitors (23months), and 79 non-nucleoside reverse transcriptase inhibitors (16months). HS was observed in 102 patients (55%): 41% grade 1; 5% grade 2, and 9% grade 3. In multivariate analysis, HCV genotype 3 and HCV viral load were moderately associated with mild steatosis but strongly with grade 2-3 steatosis. After adjustment for the period of biopsy, no association was detected between HS and exposure to any antiretroviral class or drug, or duration of ART globally or comparing genotype 3 to others.ConclusionsAmong our ART-treated HIV-HCV cohort predominantly infected with genotype 1, 55% of patients had HS which was associated with HCV-related factors, but not ART class or duration of exposure.

Effect of household passive smoking exposure on the risk of ischaemic heart disease in never-smoke female patients in Hong Kong

Objective:To investigate the relation between household passive smoking exposure and risk of ischaemic heart disease (IHD) among never-smoke female patients by a retrospective case-control analysis.Methods:This study recruited 314 patients with...

A re-evaluation of kava (Piper methysticum).

A re-evaluation of kava (Piper methysticum).

Use of antiepileptic drugs and risk of fractures

To study the association between use of antiepileptic drugs (AEDs) and risk of fractures. The authors obtained data from the General Practice Research Database (GPRD). A case-control study was nested within a cohort of patients with active epilepsy. Cases were patients with a first fracture after cohort entry. Up to four controls were matched to each case by practice, sex, year of birth, timing of first epilepsy diagnosis, index date, and duration of GPRD history. Cumulative exposure to AEDs was assessed by summing the duration of all AED prescriptions. A distinction was made between AEDs that induce the hepatic cytochrome P-450 enzyme system and AEDs that do not. Medical conditions and drugs known to be associated with bone metabolism or falls were evaluated as potential confounders. Conditional logistic regression analysis was used to calculate odds ratios (ORs) and 95% CIs. The study population comprised 1,018 cases and 1,842 matched controls. The risk of fractures increased with cumulative duration of exposure (p for trend < 0.001), with the strongest association for greater than 12 years of use: adjusted OR 4.15 (95% CI 2.71 to 6.34). Risk estimates were higher in women than in men. There was no difference between users of AEDs that induce and AEDs that do not induce the hepatic cytochrome P-450 system. Long-term use of AEDs was associated with an increased risk of fractures, especially in women. More research on mechanisms of AED-induced bone breakdown and female vulnerability to the effects of AEDs on bone health is warranted.

Estimation of time‐dependent rate ratios in case‐control studies: comparison of two approaches for exposure assessment

In pharmacoepidemiology, it is well recognized that the rate of adverse events may vary as a function of the cumulative duration of the drug exposure and/or the time since the end of the exposure. In case-control studies, two different approaches have been used to estimate temporal effects of drug exposure: the time-windows (T-Ws) approach and the duration-specific (D-S) approach. We decided to conduct a simulation study to compare the two approaches when the rate ratios (RRs) vary as a function of the cumulative duration of exposure and/or the time since the end of exposure. We generated three cohorts of 500,000 individuals in which the rate of the event was varying as a function of the cumulative duration of exposure and the time since the end of exposure. For each cohort, a nested case-control analysis was performed using both the D-S and the T-Ws approaches. In the T-Ws approach, a RR is estimated within specific periods of time prior to the outcome, while a RR is estimated within periods of cumulative duration of exposure and time since the end of exposure in the D-S approach. We found that the RRs obtained from the D-S approach exactly corresponded to the RRs obtained from the cohort analyses, while the RRs obtained from the T-Ws approach generally not. RRs obtained from the T-Ws approach were difficult to interpret in terms of the effect of the duration and timing of the exposure. The D-S approach should be used to investigate the duration-related effects of exposure in case-control studies.

Predictors of Hypertension and Changes of Blood Pressure in HIV-Infected Patients

We assessed predictors of changes in systolic (SBP) and diastolic (DBP) blood pressure during follow-up and of the development of hypertension in HIV-infected individuals. International cohort collaborative study (D:A:D) of established prospective cohorts of HIV-1-infected patients. Longitudinal analysis of changes in blood pressure (BP) was performed using mixed effects models in 17170 patients. Predictors of development of hypertension during follow-up (systolic BP > or =140 and/or diastolic BP > or =90 mmHg or initiation of antihypertensive treatment) were assessed using Cox models in 8 984 patients with a normal BP level at baseline. 73548 BP measurements with a median of 4 per patient (interquartile range [IQR]: 2-6) were recorded over a median follow-up of 2.3 years (IQR: 1.5-2.6). Risk factors significantly associated with a development of higher systolic BP and diastolic BP (differences > or =5 mmHg and P-values <0.001) during follow-up were: older age, male sex, higher body mass index (BMI) and use of BP-lowering drugs. In patients with normal BP at baseline, 1186 developed hypertension for an incidence of 72.1 per 1000 person-years (95% confidence interval: 68.2-76.0). Factors associated with development of hypertension were: male sex, higher BMI, older age, higher BP at baseline, high total cholesterol and clinical lipodystrophy. Cumulative duration of exposure to nucleoside reverse transcriptase inhibitors (P=0.75), protease inhibitors (P=0.92) as well as type of antiretroviral treatment at baseline (P=0.18) were not associated with a higher risk of hypertension. Cumulative duration of exposure to non-nucleoside reverse transcriptase inhibitors (NNRTIs) was significantly associated with lower risk of hypertension (hazard ratio=0.78 and 0.67 for those treated < or =10 months and >10 months compared with no exposure; P=0.005). Increased blood pressure in HIV-infected individuals is associated with established risk factors for hypertension. There was no evidence for an independent deleterious effect of any class of antiretroviral drugs on BP, although the use of NNRTIs was associated with a lower risk of development of hypertension.

