Conversion ratios: Why is it so challenging to construct opioid conversion tables?

Standardizing opioid management is challenging due to the absence of a ceiling dose, the unknown ideal therapeutic plasma level, and the lack of an clear relationship between dose and therapeutic response. Opioid rotation or conversion, which is switching from one opioid, route of administration, or both, to another, to improve therapeutic response and reduce toxicities, occurs in 20-40 percent of patients treated with opioids. Opioid conversion is often needed when there are adverse effects, toxicities, or inability to tolerate a certain opioid formulation. A majority of patients benefit from opioid conversion, leading to improved analgesia and less adverse effects. There are different published ways of converting opioids in the literature. This review of 20 years of literature is centered on opioid conversions and aims to discuss the complexity of converting opioids. We discuss study designs, outcomes and measures, pain phenotypes, patient characteristics, comparisons of equivalent doses between opioids, reconciling conversion ratios between opioids, routes, directional differences, half-lives and metabolites, interindividual variability, and comparison to package insert information. Palliative care specialists have not yet come to a consensus on the ideal opioid equianalgesic table; however, we discuss a recently updated table, based on retrospective evidence, that may serve as a gold standard for practical use in the palliative care population. More robust, well-designed studies are needed to validate and guide future opioid conversion data.

The Burden of Protozoal and Helminth Intestinal Infections and Related Risk Factors Among the Households of Migrant Construction Workers in Bhopal.

There are a few existing gaps and paucity of literature from Southeast Asia on the prevalence of intestinal parasitic infections among migrant construction workers. The present cross-sectional study was conducted to address this gap among migrant construction workers and their households in Bhopal. The study design included an interview questionnaire survey prior to the enrollment of participants and stool sample collection. The stool samples were processed according to the study protocol of macroscopy, occult blood testing, microscopy techniques combined with modified acid-fast, and sedimentation techniques. Participants were deemed positive if they exhibited microscopic findings in one out of three stool samples per recruit. We recommended clinical consultation for these cases and provided a report. Direct therapeutic intervention was not part of the study. The total recruits were 361. The predominant age group was young, i.e., aged 21 to 30 years (122/361, 33.8%), with the majority of females (55.2%). Most workers were occupied with work of digging soil (47.4%). The majority of participants (93.1%) practiced open field defecation (OFD). The prevalence of intestinal parasitic infections among migrant workers and households was 36.9% (133/361). Monoinfection was 88.7%, with 41% from Entamoeba histolytica/Entamoeba dispar. Monoinfection with Hymenolepis nana (10.2%) was a predominant helminth. The most common coinfection observed was of Giardia intestinalis with Ancylostoma duodenale (26.7%). Hand washing was the only independent predictor with an odds ratio of 3.6. Migrant behavior of the construction workers and their households was the major reason for not reaching the benefits of deworming schemes for children and vulnerability to intestinal parasitic infections.

Midfacial Toddler Excoriation syndrome (MiTES): case series, diagnostic criteria and evidence for a pathogenic mechanism.

BACKGROUND: PRDM12 polyalanine tract expansions cause two different disorders; Midfacial Toddler Excoriation Syndrome (MiTES) - itch with normal pain sensation associated with homozygous 18 alanines (18A), and congenital insensitivity to pain (CIP) with normal itch with homozygous 19A. Knowledge of the phenotype, genotype, and disease mechanism of MiTES is incomplete. Why PRDM12 18A versus 19A can cause almost opposite phenotypes is unknown; no other poly-alanine or poly-glutamine tract expansion disease causes two such disparate phenotypes. METHODS: We assessed the genotype and phenotype of 9 new, 9 atypical, and 6 previously reported patients diagnosed with MiTES. Using cell lines with homozygous PRDM12 of 12A (normal), 18A (MiTES) and 19A (CIP) we examined PRDM12 aggregation and subcellular localisation by image separation confocal microscopy and sub-cellular fractionation western blotting. RESULTS: MiTES presents in the first year of life, and in all cases the condition regresses over the first decade leaving scarring. The MiTES phenotype is highly distinctive. Features overlapping with PRDM12-CIP are rarely found. The genotype-phenotype study of PRDM12 polyalanine tract shows that 7A -15A are normal; 16A -18A are associated with MiTES; 19A leads to CIP; and no clinically atypical MiTES cases had an expansion. PRDM12 aggregation and sub-cellular localisation differ significantly between 18A and normal 12A cell lines and between 18A and 19A cell lines. MiTES is a new protein aggregation disease. CONCLUSION: We provide diagnostic criteria for MiTES, and improved longitudinal data. MiTES and CIP are distinct phenotypes despite their genotypes varying by a single alanine in the PRDM12 polyalanine tract. We found clear distinctions between the cellular phenotypes of normal, MiTES and CIP cells.. We hypothesise that the developmental environment of the trigeminal ganglion is unique and critically sensitive to prenatal and postnatal levels of PRDM12.

