Pharmacogenetics and Oxcarbazepine in Children and Adolescents: Beyond HLA-B*15:02.

Background: Oxcarbazepine is thought to be better-tolerated and less susceptible to drug-drug interactions than its predecessor, carbamazepine. Genetic testing for HLA-B*15:02 is recommended in specific populations to identify those at high risk of severe hypersensitivity reactions; however, other pharmacologic and pharmacogenetic factors that can impact drug disposition may be involved. Methods: We present a case of an 8-year-old boy treated with oxcarbazepine who developed drug reaction with eosinophilia and systemic symptoms (DRESS) with Stevens-Johnsons syndrome overlap and was negative for HLA-B*15:02. We review the extant literature related to oxcarbazepine disposition, and potential pharmacogenetic variants in aldoketoreductase 1C (AKR1C)2-4 that may contribute to this risk. Results: Genetic variability in oxcarbazepine disposition pathways may contribute to tolerability and toxicity, including the development of hypersensitivity reactions. Conclusions: While preemptive genetic testing for HLA-B*15:02 in individuals of Asian ancestry is recommended to prevent severe hypersensitivity reactions to oxcarbazepine, oxcarbazepine concentrations and AKR1C variation may contribute to the risk of severe adverse reactions. We provide recommendations for future study to elucidate whether these individual factors are important for reducing the risk of severe adverse events.

Ontogeny of Scaling Factors for Pediatric Physiologically Based Pharmacokinetic Modeling and Simulation: Cytosolic Protein Per Gram of Liver.

Scaling factors are necessary for translating in vitro drug biotransformation data to in vivo clearance values in physiologically-based pharmacokinetic modeling and simulation. Values for microsomal protein per gram of liver are available from several sources for use as a scaling factor to estimate hepatic clearance from microsomal drug biotransformation data. However, data regarding the distribution of cytosolic protein per gram of liver (CPPGL) values across the lifespan are limited, and sparse pediatric data have been published to date. Thus, CPPGL was determined in 160 liver samples from pediatric (n = 129) and adult (n = 31) donors obtained from multiple sources: the University of Maryland Brain and Tissue Bank, tissue retrieval services at the University of Minnesota and University of Pittsburgh, and Sekisui-XenoTech. Tissues were homogenized and subjected to differential centrifugation to isolate cytosolic fractions. Cytosolic protein content was determined by BCA assay. CPPGL varied from two- to sixfold within each age group/developmental stage. Tissue source and sex did not contribute substantially to variability in protein content. Regression analyses revealed minimal change in CPPGL over the first two decades of life (logCPPGL increases 0.1 mg/g per decade). A mean ± S.D. CPPGL value of 44.4 ± 17.4 mg/g or median 41.0 mg/g is representative of values observed between birth and early adulthood (0-18 years, n = 129). SIGNIFICANCE STATEMENT: Cytosolic protein per gram of liver (CPPGL) is a scaling factor required for physiologically based pharmacokinetic modeling and simulation of drug biotransformation by cytosolic enzymes, but pediatric data are limited. Although CPPGL varies from two- to sixfold within developmental stages, a value of 44.4 ± 17.4 mg/g (mean ± S.D.) is representative of the pediatric period (0-18 years, n = 129).

Potential biomarker of brain response to opioid antagonism in adolescents with eating disorders: a pilot study.

Background: Eating Disorders (ED) affect up to 5% of youth and are associated with reward system alterations and compulsive behaviors. Naltrexone, an opioid antagonist, is used to treat ED behaviors such as binge eating and/or purging. The presumed mechanism of action is blockade of reward activation; however, not all patients respond, and the optimal dose is unknown. Developing a tool to detect objective drug response in the brain will facilitate drug development and therapeutic optimization. This pilot study evaluated neuroimaging as a pharmacodynamic biomarker of opioid antagonism in adolescents with ED. Methods: Youth aged 13-21 with binge/purge ED completed functional magnetic resonance imaging (fMRI) pre- and post-oral naltrexone. fMRI detected blood oxygenation-level dependent (BOLD) signal at rest and during two reward probes (monetary incentive delay, MID, and passive food view, PFV) in predefined regions of interest associated with reward and inhibitory control. Effect sizes for Δ%BOLD (post-naltrexone vs. baseline) were estimated using linear mixed effects modeling. Results: In 12 youth (16-21 years, 92% female), BOLD signal changes were detected following naltrexone in the nucleus accumbens during PFV (Δ%BOLD -0.08 ± 0.03; Cohen's d -1.06, p = 0.048) and anterior cingulate cortex during MID (Δ%BOLD 0.06 ± 0.03; Cohen's d 1.25, p = 0.086). Conclusion: fMRI detected acute reward pathway modulation in this small sample of adolescents with binge/purge ED. If validated in future, larger trials, task-based Δ%BOLD detected by fMRI may serve as a pharmacodynamic biomarker of opioid antagonism to facilitate the development of novel therapeutics targeting the reward pathway, enable quantitative pharmacology trials, and inform drug dosing. Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT04935931, NCT#04935931.