Risk factors for lung cancer among nonsmoking women.

To evaluate risk factors for lung cancer in nonsmoking women, we used data of a case-control study conducted between 1991 and 1996 in Germany. A total of 234 female histologically confirmed lung cancer patients and 535 population controls who had never smoked more than 400 cigarettes in their lifetime were personally interviewed with respect to occupation, exposure to environmental tobacco smoke (ETS), family history of cancer, prior physician-diagnosed lung diseases or cancer and diet. One-year radon measurements in the last dwelling were performed. Odds ratios (OR) adjusted for age and region and 95% confidence intervals (CI) were calculated via logistic regression. When cumulative duration of exposure to ETS in hours was considered, the OR for high compared to not or low ETS exposed women was 2.62 (CI:1.35-5.06) for occupational exposure and OR=1.67 (CI:0.86-3.25) for spousal exposure, exhibiting a significant trend for ETS at work. Working more than 10 years in jobs or industries with known or suspected lung carcinogens was associated with OR=2.0 (CI:0.99-4.0). An elevated risk due to prior lung diseases was present for pneumonia (OR=1.6; CI:1.07-2.40) and tuberculosis (OR=1.6; CI:0.77-3.37). No significant increase in risk with increasing residential radon levels or with the presence of a family history of lung cancer was apparent. Protective effects were observed for high vs. low consumption of fresh vegetables (OR=0.5; CI:0.25-0.82) and cheese (OR=0.3, CI:0.21-0.55). ETS at work, occupational hazards and previous pneumonia may be risk factors for lung cancer in nonsmoking women, while a diet rich in fresh vegetables and cheese seems to be protective.

Past occupational exposure to asbestos among men in France.

This study aimed at reconstructing changes in the frequency and levels of occupational asbestos exposure in France over the past century. Work histories were collected during 11 population-based case-referent studies recently carried out in France, and an asbestos-specific job-exposure matrix including 10 625 jobs was used to estimate indices of past occupational asbestos exposure. The results were estimated from a sample of 4287 subjects, bootstrapped 200 times. The distribution of socioeconomic categories within the sample was compared with that of the general population in 1954, 1962, 1968, 1975, and 1982. The proportion of blue-collar workers was similar. The highest proportion of exposed subjects was found between 1950 and 1980. Around 10% of each 10-year age class was exposed to asbestos. For those born in 1930-1939, 15.2% was exposed between the ages of 20 and 29 years. For each age class born in 190-1939, the proportion exposed at least once by 60 years of age ranged from 18.2% to 24.5 % and, of those exposed, the cumulative duration of exposure ranged from 11.3 to 15.4 years by the age of 60 years. A population exposure index showed that the heaviest exposure occurred between 1960 and 1970 and that the age classes born between 1920 and 1929 were the most heavily exposed. Time trends showed that the mean value of this index for the men aged 20-59 years reached a peak in the 1960s and then decreased. This study presents data of reasonable validity about occupational asbestos exposure in France and its trends over the past century; the data are being used to forecast the development of male mortality from mesothelioma in France.

Do cognitive impairments recover following cessation of cannabis use ?

Our previous research with long term cannabis users established an impaired ability to focus attention and filter out irrelevant information, which was progressive with the cumulative duration of exposure to cannabis. The current study examined these processes in a group of ex-cannabis users. The results suggested a partial recovery of function but the past duration of cannabis use continued to have an adverse effect on the ability to effectively reject complex irrelevant information. There was no indication of improvement with increasing length of abstinence. Whilst relatively subtle in nature, the consequences of such an enduring deficit associated with cannabis use are worthy of further investigation.

Exposure to domestic animals and risk of immunologic sensitization in subjects with asthma

The objective of the study was to determine whether exposure to domestic animals plays a significant role, beyond atopy, in the development of immediate sensitization to animal-derived antigens. To test this hypothesis, 200 subjects with asthma (85 male subjects and 115 female subjects; mean age, 37 +/- 16 years) seen consecutively in an asthma clinic were enrolled in a cross-sectional survey. Each subject answered a questionnaire about allergy symptoms and past and current exposure to domestic animals. Skin prick testing with extracts of common inhalant allergens including antigens from eight species of animal (cat, dog, horse, rabbit, rat, mouse, guinea pig, and hamster) were also carried out. Seventy-nine percent of subjects were atopic, and 91% had kept animals at home at some point (figures were 80% for dogs, 68% for cats, 23% for rabbits, and 20% for rodents). Using two-by-two tables, we showed that skin reactivity to at least one animal antigen was strongly linked to atopy (86% of atopic subjects had skin reactions as compared with 34% of nonatopic subjects: p < 0.001) but not to previous and current exposure to domestic animals (78% of both exposed and never exposed subjects). However, with the use of logistic regression, the determinants of skin reactivity to animals were atopy (p < 0.001), followed by cumulative duration of exposure to domestic animals (p < 0.01). The number of animals times the number of species times the duration of exposure was also a significant determinant of skin reactivity (p = 0.05). We conclude that beyond the predominant role of atopy, cumulative duration of exposure to domestic animals is a significant determinant for immediate sensitization to animal-derived antigens in subjects with asthma.