Individualized prescribing portraits to reduce inappropriate initiation of opioid analgesics to opioid naïve patients in primary care: Protocol for a randomized controlled trial.

Background Opioid analgesics are frequently initiated for chronic and acute pain despite weak evidence of benefit, although prescribing rates of some analgesics decreased in the context of the epidemic. In some populations, up to a quarter of opioid naïve persons prescribed opioids for non-cancer pain develop prescription opioid use disorder (OUD). Audit and feedback interventions rely on constructive use of routinely collected data to align professional behaviours and clinical practice with best evidence. These interventions have been shown to help reduce inappropriate initiation. However, effectiveness and acceptability of individualized "portraits" of physicians' prescribing patterns, to reduce inappropriate initiation of opioid analgesics to opioid naïve persons, have not been evaluated. Methods REDONNA is a mixed-methods randomized study testing the effectiveness of individualized prescribing Portraits to reduce inappropriate initiation of opioid analgesics. This intervention to improve safety of opioid prescribing in primary care in British Columbia (BC), Canada involves mailing individual prescribing portraits to an 'early group' of 2604 family physicians, followed in 6 months by a mailing to 2553 family physicians in the 'delayed group'. Primary outcome is number of new opioid prescriptions initiated in opioid naïve people, measured using administrative data from a centralized medication monitoring database covering all prescription opioids dispensed from BC community pharmacies. Secondary endpoints will compare prescribing impact between the two groups. A qualitative sub-study will examine feasibility among a purposive sample of physicians and patients. Discussion This trial provides important evidence on the intervention's potential to steer policy and practice on inappropriate opioid analgesics initiation. Trial registration: The study was registered prospectively on 30 March 2020 at the ISRCTN Register (https://www.isrctn.com/ISRCTN34246811).

Fatty acid composition of the subcutaneous adipose tissue and risk of proliferative benign breast disease and breast cancer.

BACKGROUND: Studies in animals and geographic correlations across populations suggest that fatty acid intake may have a positive relationship with breast cancer risk, but analytic epidemiologic studies of fat intake have been less supportive. Adipose tissue analysis provides a more objective assessment of intakes of fatty acids that are not endogenously synthesized than do the questionnaire survey methods used in many epidemiologic studies. PURPOSE: This case-control study of postmenopausal women was designed to examine the relationship between fatty acid composition of subcutaneous adipose tissue and risk of breast cancer and proliferative benign breast disease. In addition, we examined specific hypotheses that breast cancer risk is negatively associated with long-chain N-3 fatty acid intake, positively associated with trans fatty acid intake, and positively associated with increased intake of polyunsaturated fat together with low intake of antioxidants. METHODS: Aspirates of subcutaneous fat from the buttocks were obtained from 380 women with newly diagnosed stage I or II breast cancer and 176 with proliferative benign breast disease. A total of 397 women who were evaluated for breast abnormalities at the same institutions but did not require breast biopsy or whose biopsy revealed nonproliferative benign breast disease served as the control group. We examined associations between saturated, monounsaturated, polyunsaturated, trans, or long-chain N-3 fatty acids and breast cancer, atypical hyperplasia, or proliferative benign breast disease without atypia. RESULTS: We observed no consistent patterns of association between breast cancer risk and any of the categories of fatty acids or the individual constituent fatty acids in the adipose tissue. Saturated fatty acids were inversely associated with risk of proliferative benign breast disease without atypia but not with atypical hyperplasia or breast cancer. This association was not observed, however, when total fat intake was taken into account. Women with high levels of polyunsaturated fatty acids in adipose tissue and low serum or dietary levels of antioxidants were not observed to be at higher risk of breast cancer. CONCLUSIONS: Using an objective measure of intake, we observed no major associations between polyunsaturated fatty acids, including long-chain N-3 fatty acids and trans fatty acids, and risk of breast cancer or proliferative benign breast disease. IMPLICATIONS: These data do not support the hypothesis that intake of specific fatty acids, particularly polyunsaturated and trans fatty acids, is an important risk factor for malignant or benign breast disease.

Hemoglobin adducts of 4-aminobiphenyl in smokers and nonsmokers.

