Utilizing a Faculty Development Program to Promote Safer Opioid Prescribing for Chronic Pain in Internal Medicine Resident Practices.

OBJECTIVE: To implement a skills-based faculty development program (FDP) to improve Internal Medicine faculty's clinical skills and resident teaching about safe opioid prescribing. DESIGN: An FDP for Internal Medicine attendings that included a one-hour didactic presentation followed immediately by an Objective Structured Clinical Examination (OSCE) that focused on assessing and managing opioid misuse risk, opioid treatment outcomes (benefits and harms), and aberrant opioid use behaviors. The evaluation compared pre- and three-months-post-FDP changes in faculty's safe opioid prescribing knowledge, attitudes, confidence (clinical and teaching), and self-reported resident teaching. RESULTS: The 25 Internal Medicine faculty participants had a mean of 13 years in clinical practice, including 10 years precepting residents. During the three months post-FDP, faculty treated a mean of 22 patients with chronic pain on long-term opioids and precepted a mean of seven residents caring for patients on long-term opioids. At three months post-FDP, there were significant improvements in correct responses to knowledge questions (68% to 79% P = 0.008), "high-level" confidence in safer opioid prescribing clinical practice (43.5% to 82.6% P = 0.007) and resident teaching (45.8% to 83.3%, P = 0.007), and improvements in alignment of desired attitudes toward safer opioid prescribing. There were nonsignificant increases in self-reported safe opioid prescribing resident teaching. CONCLUSIONS: A skills-based faculty development program that includes a lecture followed by an OSCE can improve Internal Medicine faculty safe opioid prescribing knowledge, attitudes, and clinical and teaching confidence. Improving resident teaching may require additional training in safe opioid prescribing teaching skills.

Effects of a Lutein and Zeaxanthin Intervention on Cognitive Function: A Randomized, Double-Masked, Placebo-Controlled Trial of Younger Healthy Adults.

Background: Past studies have suggested that higher lutein (L) and zeaxanthin (Z) levels in serum and in the central nervous system (as quantified by measuring macular pigment optical density, MPOD) are related to improved cognitive function in older adults. Very few studies have addressed the issue of xanthophylls and cognitive function in younger adults, and no controlled trials have been conducted to date to determine whether or not supplementation with L + Z can change cognitive function in this population. Objective: The purpose of this study was to determine whether or not supplementation with L + Z could improve cognitive function in young (age 18-30), healthy adults. Design: A randomized, double-masked, placebo-controlled trial design was used. Fifty-one young, healthy subjects were recruited as part of a larger study on xanthophylls and cognitive function. Subjects were randomized into active supplement (n = 37) and placebo groups (n = 14). MPOD was measured psychophysically using customized heterochromatic flicker photometry. Cognitive function was measured using the CNS Vital Signs testing platform. MPOD and cognitive function were measured every four months for a full year of supplementation. Results: Supplementation increased MPOD significantly over the course of the year, vs. placebo (p < 0.001). Daily supplementation with L + Z and increases in MPOD resulted in significant improvements in spatial memory (p < 0.04), reasoning ability (p < 0.05) and complex attention (p < 0.04), above and beyond improvements due to practice effects. Conclusions: Supplementation with L + Z improves CNS xanthophyll levels and cognitive function in young, healthy adults. Magnitudes of effects are similar to previous work reporting correlations between MPOD and cognition in other populations.

The Surgeon General's Facing Addiction report: An historic document for health care.

The publication of Facing Addiction in America: The Surgeon General's Report on Alcohol, Drugs, and Health presents an historic moment not only for the field of addiction medicine, but also for the United States as a nation. The Board of Directors of the Association for Medical Education and Research in Substance Abuse (AMERSA), on behalf of our organization, would like to express our appreciation of the efforts of Dr. Vivek Murthy and the Surgeon General's Office to publish the first surgeon general's report covering substance misuse and substance use disorders.

A unique combination of micronutrients rejuvenates cognitive performance in aged mice.