Inpatient Transition from Methadone to Buprenorphine-Naloxone Using a Microdosing Strategy in a Postoperative Cancer Patient: A Case Report.

Background: Buprenorphine initiation in opioid-tolerant patients usually requires decreasing the total opioid intake per day due to its potential for precipitating withdrawal. However, this strategy may not be tolerated in patients who require higher amounts of opioids, such as those with cancer pain. Case Presentation: We utilized a buprenorphine microdosing strategy for a postoperative cancer patient who was previously taking buprenorphine-naloxone for chronic noncancer pain, then initiated on methadone for uncontrolled cancer-related pain. He had a planned cancer resection in the hospital. He subsequently underwent a successful transition from methadone to buprenorphine-naloxone through microdosing in one week with close monitoring in the inpatient setting. Conclusions: Using a microdosing strategy to transition from methadone to buprenorphine-naloxone in a span of days was achieved in this case report. More research regarding the feasibility and tolerability of microinductions is needed, especially in the setting of chronic pain or cancer-related pain.

O-Glycome Profiling of Breast Cancer Cell Lines to Understand Breast Cancer Brain Metastasis.

Breast cancer is the second leading cause of cancer-related death among women and a major source of brain metastases. Despite the increasing incidence of brain metastasis from breast cancer, the underlying mechanisms remain poorly understood. Altered glycosylation is known to play a role in various diseases including cancer metastasis. However, profiling studies of O-glycans and their isomers in breast cancer brain metastasis (BCBM) are scarce. This study analyzed the expression of O-glycans and their isomers in human breast cancer cell lines (MDA-MB-231, MDA-MB-361, HTB131, and HTB22), a brain cancer cell line (CRL-1620), and a brain metastatic breast cancer cell line (MDA-MB-231BR) using nanoLC-MS/MS, identifying 27 O-glycan compositions. We observed significant upregulation in the expression of HexNAc1Hex1NeuAc2 and HexNAc2Hex3, whereas the expression of HexNAc1Hex1NeuAc1 was downregulated in MDA-MB-231BR compared to other cell lines. In our isomeric analysis, we observed notable alterations in the isomeric forms of the O-glycan structure HexNAc1Hex1NeuAc1 in a comparison of different cell lines. Our analysis of O-glycans and their isomers in cancer cells demonstrated that changes in their distribution can be related to the metastatic process. We believe that our investigation will contribute to an enhanced comprehension of the significance of O-glycans and their isomers in BCBM.

Dynamic intervention to enhance the stability of PEGylated Ibrutinib loaded lipidic nano-vesicular systems: transitioning from colloidal dispersion to lyophilized product.

Liposomes being a promising colloidal system facilitates delivery of drugs with limited pharmacokinetic properties to achieve desirable clinical applications. However, development of a stable liposomal system is always challenging due to multiple complexities involved. Aqueous instability of liposomes and impact of various process and formulation parameters can lead to serious alteration of its therapeutic performance. In the proposed work, the authors aim to develop stable Ibrutinib-loaded liposomes using lyophilization and Quality-by-Design and assess their long-term stability. Ibrutinib-loaded liposomes were developed and optimized using Quality-by-Design technique and were further PEGylated and characterized for the same. Effect of cryoprotectants during lyophilization and other parameters are evaluated to obtain a robust formulation. The stability studies were conducted upto 6 months at various storage conditions to evaluate the effect of lyophilization. The impact of formulation, processing and lyophilization parameters on physicochemical properties of developed liposomal systems were evaluated and are critically discussed. Liquid dispersion exhibited a %degradation of 16-36% at 25 °C/60% RH which was reduced for less than 1% in lyophilized formulation for 6 months. Critical analysis and assessment of various parameters lead to identification of optimum conditions to manufacture this drug product and also opens way forward for further evaluation and translational possibilities.

Chatbot Performance in Defining and Differentiating Palliative Care, Supportive Care, Hospice Care.