A quantitative method has been developed for the analysis of 4-aminobiphenyl (4-ABP) covalently bound as the sulfinic acid amide to the 93 beta cysteine of human hemoglobin. The method uses mild basic hydrolysis of hemoglobin to release the parent amine, derivatization to form the pentafluoropropionamide, and capillary gas chromatography with detection by negative-ion chemical ionization mass spectrometry. The method is precise and gives reproducible results on multiple blood samples taken from individuals over 48 h. Application of this method to blood samples from cigarette smokers and nonsmokers revealed consistently higher adduct levels in smokers. The mean value for smokers was 154 pg 4-ABP per g Hb compared to 28 pg/g Hb for nonsmokers, with no overlap of adduct levels between the two groups. Studies on quitting smokers revealed that adduct levels declined over a period of 6-8 weeks to nonsmoker levels. The finding of 4-ABP adducts in all nonsmokers was not anticipated but is consistent with low-level ubiquitous contamination of air, food, or water. In other animals sampled, rats and dogs had measurable adduct levels, but monkeys and fish did not. The hemoglobin adduct of 4-ABP is the product of a series of reactions between the hemoprotein and N-hydroxy-4-ABP. The formation of hydroxylamines from carcinogenic aromatic amines and their subsequent reactions with DNA are generally thought to be critical events in the initiation of bladder tumors. We suggest that the observed hemoglobin adduct levels formed by this proximate carcinogen will reflect the extent to which these steps have occurred. This is the first report of 4-ABP adducts in human blood.

Decline of the hemoglobin adduct of 4-aminobiphenyl during withdrawal from smoking.

The hemoglobin adduct of the human bladder carcinogen 4-aminobiphenyl (4ABP-Hb) declined in the blood of 34 smokers enrolled in a withdrawal program, from a mean of 120 +/- 7 (SE) pg/g of hemoglobin at the start to a mean of 82 +/- 6 pg/g after 3 weeks and a mean of 34 +/- 5 pg/g among the 15 exsmokers who had not resumed smoking after 2 months. Although 4ABP-Hb declined faster than expected under the assumption that the human erythrocyte has a life span of 120 days, it persisted much longer than cotinine. Therefore, 4ABP-Hb may complement the use of cotinine as a marker of exposure to tobacco smoke. The strength of the within-person association of 4ABP-Hb with smoking, coupled with the weakness of the between-person association (correlation coefficient, 0.33), is evidence that between-person variation in modifying factors is substantial. Study of the modifiers of 4ABP-Hb levels may help elucidate the etiology of human susceptibility to aromatic amine-induced bladder cancer.

Triggering of myocardial infarction by cocaine.

BACKGROUND: Cocaine has been implicated as a trigger of acute myocardial infarction in patients with and those without underlying coronary atherosclerosis. However, the magnitude of the increase in risk of acute myocardial infarction immediately after cocaine use remains unknown. METHODS AND RESULTS: In the Determinants of Myocardial Infarction Onset Study, we interviewed 3946 patients (1282 women) with acute myocardial infarction an average of 4 days after infarction onset. Data were collected on the use of cocaine and other potential triggers of myocardial infarction. We compared the reported use of cocaine in the hour preceding the onset of myocardial infarction symptoms with its expected frequency by using self-matched control data based on the case-crossover study design. Of the 3946 patients interviewed, 38 (1%) reported cocaine use in the prior year and 9 reported use within the 60 minutes preceding the onset of infarction symptoms. Compared with nonusers, cocaine users were more likely to be male (87% vs 67%, P=0.01), current cigarette smokers (84% vs 32%, P<0.001), younger (44+/-8 vs 61+/-13 years, P<0.001), and minority group members (63% vs 11%, P<0.001). The risk of myocardial infarction onset was elevated 23.7 times over baseline (95% CI 8.5 to 66.3) in the 60 minutes after cocaine use. The elevated risk rapidly decreased thereafter. CONCLUSIONS: Cocaine use is associated with a large abrupt and transient increase in the risk of acute myocardial infarction in patients who are otherwise at relatively low risk. This finding suggests that studying the pathophysiological changes produced by cocaine may provide insights into the mechanisms by which myocardial infarction is triggered by other stressors.

Triggering myocardial infarction by marijuana.