It is widely believed that diet can influence the onset and severity of cognitive aging, but the optimal combination of micronutrients and molecular and cellular mechanisms remain elusive. The purpose of this study was to compare the effects of eight distinct diets, consisting of various concentrations of selected micronutrients, on learning and memory as well as markers of neuronal plasticity, and metabolic and neuro-immune status of the aged hippocampus. Eighteen-month-old male and female C57BL/6J mice were fed the diets for 16 weeks, followed by learning and memory trials on the active avoidance task. Number of immature neurons were measured by immunohistochemical detection of doublecortin (DCX+) in the granule layer of the dentate gyrus. Amount of mitochondrial DNA (mtDNA) and gene expression of molecular markers of mitochondrial biogenesis (Ppargc1α, Sirt1, Tfam), and neuroinflammation (IL-10, Alox15, Ptgs2, IL-1ß, IL-6 and Tnf) were assessed by quantitative real time polymerase chain reaction (qRT-PCR) of hippocampal samples. Tissue levels of selected micronutrients and a number of metabolites were measured by liquid chromatography-mass spectrometry. The diet supplemented with RRR d-alpha tocopheryl acetate, citicholine, 5-methyltetrahydrofolic acid, quercetin and the n-3 fatty acid phosphatidylserine-docosahexaenoic acid, improved performance on the active avoidance learning and memory task compared to all the other less-complex diets. This diet also increased IL-10 expression and attenuated the age-related change in mtDNA content in the hippocampus without affecting metabolite levels. Results suggest cognitive benefits of wholesome diets are partially mediated through combined antioxidant and anti-inflammatory activities of optimized mixtures of micronutrients.

Long-lasting impairments in adult neurogenesis, spatial learning and memory from a standard chemotherapy regimen used to treat breast cancer.

The negative impact of chemotherapy on cognitive function in cancer patients has gained increasing attention in the last decade. Whilst the short-term acute effects on cognition are expected following chemotherapy, the persistence of such impairments in the long-term is still in question. This is despite clinical evidence indicating cognitive difficulties may persist well beyond treatment and affect quality of life. In the present study, we assessed the long-term (3 months) cognitive impact of chemotherapy in a mouse model intended to mimic the human female post-menopausal population receiving chemotherapy for breast cancer. Ovariectomized, female, C57BL/6J mice received two doses of Doxorubicin, Cyclophosphamide, and 5-Fluorouracil or saline vehicle (control), separated by one week. During this interval, mice received BrdU injections to label dividing cells. Results indicate a persistent impairment in learning and recall (1h, 24h and 48h) on the Morris water maze, reduced survival and differentiation of new neurons (BrdU+/NeuN+), and a persistent decline in proliferation of new cells (Ki67(+)) in the dentate gyrus. Locomotor activity, motor performance, and anxiety-like behavior were unaffected. We further evaluated the efficacy of a diet enriched in omega-3-fatty acids (DHA+EPA+DPA), in reversing long-term chemotherapy deficits but no rescue was observed. The model described produces long-term cognitive and cellular impairments from chemotherapy that mimic those observed in humans. It could be useful for identifying mechanisms of action and to test further the ability of lifestyle interventions (e.g., diet) for ameliorating chemotherapy-induced cognitive impairments.

Risk Factors for Relapse and Higher Costs Among Medicaid Members with Opioid Dependence or Abuse: Opioid Agonists, Comorbidities, and Treatment History.

Clinical trials show that opioid agonist therapy (OAT) with methadone or buprenorphine is more effective than behavioral treatments, but state policymakers remain ambivalent about covering OAT for long periods. We used Medicaid claims for 52,278 Massachusetts Medicaid beneficiaries with a diagnosis of opioid abuse or dependence between 2004 and 2010 to study associations between use of methadone, buprenorphine or other behavioral health treatment without OAT, and time to relapse and total healthcare expenditures. Cox Proportional Hazards ratios for patients treated with either methadone or buprenorphine showed approximately 50% lower risk of relapse than behavioral treatment without OAT. Expenditures per month were from $153 to $233 lower for OAT episodes compared to other behavioral treatment. Co-occurring alcohol abuse/dependence quadrupled the risk of relapse, other non-opioid abuse/dependence doubled the relapse risk and severe mental illness added 80% greater risk compared to those without each of those disorders. Longer current treatment episodes were associated with lower risk of relapse. Relapse risk increased as prior treatment exposure increased but prior treatment was associated with slightly lower total healthcare expenditures. These findings suggest that the effectiveness of OAT that has been demonstrated in clinical trials persists at the population level in a less controlled setting and that OAT is associated with lower total healthcare expenditures compared to other forms of behavioral treatment for patients with opioid addiction. Co-occurring other substance use and mental illness exert strong influences on cost and risk of relapse, suggesting that individuals with these conditions need more comprehensive treatment.