CONTEXT: Artificial intelligence (AI) chatbot platforms are increasingly used by patients as sources of information. However, there is limited data on the performance of these platforms, especially regarding palliative care terms. OBJECTIVES: We evaluated the accuracy, comprehensiveness, reliability, and readability of three AI platforms in defining and differentiating "palliative care," "supportive care," and "hospice care." METHODS: We asked ChatGPT, Microsoft Bing Chat, Google Bard to define and differentiate "palliative care," "supportive care," and "hospice care" and provide three references. Outputs were randomized and assessed by six blinded palliative care physicians using 0-10 scales (10 = best) for accuracy, comprehensiveness, and reliability. Readability was assessed using Flesch Kincaid Grade Level and Flesch Reading Ease scores. RESULTS: The mean (SD) accuracy scores for ChatGPT, Bard, and Bing Chat were 9.1 (1.3), 8.7 (1.5), and 8.2 (1.7), respectively; for comprehensiveness, the scores for the three platforms were 8.7 (1.5), 8.1 (1.9), and 5.6 (2.0), respectively; for reliability, the scores were 6.3 (2.5), 3.2 (3.1), and 7.1 (2.4), respectively. Despite generally high accuracy, we identified some major errors (e.g., Bard stated that supportive care had "the goal of prolonging life or even achieving a cure"). We found several major omissions, particularly with Bing Chat (e.g., no mention of interdisciplinary teams in palliative care or hospice care). References were often unreliable. Readability scores did not meet recommended levels for patient educational materials. CONCLUSION: We identified important concerns regarding the accuracy, comprehensiveness, reliability, and readability of outputs from AI platforms. Further research is needed to improve their performance.

Coping Strategies and Associated Symptom Burden Among Patients With Advanced Cancer.

BACKGROUND: Few studies examine how patients with advanced cancer cope with stress. The objective of our study was to evaluate coping strategies adopted by patients with cancer and their relationship with symptom burden. METHODS: A secondary data analysis of a prospective cross-sectional survey of patients with cancer and tobacco use was conducted, which examined demographics, symptom burden (Edmonton Symptom Assessment System), and coping strategies (the Brief COPE Questionnaire). Demographic characteristics were summarized by standard summary statistics; we also examined associations between patient characteristics and coping strategies using t-test, rank-sum test, chi-squared test, or Fisher's exact test depending on the distribution of data. RESULTS: Among 399 patients, the majority were female (60%), Caucasian (70%), the mean age was 56.5 (±12.0) years, and the most common malignancies were gastrointestinal (21%) and breast (19%). Patients with cancer adopted multiple adaptive coping strategies, most frequently acceptance (86.7%) and emotional support (79.9%), with humor (18.5%) being the least. Common maladaptive strategies included venting (14.5%) and self-distraction (36.6%), while substance use (1.0%) was infrequently reported. Of the adaptive strategies, female gender was significantly associated with higher engagement with emotional and instrumental support, positive reframing, religious coping, and acceptance (P < .05 for all). College educated patients reported significantly higher implementation of humor, planning, and acceptance. Maladaptive coping strategies such as denial were associated with increased pain and depression, while patients adopting emotional-focused strategies rated decreased emotional distress. CONCLUSIONS: The majority of patients with advanced cancer reported adopting multiple, adaptive coping strategies, and a minority utilized maladaptive or avoidant strategies, rarely substance use, and may need additional psychological support.

Routine Monitoring of QTc Interval as a Barrier for Efficient Use of Methadone in Palliative Care.

BACKGROUND: Methadone is a commonly prescribed opioid amongst cancer patients. It has unique pharmacological properties which can benefit in treating complex pain syndromes and neuropathic pain. However, strict guidelines have been created in a generalized manner for chronic pain and long-term survival patients. These guidelines, such as QT interval monitoring can lead to limitations for methadone use in patients with comfort-associated goals. We present two cases of patients with metastatic cancer who were treated for pain with methadone and had to undergo opioid rotation due to abnormal QT intervals. CASE DESCRIPTION: Case one was a female with open ulcerated wounds due to metastatic breast cancer who presented with uncontrolled pain on her current opioid regimen. She achieved pain relief when rotated to methadone but a repeat electrocardiogram a few months later showed QTc prolongation. She underwent opioid rotation with different medications, but her pain remained poorly controlled. Case two was a female with poorly controlled pain in the setting of bilateral breast cancer. She presented with concerns for opioid-induced neurotoxicity and was rotated to methadone. She achieved optimal pain relief. A few weeks later, her machine read QT interval was prolonged and she was rotated off methadone. The electrocardiogram was manually read which showed a normal QT interval and she was restarted on methadone with pain relief. CONCLUSION: In the palliative care setting, monitoring QTc per chronic pain guidelines may lead to uncontrolled pain and a significant impact on quality of life.