BACKGROUND: Marijuana use in the age group prone to coronary artery disease is higher than it was in the past. Smoking marijuana is known to have hemodynamic consequences, including a dose-dependent increase in heart rate, supine hypertension, and postural hypotension; however, whether it can trigger the onset of myocardial infarction is unknown. METHODS AND RESULTS: In the Determinants of Myocardial Infarction Onset Study, we interviewed 3882 patients (1258 women) with acute myocardial infarction an average of 4 days after infarction onset. We used the case-crossover study design to compare the reported use of marijuana in the hour preceding symptoms of myocardial infarction onset to its expected frequency using self-matched control data. Of the 3882 patients, 124 (3.2%) reported smoking marijuana in the prior year, 37 within 24 hours and 9 within 1 hour of myocardial infarction symptoms. Compared with nonusers, marijuana users were more likely to be men (94% versus 67%, P<0.001), current cigarette smokers (68% versus 32%, P<0.001), and obese (43% versus 32%, P=0.008). They were less likely to have a history of angina (12% versus 25%, P<0.001) or hypertension (30% versus 44%, P=0.002). The risk of myocardial infarction onset was elevated 4.8 times over baseline (95% confidence interval, 2.4 to 9.5) in the 60 minutes after marijuana use. The elevated risk rapidly decreased thereafter. CONCLUSIONS: Smoking marijuana is a rare trigger of acute myocardial infarction. Understanding the mechanism through which marijuana causes infarction may provide insight into the triggering of myocardial infarction by this and other, more common stressors.

Educational attainment, anger, and the risk of triggering myocardial infarction onset. The Determinants of Myocardial Infarction Onset Study Investigators.

BACKGROUND: While it has recently been shown that anger may trigger the onset of acute myocardial infarction, there has been no study of the role of socioeconomic factors in such triggering. Socioeconomic factors, such as educational attainment, may modulate the risk of triggering because of their influence on individual reactivity to external stressors and on the prevalence of traditional cardiac risk factors. OBJECTIVE: To evaluate the influence of educational attainment on the relative risk of myocardial infarction onset following episodes of anger. METHODS: We interviewed 1623 patients (501 women) an average of 4 days following a myocardial infarction. Data were collected on standard demographic variables as well as risk factors for coronary artery disease. Educational attainment was categorized into 3 levels: less than high school, completed high school, and at least some college. Anger was assessed by the Onset Anger Scale, a single-item, 7-level, self-report scale. Occurrence of anger in the 2 hours preceding the onset of myocardial infarction was compared with its expected frequency using self-matched control data based on the case-crossover study design. RESULTS: The risk of having a myocardial infarction triggered by isolated episodes of anger declined consistently and significantly with increasing levels of educational attainment (P = .03). The relative risk was twice as high among those with less than high school education (relative risk, 3.3; 95% confidence interval, 2.0-5.4) compared with patients with at least some college education (relative risk, 1.6; 95% confidence interval, 0.9-2.9). CONCLUSIONS: These findings indicate that socioeconomic factors are potent modulators of the risk of triggering acute cardiovascular disease onset. A better understanding of the physiological mechanisms underlying this association may lead to novel approaches to prevent acute cardiovascular events.

Impact of diabetes on long-term survival after acute myocardial infarction: comparability of risk with prior myocardial infarction.

OBJECTIVE: To determine the effect of diabetes on long-term survival after acute myocardial infarction and to compare its effect with that of a previous myocardial infarction. RESEARCH DESIGN AND METHODS: In a prospective cohort study, we followed 1,935 patients hospitalized with a confirmed acute myocardial infarction at 45 U.S. medical centers between 1989 and 1993, as part of the Determinants of Myocardial Infarction Onset Study. Trained interviewers performed chart reviews and face-to-face interviews with all patients. We analyzed survival using Cox proportional hazards regression to control for potentially confounding factors. RESULTS: Of the 1,935 patients, 320 (17%) died during a mean follow-up of 3.7 years. A total of 399 patients (21%) had previously diagnosed diabetes. Diabetes was associated with markedly higher total mortality in unadjusted (hazard ratio [HR] 2.4; 95% CI 1.9-3.0) and adjusted (1.7; 1.3-2.1) analyses. The magnitude of the effect of diabetes was identical to that of a previous myocardial infarction. The effect of diabetes was not significantly modified by age, smoking, household income, use of thrombolytic therapy, type of hypoglycemic treatment, or duration of diabetes, but the risk associated with diabetes was higher among women than men (adjusted HRs 2.7 vs. 1.3, P = 0.01). CONCLUSIONS: Diabetes is associated with markedly increased mortality after acute myocardial infarction, particularly in women. The increase in risk is of the same magnitude as a previous myocardial infarction and provides further support for aggressive treatment of coronary risk factors among diabetic patients.