Adherence to Buprenorphine Treatment Guidelines in a Medicaid Program.

BACKGROUND: Buprenorphine is the most frequently prescribed medication for treating substance use disorders in the United States, but few studies have evaluated the structure of treatment delivered in real-world settings. The purpose of this study is to investigate adherence to current buprenorphine treatment guidelines using administrative data for Massachusetts Medicaid. METHODS: We identified buprenorphine treatment episodes beginning in 2009 through pharmacy claims. We then used service claims to identify treatment-related physician, behavioral, and laboratory services received in the induction, stabilization, and maintenance phases of these treatment episodes. Rates of service utilization were compared with those recommended in treatment guidelines. RESULTS: A total of 3674 treatment episodes met inclusion criteria, representing 3005 unique Medicaid beneficiaries. Liver enzymes were tested in 47.3% of episodes, but testing for hepatitis C (23.2%), hepatitis B (19.6%), and human immunodeficiency virus (HIV; 13.7%) was less frequent. Adherence to recommended physician visit frequency was 37.6% during induction, 39.7% during stabilization, and 51.2% during maintenance. For behavioral care, adherence rates were 40.0% during induction, 41.2% during stabilization, and 41.0% during maintenance. Rates of toxicology testing met or exceeded recommendations in just over 60% of episodes in the induction (61.1%), stabilization (62.1%), and maintenance (61.4%) phases. Although rates varied by treatment phase, substantial proportions of episodes showed no evidence of physician visits (27.2-42.8%), behavioral care (44.3-60.0%), and toxicology screening (25.3-39.0%). CONCLUSIONS: Our data suggest that there is significant variability in the structure of buprenorphine treatment provided to Massachusetts Medicaid beneficiaries, and that half or less of episodes include physician and behavioral visits at recommended frequencies. The use of administrative data for this type of analysis is limited by the potential for missing or inaccurate data. More research is needed to establish the levels of services most closely associated with positive outcomes to help guide providers in offering the highest-quality care.

Co-occurring risk factors for arrest among persons with opioid abuse and dependence: implications for developing interventions to limit criminal justice involvement.

Persons who abuse or are dependent on opioids are at elevated risk for arrest. Co-occurring behavioral health problems may exacerbate that risk, although the extent of any such increase has not been described. This study examines such risk factors among 40,238 individuals with a diagnosis of opioid abuse or dependence who were enrolled in the Massachusetts Medicaid program in 2010. Medicaid data were merged with statewide arrest data to assess the effects of co-existing mental illness, substance abuse, and previous arrests on arrest during 2010. Persons with serious mental illnesses (psychotic and bipolar disorders) and those with two or more pre-2010 arrests had significantly increased greater odds of arrest. We believe this to be the first study examining effects of co-occurring risk factors on arrest in a large population with opioid dependency/abuse. These findings identify predictors of arrest that could be used to design interventions targeting specific co-occurring risk factors.

The impact of prior authorization on buprenorphine dose, relapse rates, and cost for Massachusetts Medicaid beneficiaries with opioid dependence.

OBJECTIVE: To assess the impact of a 2008 dose-based prior authorization policy for Massachusetts Medicaid beneficiaries using buprenorphine + naloxone for opioid addiction treatment. Doses higher than 16 mg required progressively more frequent authorizations. DATA SOURCES: Mediciaid claims for 2007 and 2008 linked with Department of Public Health (DPH) service records. STUDY DESIGN: We conducted time series for all buprenorphine users and a longitudinal cohort analysis of 2,049 individuals who began buprenorphine treatment in 2007. Outcome measures included use of relapse-related services, health care expenditures per person, and buprenorphine expenditures. DATA COLLECTION/EXTRACTION METHODS: We used ICD-9 codes and National Drug Codes to identify individuals with opioid dependence who filled prescriptions for buprenorphine. Medicaid and DPH data were linked with individual identifiers. PRINCIPAL FINDINGS: Individuals using doses >24 mg decreased from 16.5 to 4.1 percent. Relapses increased temporarily for some users but returned to previous levels within 3 months. Buprenorphine expenditures decreased but total expenditures did not change significantly. CONCLUSION: Prior authorization policies strategically targeted by dose level appear to successfully reduce use of higher than recommended buprenorphine doses. Savings from these policies are modest and may be accompanied by brief increases in relapse rates. Lower doses may decrease diversion of buprenorphine.