Effects of genotype and food on naltrexone exposure in adolescents.

Naltrexone (NTX), an opioid antagonist metabolized by aldo-keto reductase 1C4 (AKR1C4), is prescribed for psychiatric conditions like eating disorders with variable response. Systemic exposure is highly variable in adults, yet no data exist in children. The purpose of this study was to evaluate NTX exposure in adolescents with eating disorders. Adolescents aged 12-21 years with eating disorders underwent postdose blood sampling in the fasted and/or fed state. NTX and primary active metabolite, 6-ß-naltrexol, were determined by ultra-high performance liquid chromatography tandem mass spectrometry. Pharmacokinetic parameters were determined by noncompartmental analysis. DNA was genotyped for AKR1C4 missense mutations associated with decreased activity (rs3829125 and rs17134592). Linear mixed effects modeling was performed. In 21 participants, aged 16.9 ± 1.9 years (15-21 years), 81% female participants, maximum concentration (Cmax ) was 90.4 ± 129 nM/mg/kg, area under the concentration-time curve from zero to infinity (AUC0-∞ ) was 166 ± 154 nM h/mg/kg, and varied 63-fold and 21-fold, respectively. Compared with wildtype, those with AKR1C4 allelic variations (n = 7) displayed 3.2-fold higher AUC0-∞ , four-fold higher Cmax and delayed time to Tmax . Linear mixed effects modeling demonstrated a large effect of genotype on AUC0-∞ (Cohen's d -2.3) and Cmax (Cohen's d -1.4). Food effect was large for AUC0-∞ (Cohen's d 2.6), but highly variable and failed to reach significance for Cmax. The respective model accounted for 82% of the variance in NTX AUC0-∞ and 46% of the variance in Cmax . NTX systemic exposure is highly variable in adolescents with eating disorders and modulated, in part, by AKR1C4 genotype and food intake. These findings may, in part, explain the large degree of interindividual variability observed response to NTX.

The Impact of Age and Genetics on Naltrexone Biotransformation.

Naltrexone, an opioid antagonist primarily metabolized by aldo-keto reductase 1C4 (AKR1C4), treats pediatric conditions involving compulsiveness (e.g., autism spectrum, Prader-Willi, eating disorders, non-suicidal self-injury). Pharmacokinetic variability is apparent in adults, yet no data are available for children. This study aimed to examine the impact of age and genetic variation on naltrexone biotransformation. Human liver cytosol (HLC) samples (n = 158) isolated from children and adult organ donors were incubated with therapeutically relevant concentrations of naltrexone (0.1, 1 µM). Naltrexone biotransformation was determined by ultraperformance mass spectrometry quantification of the primary metabolite, 6-beta-naltrexol (6ßN), and 6ßN formation rates (pmol/mg protein/min) were calculated. HLCs from organ donors, age range 0-79 y (mean 16.0 ± 18.2 y), 37% (n = 60) female, 20% (n = 33) heterozygous and 1.2% (n = 2) homozygous for co-occurring AKR1C4 variants (S145C/L311V) showed >200-fold range in 6ßN formation (0.37-76.5 pmol/mg protein/min). Source of donor samples was found to be a substantial contributor to variability. Model estimates for a trimmed data set of source-adjusted pediatric samples (aged 0-18 y) suggested that AKR1C4 genetic variation, age, and sex explained 36% of the variability in 6ßN formation. Although activity increased steadily from birth and peaked in middle childhood (2-5 years), genetic variation (S145C/L311V) demonstrated a greater effect on activity than did age. Naltrexone biotransformation is highly variable in pediatric and adult livers and can be partly accounted for by individual factors feasible to obtain (e.g., genetic variability, age, sex). These data may inform a precision therapeutics approach (e.g., exposure optimization) to further study Naltrexone responsiveness in children and adults. SIGNIFICANCE STATEMENT: Biotransformation of the commonly used opioid antagonist naltrexone is highly variable and may contribute to reduced therapeutic response. Age, sex, and genetic variation in the drug-metabolizing enzyme, AKR1C4, are potential factors contributing to this variability. In pediatric samples, genetic variation (S145C/L311V) demonstrates a greater impact on activity than age. Additionally, the source of donor samples was identified as an important contributor and must be accounted for to confidently elucidate the biological variables most impactful to drug biotransformation.