A prospective cohort study of nutrient intake and age at menarche.

A cohort of 213 girls (aged 10 y, range +/- 9 mo) whose parents reported their dietary intakes (including nutritional supplements) using a semiquantitative food frequency questionnaire, was followed for 4 y until 82% of the 194 parents who responded to follow-up letters had reported that their daughters had had their first menstrual periods. The relative risk (RR) of menarche before age 12.5 y was 2.0 [95% confidence interval (CI) = 1.1-3.8] for the tallest girls (greater than 150 cm) compared with the shortest girls (less than 130 cm). The RR was 2.1 (95% CI = 1.1-3.8) for the fattest girls [Quetelet's index of relative weight (in kg/m2) greater than 19] vs the leanest girls (less than 15). After adjusting for height and Quetelet's index, menarcheal age was not associated with intake of energy nor energy-adjusted intake of protein, fat, or carbohydrate. The overall results are consistent with the hypothesis that nutritional factors influence age at menarche mainly through their effects on accumulation of adipose tissue.

Height is not associated with long-term survival after acute myocardial infarction.

BACKGROUND: Studies show an inverse association between height and risk of myocardial infarction. How height affects survival after acute myocardial infarction is uncertain. METHODS: In the Determinants of Myocardial Infarction Onset Study, trained interviewers performed chart reviews and face-to-face interviews with 1935 patients hospitalized with acute myocardial infarction in 45 US medical centers between 1989 and 1993. We excluded 15 patients with missing information on height. After a search of the National Death Index for patients who died before 1996, we analyzed the relationship of height and survival with Cox proportional hazards regression. RESULTS: Of the 1920 eligible patients, 317 (17%) died during a median follow-up of 3.8 years. Height was positively associated with younger age, greater educational attainment, and a lower likelihood of being sedentary among both men and women. Height was not associated with long-term survival among women in unadjusted or adjusted analyses. Among men, height was associated with survival only in unadjusted analyses; adjustment for age eliminated this association. We found no relationship between height and survival in any individual age group among men or women. CONCLUSIONS: Although stature may be associated with the risk of acute myocardial infarction, it is not associated with long-term survival after such an event.

Increased onset of sudden cardiac death in the first three hours after awakening.

A circadian variation of sudden cardiac death has been documented, but its relation to individual time of awakening and possible triggering events has not been studied in the general population. By monitoring of mortality records in 4 cities and towns in Massachusetts, 148 potential cases of sudden cardiac death were identified. In 94 cases, the informants listed on the death certificates were contacted, the diagnosis of sudden cardiac death was established, and a telephone interview was completed within a mean of 19 days (range 8 to 28) after the death. The time of day of all 94 cases of sudden cardiac death (mean age 61 +/- 9 years, 74% men) demonstrated a circadian variation (p less than 0.05) with a peak from 9:00 A.M. to 12:00 noon. An analysis of time of death adjusted for individual wake-times of the decedents demonstrated an increased onset of sudden cardiac death during the initial 3-hour interval after awakening with a relative risk of 2.6 (95% confidence interval 1.6, 4.2) compared with other times of the day. The increased risk of sudden cardiac death soon after awakening suggests specific triggering factors or mechanisms that are particularly likely to occur during this time. The narrowing of the time interval during which the risk of sudden cardiac death is increased should facilitate the study of possible pathogenetic mechanisms and triggering factors of the disease and may aid in the design of more effective preventive strategies.

Analysis of possible triggers of acute myocardial infarction (the MILIS study).