The evidence doesn't justify steps by state Medicaid programs to restrict opioid addiction treatment with buprenorphine.

Many state Medicaid programs restrict access to buprenorphine, a prescription medication that relieves withdrawal symptoms for people addicted to heroin or other opiates. The reason is that officials fear that the drug is costlier or less safe than other therapies such as methadone. To find out if this is true, we compared spending, the use of services related to drug-use relapses, and mortality for 33,923 Massachusetts Medicaid beneficiaries receiving either buprenorphine, methadone, drug-free treatment, or no treatment during the period 2003-07. Buprenorphine appears to have significantly expanded access to treatment because the drug can be prescribed by a physician and taken at home compared with methadone, which by law must be administered at an approved clinic. Buprenorphine was associated with more relapse-related services but $1,330 lower mean annual spending than methadone when used for maintenance treatment. Mortality rates were similar for buprenorphine and methadone. By contrast, mortality rates were 75 percent higher among those receiving drug-free treatment, and more than twice as high among those receiving no treatment, compared to those receiving buprenorphine. The evidence does not support rationing buprenorphine to save money or ensure safety.

Predictors of prenatal and postpartum care adequacy in a medicaid managed care population.

PURPOSE: To examine factors affecting prenatal and postpartum care for an insured, but vulnerable, population. METHODS: Individual-level data on three measures of care adequacy were obtained for Massachusetts Medicaid Managed Care women who met the National Committee on Quality Assurance's Healthcare Effectiveness Data and Information Set denominator criteria for the prenatal and postpartum care measures in 2007 (n = 1,882). We modeled individual compliance with each measure separately as a binomial logistic function with individual and neighborhood characteristics, provider type, and health plan as explanatory variables. FINDINGS: In our sample, 85% of women initiated care in the first trimester, but only 62% met the goal of receiving more than 80% of the recommended number of prenatal visits. Just 60% had a timely postpartum care visit. Having a diagnosis of substance abuse or dependence reduced the odds of meeting all measures. Women with disabilities were less likely to attain two of the three measures of adequate care, as were women with other children in the household. Women who enrolled in Medicaid in the first trimester were more likely to receive the recommended number of prenatal visits than those who were enrolled before pregnancy. CONCLUSION: Given the importance of prenatal and postpartum care for maternal and child health and the recent national declining trend in timely care, initiatives to improve rates of timely and adequate care are crucial and must include components tailored toward particularly vulnerable subpopulations.

Factors associated with Medicaid patients' access to buprenorphine treatment.

Some studies have shown that patients entering buprenorphine treatment differ from those in other modalities. This study compares Massachusetts Medicaid beneficiaries who received buprenorphine, methadone or other treatment for opioid addiction in 2007. Patients' characteristics and comorbidities were identified through claims data, and associations between these factors and treatment type were investigated using multivariate analysis. Among patients receiving opioid agonist treatments, patients with prior buprenorphine treatment, HIV, bipolar disease, and other substance use disorders were more likely to receive buprenorphine treatment compared with methadone, whereas patients with heart failure, diabetes, hepatitis C, major depression, and anxiety were less likely to receive buprenorphine treatment. These differences may suggest variability in patient access, treatment preferences, and a need for different levels of services in different modalities. This information is important for understanding the impact of this new treatment in Medicaid populations and for developing treatment systems to best meet patients' needs.

Disparities in routine breast cancer screening for Medicaid managed care members with a work-limiting disability.