Target to treatment: A charge to develop biomarkers of response and tolerability in child and adolescent psychiatry.

The current pediatric mental health crisis is characterized by staggering rates of depression, anxiety, and suicide. Beyond this, first-line pharmacologic interventions for depressive and anxiety disorders in children and adolescents produce variable responses with two in five youths failing to respond. Given the heterogeneity of treatment response in pediatric depressive and anxiety disorders, pharmacodynamic biomarkers are necessary to develop precision therapeutics by identifying clear targets to guide treatment. This mini-review summarizes candidate biomarkers and their development in pediatric mental health conditions. A framework for how these biomarkers may relate to safety, efficacy (e.g., surrogates for clinical endpoints), tolerability or target engagement (i.e., drug action) in children and adolescents is also presented. Taken together, accumulating data suggest that, in children and adolescents with myriad psychiatric disorders, pharmacodynamic biomarkers could facilitate developing drugs with well-defined targets in specific populations, could inform treatment decisions, and hasten patients' recovery.

Developmental Considerations for the Use of Naltrexone in Children and Adolescents.

Naltrexone (NTX) is a well-tolerated drug with a wide safety margin and mechanism of action that affords use across a wide variety of indications in adults and children. By antagonizing the opioid reward system, NTX can modulate behaviors that involve compulsivity or impulsivity, such as substance use, obesity, and eating disorders. Evidence regarding the disposition and efficacy of NTX is mainly derived from adult studies of substance use disorders and considerable variability exists. Developmental changes, plausible disease-specific alterations and genetic polymorphisms in NTX disposition, and pharmacodynamic pathways should be taken into consideration when optimizing the use of NTX in the pediatric population. This review highlights the current state of the evidence and gaps in knowledge regarding NTX to facilitate evidence-based pharmacotherapy of mental health conditions, for which few pharmacologic options exist.

Long-acting reversible contraceptives (LARCs) as harm reduction: a qualitative study exploring views of women with histories of opioid misuse.

BACKGROUND: The sharp rise in opioid use disorder (OUD) among women coupled with disproportionally high rates of unintended pregnancy have led to a four-fold increase in the number of pregnant women with OUD in the United States over the past decade. Supporting intentional family planning can have multiple health benefits and reduce harms related to OUD but requires a comprehensive understanding of women's perspectives of preventing unintended pregnancies. The purpose of this study was to comprehensively evaluate the knowledge, attitudes and experiences as they relate to seeking contraception, particularly LARCs, among women with active or recovered opioid misuse. METHODS: In-depth interviews and focus group discussions with 36 women with current or past opioid misuse were recorded and transcribed. Transcripts were coded by ≥ 2 investigators. Themes related to contraceptive care seeking were identified and contextualized within the Health Belief Model. RESULTS: Our analysis revealed seven interwoven themes that describe individual level factors associated with contraceptive care seeking in women with current or past opioid misuse: relationship with drugs, reproductive experiences and self-perceptions, sexual partner dynamics, access, awareness of options, healthcare attitudes/experiences, and perceptions of contraception efficacy/ side effects. Overall, perceived susceptibility and severity to unintended pregnancy varied, but most women perceived high benefits of contraception, particularly LARC. However, perceived barriers were too high for most to obtain desired contraception to support family planning intentions. CONCLUSIONS: The individual-level factors identified should inform the design of integrated services to promote patient-centered contraceptive counseling as a form of harm reduction. Interventions should reduce barriers to contraceptive access, particularly LARCs, and establish counseling strategies that use open, non-judgmental communication, acknowledge the continuum of reproductive needs, explore perceived susceptibility to pregnancy, and utilize peer educators.