Recent documentation of a circadian variation in acute myocardial infarction (AMI) suggests that AMI is not a random event, but may frequently result from identifiable triggering activities. The possible triggers reported by 849 patients enrolled in the Multicenter Investigation of Limitation of Infarct Size were analyzed. Possible triggers were identified by 48.5% of the population; the most common were emotional upset (18.4%) and moderate physical activity (14.1%). Multiple possible triggers were reported by 13% of the population. Younger patients, men and those without diabetes mellitus were more likely to report a possible trigger than were older patients, women and those with diabetes. The likelihood of reporting a trigger was not affected by infarct size. This study suggests that potentially identifiable triggers may play an important role in AMI. Because potential triggering activities are common in persons with coronary artery disease, yet infrequently result in AMI, further studies are needed to identify (1) the circumstances in which a potential trigger may cause an event, (2) the specific nature of potential triggering activites, (3) the frequency of such activities in individuals who do not develop AMI and (4) the presence or absence of identifiable triggers in various subgroups of patients with infarction.

Taxonomic axes of epidemiologic study designs: a refutationist perspective.

Overlap among the axes of study design used for classifying epidemiologic research creates a taxonomic problem, the complexity of which may be illustrated by Venn diagrams. The diagrams also suggest a solution: to rank axes according to their bearing on study validity. This is consistent with the refutationist criterion for distinguishing strong from weak science--the potential to refute alternative explanations. In epidemiology, this means refuting confounding, reverse-causation bias, selection or allocation bias, and misclassification bias. Using susceptibility to bias as a criterion for ranking axes, a simple taxonomy emerges that is compatible with widespread usage of terminology.

Multivariate refutation of aetiological hypotheses in non-experimental epidemiology.

Extension of Karl Popper's logic of refutation from the realm of contingency tables to multivariate modelling leads to the conclusion that rigorously scientific multivariate analysis in non-experimental epidemiology differs from the traditional quasi-scientific approach. Instead of aiming for high sensitivity in detecting aetiological agents, the goal in refutation is high specificity--to give the best defence of the 'innocence' of every exposure hypothesized as being a cause. Instead of 'forward selection' or 'backward elimination', multivariate refutation uses the method of 'forward elimination'. This entails a likelihood approach (which may be complemented by, but should be demarcated from, Bayesian methods) not only for statistical inference but also, by analogy, for study design and conduct: one starts with the conclusion (the estimate or hypothesis) and works backwards to the observations (the likelihood of the data or the design of the study). Differences in practice can sometimes be large, as illustrated by a study of hypothesized triggers of myocardial infarction. Multivariate refutation should replace the concept of multivariate modelling in non-experimental epidemiology.

Use of comorbidity scores for control of confounding in studies using administrative databases.

BACKGROUND: Comorbidity scores are increasingly used to reduce potential confounding in epidemiological research. Our objective was to compare metrical and practical properties of published comorbidity scores for use in epidemiological research with administrative databases. METHODS: The literature was searched for studies of the validity of comorbidity scores as predictors of mortality and health service use, as measured by change in the area under the receiver operating characteristic (ROC) curve for dichotomous outcomes, and change in R(2) for continuous outcomes. RESULTS: Six scores were identified, including four versions of the Charlson Index (CI) which use either the three-digit International Classification of Diseases, Ninth Revision (ICD-9) or the full ICD-9-CM (clinical modification) code, and two versions of the Chronic Disease Score (CDS) which used outpatient pharmacy records. Depending on the population and exposure under study, predictive validities varied between c = 0.64 and c = 0.77 for in-hospital or 30-day mortality. This is only a slight improvement over age adjustment. In one study the simple measure 'number of diagnoses' outperformed the CI (c = 0.73 versus c = 0.65). Proprietary scores like Ambulatory Diagnosis Groups and Patient Management Categories do not necessarily perform better in predicting mortality. Comorbidity indices are susceptible to a variety of coding errors. CONCLUSIONS: Comorbidity scores, particularly the CDS or D'Hoore's CI based on three-digit ICD-9 codes, may be useful in exploratory data analysis. However, residual confounding by comorbidity is inevitable, given how these scores are derived. How much residual confounding usually remains is something that future studies of comorbidity scores should examine. In any given study, better control for confounding can be achieved by deriving study-specific weights, to aggregate comorbidities into groups with similar relative risks of the outcomes of interest.

Relative activity of unsaturated fatty acid metabolic pathways in humans.