OBJECTIVE: Examine disparities in routine mammography for women who qualify for Medicaid, because of a work-limiting disability. METHODS: Individual-level data were obtained for women enrolled in Massachusetts Medicaid Managed Care plans who met the 2007 Healthcare Effectiveness Data and Information Set (HEDIS) criteria for the breast cancer screening measure (n=35,171). Disability status was determined from Medicaid eligibility records. Mammography screening was modeled using multivariate logistic regression. Separate models for women with and without a disability were also estimated. RESULTS: Although unadjusted breast cancer screening rates were roughly equal for women with and without disability, after adjusting for confounders disability status had a significant negative association with screening mammography (OR=0.74; p<0.0001). Living farther from a mammography facility or having a diagnosis of domestic violence reduced the odds of screening for women with disabilities, but not for other women. Having a higher illness burden was more detrimental to screening for women with a disability than for those without. Both groups benefited similarly from the first 26 ambulatory care visits, but the impact of additional visits on screening was much larger among women with disabilities. CONCLUSION: Nationwide, rates of routine mammography for Medicaid managed care plans averaged below 50% in 2006. Given that a majority of eligible women served by Medicaid have disabilities, and studies have shown that women with disabilities are more likely to be diagnosed with late stage disease, a focus on improving rates of screening for women with disabilities is overdue.

Beyond health plans: behavioral health disorders and quality of diabetes and asthma care for Medicaid beneficiaries.

BACKGROUND: Most health insurance plans monitor ambulatory care quality using the Healthcare Effectiveness Data and Information Set (HEDIS), publicly reporting results at the plan level. Plan-level comparisons obscure the influence of patients served or settings where care is delivered. Mental illness, substance abuse, and other physical comorbidities, particularly prevalent among Medicaid beneficiaries, can impact adherence to recommended care. We analyzed individual-level HEDIS measures for diabetes and asthma from 5 Medicaid managed care plans to understand how these factors contribute to quality. METHODS: We used claims and medical records to study HEDIS measures for persistent asthma (n = 9103) and diabetes (n = 1790) among beneficiaries enrolled in Massachusetts' Medicaid program during 2004 and 2005. Logistic regression models included patient-level demographic and health factors, provider type, region, and managed care plan. RESULTS: Alcohol and drug use disorders and emergency department use were associated with lower quality care for most measures. Glycemic control was better for patients with diabetes and severe mental illness. Patients with higher illness burden and with more frequent ambulatory visits received higher quality care for both conditions. Younger adults received recommended care less often than older adults. Quality varied across plans. CONCLUSIONS: Additional efforts to improve quality of care for asthma and diabetes for Medicaid beneficiaries are needed for individuals with substance use disorders and young adults. Although evidence of higher quality for patients with multiple conditions is encouraging, improving quality for comparatively healthier individuals might also produce significant long-term benefits.

Comparative evaluation of two asthma care quality measures among Medicaid beneficiaries.

BACKGROUND: The relative performance of asthma care quality measures has not been evaluated in Medicaid populations. METHODS: Using complete claims and pharmaceutical data for 19,076 patients with persistent asthma (based on Health Effectiveness and Data Information Set criteria) in five Medicaid populations, we compared the following two measures of asthma care quality: filling prescriptions for controller asthma medications within 1 year and the ratio of controller medication to the total number of asthma medication prescriptions filled within 1 year. We calculated whether meeting each quality measure was associated with decreased odds of emergency department (ED) treatment episodes. We then compared the odds ratios, receiver operating characteristic (ROC) curves, and deviances between models, using each measure to predict ED utilization in Medicaid populations. RESULTS: Although meeting each measure was associated with lower odds of ED utilization, this decrease was larger if the controller asthma medication measure was met rather than the ratio measure. Additionally, models using the controller medication measure had greater areas under the ROC curve and smaller deviances than models using the ratio measure. CONCLUSIONS: Both administrative measures of asthma care quality were associated with lower odds of ED utilization. The controller medication measure of asthma care quality may be better than the ratio measure in relation to emergency asthma care utilization by Medicaid beneficiaries.

The quality of asthma care among adults with substance-related disorders and adults with mental illness.