Profiling Pretomanid as a Therapeutic Option for TB Infection: Evidence to Date.

Tuberculosis (TB) is the most deadly infectious disease globally. Although most individuals achieve a cure, a substantial portion develop multi-drug resistant TB which is exceedingly difficult to treat, and the number of effective agents is dwindling. Development of new anti-tubercular medications is imperative to combat existing drug resistance and accelerate global eradication of TB. Pretomanid (PA-824) represents one of the newest drug classes (ie, nitroimidazooxazines) approved in 2019 by the United States Food and Drug Administration as part of a multi-drug regimen (with bedaquiline and linezolid, BPaL) and recommended by the World Health Organization (WHO) to treat extensively-resistant (XR-TB) and multi-drug resistant tuberculosis (MDR-TB). Approval was granted through the FDA's Limited Population Pathway for Antibacterial and Antifungal Drugs, which accelerates approval for antimicrobial drugs used to treat life-threatening or serious infections in a limited population with unmet need. This review details the pharmacology, efficacy, and safety of this new agent and describes evidence to date for its role in the treatment of drug resistant TB including published, ongoing, and planned studies.

Brief Motivational Intervention to Improve Adolescent Sexual Health Service Uptake: A Pilot Randomized Controlled Trial in the Emergency Department.

OBJECTIVE: To test the hypothesis that our motivational sexual health intervention (SexHealth) would increase health service uptake when compared with control. STUDY DESIGN: In a randomized controlled trial at a pediatric emergency department, sexually active adolescents received either the SexHealth intervention or printed materials (control). SexHealth, delivered by a health educator, was a tablet-based, interactive intervention that included motivational techniques to promote sexual health, condom skills training, and tailored service recommendations. We assessed feasibility (eg, intervention completion, recommendations discussed, intervention duration), acceptability (ie, proportion enrolled and rating intervention as satisfactory), and efficacy; secondary outcomes were sexual and care-seeking behaviors at 6 months. The efficacy outcome was completion of ≥1 service at the index visit (ie, counseling, condoms, emergency contraception for immediate or future use, pregnancy/sexually transmitted infection/HIV testing, sexually transmitted infection treatment, and clinic referral). RESULTS: We enrolled 91 participants (intervention = 44; control = 47). The intervention demonstrated high feasibility: 98% completed the intervention; 98% of recommendations were discussed; duration was 24.6 minutes, and acceptability: 87% of eligible adolescents enrolled and 93% rated the intervention as fairly to very satisfactory. Compared with controls, intervention participants were more likely to complete ≥1 service (98% vs 70%, P < .001) including HIV testing (33% vs 6%, P = .02) and emergency contraception (80% vs 0%, P = .01). There were no meaningful differences between arms in behaviors at follow-up. CONCLUSIONS: SexHealth was feasible to implement, acceptable to youth, and resulted in increased uptake of health services during the emergency department visit. Additional strategies may be needed to extend intervention effects over time. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; NCT03341975.

Adolescent perceptions of pharmacogenetic testing.

Background: Despite the expansion of pharmacogenetics (PGx), the views of pediatric patients remain unknown. This study explores adolescents' understanding and perceptions of PGx testing. Methods: Adolescents who had PGx testing were interviewed and their electronic health records were reviewed. Results: Adolescents accurately described reason for testing and most felt the results impacted their current and future care. None perceived risks to securing future employment or insurance. All felt PGx would benefit their peers. Conclusion: Adolescents understand the reasons for PGx and perceive testing to be useful, low risk and applicable to peers. Findings from this study advocate for the inclusion of adolescents in shared decision-making regarding testing and for active engagement in the discussion of results.

Retrospective Review of Pharmacogenetic Testing at an Academic Children's Hospital.