The four families of unsaturated fatty acids (w9, w7, w6, w3) appear to be elongated and desaturated by enzymes shared among all families. The order of relative pathway activity is hypothesized to be w3 greater than w6 greater than w9 greater than w7. In order to examine this question, we measured by high resolution capillary column gas-liquid chromatography, the relative concentrations of the various fatty acids in plasma from 20 healthy reference subjects, 33 randomly selected subjects from the Framingham Heart Study, and six patients with intestinal malabsorption and suspected severe essential fatty acid deficiency (SEFAD). The ratios of the concentrations of daughter (derivative) fatty acids (DFA) to parent (precursor) fatty acids (PFA) within each family was found to reflect the hypothesized pathway activity. DFA/PFA ratios were 10 to 20 times greater for w3 than for w6 fatty acids (P less than .01), and 5 to 10 times greater for w6 than w9 fatty acids (P less than .01). Patients with SEFAD had lower levels of w3 and w6 fatty acids than the other two groups (P less than .01), higher DFA/PFA in each family (P less than .01), and increased production of both PFA9 and DFA9, consistent with a previously shown shift towards production of w9 fatty acids and with regulation of the pathways by their end products. We also examined the rate of restoration of levels of DFA in the w3 and w6 families in a SEFAD patient intravenously fed soybean oil (55% linoleic acid and 8% linolenic acid). Levels of DFA3s were restored faster than levels of DFA6s, indicating higher w3 pathway activity.(ABSTRACT TRUNCATED AT 250 WORDS)

On the evaluation of drug benefits policy changes with longitudinal claims data: the policy maker's versus the clinician's perspective.

Cost containment in pharmaceutical-benefit plans are often controversially debated for their potential of unintended consequences on health and overall expenditures. Thorough evaluations are needed but hypotheses and design considerations are complex. Our objective is to provide a structured framework for the evaluation of drug-benefit changes using longitudinal claims data. Differential cost sharing (DCS) will serve as a recent example. Benefit-plan managers are mainly interested in the overall performance of their plan. In a policy model, any observed policy-related effects may be compared with what would have happened had the intervention not been implemented by extrapolating the pre-policy trend from the same patients. These estimates will reflect the global consequences of the policy maker's decision. However, such estimates represent summary effects of benefits and harms, separately identifiable in those complying with the intended policy and those not complying. Results from a policy model apply only to a specific policy implementation and tend to underestimate effects when non-compliance is high. Clinical-decision makers and patients, by contrast, are interested in the consequences of patients' actual compliance to the policy. A clinical model assesses the effects of DCS depending on the actual treatment in contrast to the treatment intended by the policy. However, this model must sometimes make, unprovable assumptions about the appropriate control of selection factors. In conclusion, both policy and clinical models should be tested with a clear understanding of their perspectives, hypotheses, and interpretations, using quasi-experimental time-series designs to evaluate the effects of drug cost-containment policies.

Statistical linkage of treatment to diagnosis for research and monitoring of practice patterns.

OBJECTIVES: At each patient contact general practitioners enter information about the diagnoses and the interventions in the electronic medical record (EMR) system. If there is only one diagnosis during a single patient-physician contact, then a causal connection between the diagnosis and the intervention is established. Otherwise it is uncertain what may have been the cause of the intervention. METHODS: Ideally the general practitioners would record a match between each intervention and the diagnosis that justifies it. However, most EMR software is not capable of recording explanatory matches. Furthermore, supplying the matches is a resource-demanding task. In this study the general practitioners were supplied with a matching module for the EMR, so data with full matching between intervention and diagnosis was collected (our "gold standard"). The study models how close the full matching can be recreated by model linkage using different kinds of simple assumptions. RESULTS: The modeling demonstrates a raise in the measure of prediction (sensitivity) from 41.9 percent for a completely random linkage to 90.9 percent based on simple assumptions in the model. The small substantial potential further gain makes it less attractive to apply more intricate assumptions or use more complex modeling (including neural networks). CONCLUSIONS: The perspective of the study lies in the support of the general practitioners with software for comparison of their decisions with those of their peers and also with guidelines. Thus a system for simple quality assurance and awareness to untypical decisions could be incorporated into the electronic medical record systems.