OBJECTIVE: The purpose of this study was to investigate whether the presence of substance-related disorders or mental illness may affect the quality of medication management in asthma care. METHODS: Claims from 1999 for adult Medicaid patients with persistent asthma from five states were analyzed. Sample sizes ranged from 1,207 to 5,815. The adjusted odds of meeting two quality-of-care measures for asthma were calculated: the Health Effectiveness Data and Information Set (HEDIS) measure of filling a single prescription for a controller medication and a non-HEDIS measure of achieving a ratio of long-term controller medications to total asthma medications of > or = .5. RESULTS: Odds of achieving the HEDIS measure were lower for patients with substance-related or schizophrenia disorders in two states (range of odds ratio [OR]=.69, 95% confidence interval [CI]=.53-.90, to OR=.81, 95% CI=.69-.96), but the odds increased for patients with depressive disorders in two states (OR=1.34, CI= 1.12-1.61; OR=1.37, CI=1.05-1.77) and for patients with bipolar disorder in one state (OR=1.69, CI=1.13-2.55). Odds of achieving the ratio measure were lower for patients with substance-related disorders in four states (range of OR=.63, CI=.47-.88, to OR=.75, CI=.62-.92) and higher for patients with depressive disorders, although only in one state (OR=1.25, CI=1.03-1.53). CONCLUSIONS: Patients with substance-related disorders and those with schizophrenia disorders may be receiving lower-quality asthma care, whereas patients with some other forms of mental illness may be receiving higher-quality care. Further studies are needed to identify the determinants of high-quality asthma care and the validity of quality measures based on administrative data in these populations.

Patterns of health care utilization for asthma treatment in adults with substance use disorders.

OBJECTIVES: : National goals for improving asthma outcomes include decreasing emergency room utilization and increasing adherence to outpatient treatment guidelines. Few studies have examined the impact of substance use disorders on asthma treatment. The objective of this study was to describe correlations between substance use disorders and patterns of healthcare utilization for asthma care. METHODS: : We performed a retrospective analysis of 1999 Medicaid claims for adults with asthma from 5 states. Adjusted odds of receiving asthma treatment in outpatient, inpatient, and emergency settings were calculated for patients with substance use disorder (SUD). RESULTS: : Consistent patterns emerge demonstrating significantly lower odds of utilization of outpatient services for asthma in patients with SUD. A trend toward increased utilization of acute care resources was observed, with odds of emergency care for asthma significantly increased in New Jersey (odds ratio [OR], 1.14; 95% confidence interval [CI], 1-1.31) and Georgia (OR, 1.24; 95% CI, 1.04-1.48), and odds of inpatient care for asthma significantly increased in Georgia (OR, 1.42; 95% CI, 1.03-1.95). CONCLUSIONS: : Substance use disorders are associated with decreased odds of receiving outpatient care and equivalent or increased odds of receiving emergency and inpatient care for asthma. Consequently, outpatient-based strategies to improve asthma care may have a very limited impact for this population. Identifying asthma patients with SUD in acute care settings and enhancing the care they receive in these settings may be necessary to improve adherence to treatment guidelines and decrease utilization in this population.

Signaling pathways initiated by beta-hydroxy-beta-methylbutyrate to attenuate the depression of protein synthesis in skeletal muscle in response to cachectic stimuli.

To investigate the mechanism by which beta-hydroxy-beta-methylbutyrate (HMB) attenuates the depression of protein synthesis in the skeletal muscle of cachectic mice, a study has been carried out in murine myotubes in the presence of proteolysis-inducing factor (PIF). PIF inhibited protein synthesis by 50% within 4 h, and this was effectively attenuated by HMB (25-50 muM). HMB (50 muM) alone stimulated protein synthesis, and this was attenuated by rapamycin (27 nM), an inhibitor of mammalian target of rapamycin (mTOR). Further evidence for an involvement of this pathway was shown by an increased phosphorylation of mTOR, the 70-kDa ribosomal S6 kinase (p70(S6k)), and initiation factor 4E-binding protein (4E-BP1) and an increased association of eukaryotic initiation factor 2 (eIF4E) with eIF4G. PIF alone induced a transient (1-2 h) stimulation of phosphorylation of mTOR and p70(S6k). However, in the presence of HMB, phosphorylation of mTOR, p70(S6k), and 4E-BP1 was increased, and inactive 4E-BP1-eIF4E complex was reduced, whereas the active eIF4G.eIF4E complex was increased, suggesting continual stimulation of protein synthesis. HMB alone reduced phosphorylation of elongation factor 2, but this effect was not seen in the presence of PIF. PIF induced autophosphorylation of the double-strand RNA-dependent protein kinase (PKR), leading to phosphorylation of eIF2 on the alpha-subunit, which would inhibit protein synthesis. However, in the presence of HMB, phosphorylation of PKR and eIF2alpha was attenuated, and this was also observed in skeletal muscle of cachectic mice administered HMB (0.25 g/kg). These results suggest that HMB attenuates the depression of protein synthesis by PIF in myotubes through multiple mechanisms.