There is limited evidence to support pharmacogenetic (PGx) testing in children. We conducted a retrospective review of PGx testing among 452 patients at an academic children's hospital to determine the potential utility of PGx in diseases of childhood and to identify targets for future pediatric pharmacogenetic research. An actionable gene-drug pair associated with the 28 genes tested (Clinical Pharmacogenetics Implementation Consortium (CPIC) level A or B, Pharmacogenomics Knowledge Base (PharmGKB) level 1A or B, or US Food and Drug Administration (FDA) recommendation and a PharmGKB level) was present in 98.7% of patients. We identified 203 actionable gene-drug-diagnosis groups based on the indications for each actionable drug listed in Lexicomp. Among patients with an actionable gene-drug-diagnosis group, 49.3% had a diagnosis where the drug was a therapeutic option and PGx could be used to guide treatment selection. Among patients with an associated diagnosis, 30.9% had a prescription for the actionable drug allowing PGx guided dosing. Three genes (CYP2C19, CYP2D6, and CYP3A5) accounted for all the gene-drug-diagnosis groups with matching diagnoses and prescriptions. The most common gene-drug-diagnosis groups with matching diagnoses and prescriptions were CYP2C19-citalopram-escitalopram-depression 3.3% of patients tested; CYP2C19-dexlansoprazole-gastritis-esophagitis 3.1%; CYP2C19-omeprazole-gastritis-esophagitis 2.4%; CYP2D6-atomoxetine-attention deficit hyperactivity disorder 2.2%; and CYP2C19-citalopram-escitalopram-obsessive-compulsive disorder 1.5%. PGx could be used to guide selection of current treatment options or medication dosing in almost half (48.7%) of pediatric patients tested. Mood disorders and gastritis/esophagitis are promising targets for future study of PGx testing because of the high prevalence of these diagnoses and associated actionable gene-drug pairs in the pediatric population.

Naltrexone Reduces Binge Eating and Purging in Adolescents in an Eating Disorder Program.

Objective: Little evidence exists for pharmacologic treatment of binge eating and purging in adolescents with eating disorders. Given the role of the opioid reward system in compulsive binge eating and purging, naltrexone, an opioid antagonist, may be effective in reducing these behaviors. Previous studies have demonstrated that naltrexone reduces binge eating and purging in adults, yet evidence for its use in adolescents is lacking. This case series describes naltrexone utilization, response, and safety in adolescents with eating disorders. Methods: A retrospective chart review of adolescent patients prescribed naltrexone at an academic eating disorder program was completed. Results: Thirty-three adolescents aged 15.3 ± 1.49 years, 94% female gender identity, were treated with naltrexone with the most common expected outcome "to reduce vomiting." Naltrexone was prescribed for 129 ± 125 days. Over half of patients (52%, n = 17) had liver function tests during follow-up, all of which were within normal limits. Three patients (9.1%) experienced nausea related to naltrexone. Just over half of adolescents (67%; n = 22) had documentation of positive naltrexone response (e.g., reduced purging or urge to purge). The mean Clinical Global Impressions-Improvement score was 2.7 ± 1.3 (2 = much improved; 3 = minimally improved). Conclusions: Naltrexone is safe, well tolerated, and effective for the treatment of adolescents with binge eating and/or purging as part of a comprehensive eating disorder treatment plan. Further study is necessary to confirm the effectiveness of naltrexone prospectively and evaluate factors contributing to naltrexone response vs. nonresponse to promote an individualized approach to treatment of binge eating and purging behavior.

Evaluating metronidazole as a novel, safe CYP2A6 phenotyping probe in healthy adults.

AIMS: CYP2A6 is a genetically polymorphic enzyme resulting in differential substrate metabolism and health behaviours. Current phenotyping probes for CYP2A6 exhibit limitations related to procurement (deuterated cotinine), toxicity (coumarin), specificity (caffeine) and age-appropriate administration (nicotine, NIC). In vitro, CYP2A6 selectively forms 2-hydroxymetronidazole (2HM) from metronidazole (MTZ). The purpose of this study was to evaluate MTZ as a CYP2A6 phenotyping probe drug in healthy adults against the well-established method of measuring trans-3-hydroxycotinine (3HC)/cotinine (COT). METHODS: A randomized, cross-over, pharmacokinetic study was completed in 16 healthy, nonsmoking adults. Separated by a washout period of at least 2 weeks, MTZ 500 mg and NIC gum 2 mg were administered and plasma was sampled over 48 hours and 8 hours, respectively. Correlations of plasma metabolite/parent ratios (2HM/MTZ; 3HC/COT) were assessed by Pearson coefficient. CYP2A6 genotyping was conducted and incorporated as a variable of plasma ratio response. RESULTS: Correlations between the plasma ratio 2HM/MTZ and 3HC/COT were ≥ 0.9 at multiple time points (P < 0.001), demonstrating a wide window during which 2HM/MTZ can be queried post-MTZ dose. CYP2A6 genotype had significant impacts on both MTZ and NIC phenotyping ratios with decreased activity predicted phenotypes demonstrating 2HM/MTZ ratios ≤58% and 3HC/COT ratios ≤56% compared with extensive activity predicted phenotypes at all time points examined in the study (P < 0.05). No adverse events were reported in the MTZ arm while 38% (n = 6) of participants reported mild adverse events in the NIC arm. CONCLUSIONS: Metronidazole via 2HM/MTZ performed well as a novel, safe phenotyping probe for CYP2A6 in healthy adults.

Development of a UPLC-MS/MS method for quantitation of metronidazole and 2-hydroxy metronidazole in human plasma and its application to a pharmacokinetic study.

An ultra-performance liquid-chromatography mass-spectrometry (UPLC-MS/MS) method for simultaneous quantitation of metronidazole and 2-hydroxymetronidazole in human plasma was developed and validated. Metronidazole and 2-hydroxymetronidazole were extracted from a small volume of human plasma (10 µL) by hydrophilic lipophilic balanced solid phase extraction on 96-well µ-elution plates. Chromatographic separation of analytes was achieved on an Acquity UPLC BEH C18 column (1.7 µm, 2.1 × 100 mm) using gradient elution with a blend of 0.1% formic acid in water and 0.1% formic acid in methanol at a flow rate of 0.25 mL/min. Mass spectrometric detection was achieved using multiple reaction monitoring (MRM) in positive-ion electrospray-ionization (ESI) mode. Ion transitions were optimized at m/z 171.85->127.9 for metronidazole and m/z 187.9->125.9 for 2-hydroxymetronidazole. The assay was linear for both analytes over the concentration range of 0.1-300 µM; intra- and inter-assay precisions and accuracies were <13%. Recoveries for metronidazole and 2-hydroxymetronidazole ranged from 88 to 99% and 78 to 86%, respectively. Matrix effects for metronidazole and 2-hydroxymetronidazole in plasma ranged from 102 to 105% and 99 to 106%, respectively. The method was successfully applied to determine metronidazole and 2-hydroxymetronidazole plasma concentrations in a pharmacokinetic study conducted in adults administered an oral dose of 500 mg metronidazole. Pharmacokinetic parameters were comparable to previously reported values. By design, this method is amenable to high sample throughput and has the potential to be automated.

Contraceptive Provision to Adolescent Females Prescribed Teratogenic Medications.

BACKGROUND AND OBJECTIVES: Rates of adult women receiving contraceptive provision when simultaneously prescribed a known teratogen are alarmingly low. The prevalence of this behavior among pediatric providers and their adolescent patients is unknown. The objective of this study was to describe pediatric provider behaviors for prescribing teratogens concurrently with counseling, referral, and/or prescribing of contraception (collectively called contraceptive provision) in the adolescent population. METHODS: A retrospective review was conducted examining visits in 2008-2012 by adolescents aged 14 to 25 years in which a known teratogen (US Food and Drug Administration pregnancy risk category D or X) was prescribed. The electronic medical records were queried for demographic information, evidence of contraceptive provision, and menstrual and sexual histories. The data were analyzed using standard statistical methods. RESULTS: Within 4172 clinic visits, 1694 females received 4506 prescriptions for teratogenic medications. The most commonly prescribed teratogens were topiramate, methotrexate, diazepam, isotretinoin, and enalapril. The subspecialties prescribing teratogens most frequently were neurology, hematology-oncology, and dermatology. Overall, contraceptive provision was documented in 28.6% of the visits. Whites versus nonwhites and older versus younger girls were more likely to receive contraceptive provision. The presence of a federal risk mitigation system for the teratogen also increased the likelihood of contraceptive provision. CONCLUSIONS: Our data demonstrate female adolescents prescribed teratogens receive inadequate contraception provision, which could increase their risk for negative pregnancy outcomes. Although the presence of a federal risk mitigation system appears to improve contraceptive provision, these systems are costly and, in some instances, difficult to implement. Efforts to improve provider practices are needed.