Cholestatic Pruritus Mimicking a Cutaneous Drug Eruption.

Pruritus, colloquially known as itch, is a common clinical symptom seen in a variety of dermatological conditions and systemic disorders. Pruritus can broadly be classified into four categories: neuropathic, neurogenic/systemic, psychogenic, and pruritoceptive. Initial categorization depends on anatomical and pathophysiological aspects of presentation and is reflective of underlying etiology. We report a case of an 83-year-old man presenting with generalized pruritus secondary to cholestasis from bile duct malignancy. This case is notable for atypical presenting features, including a trunk eruption comprised of excoriated papules with onset following meloxicam initiation, mimicking a cutaneous adverse drug reaction. Providers should consider systemic etiologies of pruritus in patients presenting with cutaneous eruptions with atypical features. Accurate categorization of pruritus can facilitate treatment and/or additional investigation of systemic disease.

Practice Patterns on the Incorporation of Integrative Medicine Into the Oncologic Care of Patients With Cancer.

BACKGROUND: With rising interest in complementary approaches to symptom management, awareness of real-world practice patterns in the incorporation of integrative oncology (IO) into cancer care is limited. Therefore, we examined the reasons for referral, symptom burdens, and clinical outcomes for cancer patients who underwent initial IO consultations. METHODS: The records of adult patients with cancer who underwent initial outpatient IO consultations at our cancer center for a representative 10-day period at the start of each month for 12 months starting January 1, 2017, were reviewed retrospectively. Patient demographic and medical characteristics and outpatient IO consultation details, including patient-reported outcome measures of symptom burden, were extracted. Descriptive summary statistics and logistic regression were used to analyze the data. RESULTS: Among the 473 study patients, 71% were women, breast cancer (42%) was the most common cancer type, and 31% had metastatic cancer. Referring clinicians listed an integrative approach (57%) as the most common reason for referral, followed by diet (26%), pain (19%), discussion of herbs and supplements (18%), and stress (18%). In comparison, patients listed their primary concerns as diet (16%), pain (15%), and an integrative approach to overall health (11%). After the IO consultations, the highest likelihood of subsequent recommendations were acupuncture for hot flashes (odds ratio [OR], P = .002) or peripheral neuropathy (OR = 6.59, P < .001), oncology massage for pain (OR = 3.04, P < .001), psychology referral for patient's self-reported anxiety (OR = 2.35, P < .001), and mind-body therapies for stress (OR = 2.57, P < .001). CONCLUSION: Cancer patients' top concerns regarding IO consultation may not always match providers' reasons for referral. Longitudinal data analysis is needed to determine the effect of integrative interventions on symptom burden.

Deficiencies with CAGE-AID questionnaire in identifying nonmedical opioid use-a report of two cases.

BACKGROUND: The CAGE-AID questionnaire (Cut-down, Annoyed, Guilty, Eye-opener scale Adapted to Include Drugs) is used to screen patients for substance use disorder and nonmedical opioid use (NMOU). Major pain guidelines encourage using such screening tools for all patients including cancer patients before initiating opioids. We present two cases where the CAGE-AID results did not accurately identify the risk for NMOU. CASE DESCRIPTION: Patient 1 is a male in his 60s with metastatic prostate cancer was admitted for uncontrolled pain. Imaging revealed extensive spinal metastasis, needing initiation of methadone and hydromorphone. The CAGE-AID score was positive, placing him at risk for NMOU. This likely biased the providers, delaying opioid titration. Subsequently, doses were adjusted, and he was discharged with adequate pain control and no evidence of NMOU. Patient 2 is a male in his 40s with metastatic cholangiocarcinoma admitted for uncontrolled abdominal pain. The patient had multiple hospitalizations at different facilities with similar symptoms. The CAGE-AID score was negative. Despite this, the patient demonstrated behaviors such as demanding intravenous opioids, dose escalation, or interventions such as nerve blocks. The workup did not identify any etiology for the increased pain. The patient left the hospital against medical advice when his demands for intravenous opioids were not met. CONCLUSIONS: The CAGE-AID questionnaire alone does not accurately identify risks for NMOU. Screening tools must always be accompanied by a thorough clinical assessment of behaviors and pain mechanism. More research is needed to better characterize CAGE-AID false positives and negatives among patients with cancer pain.

Sebaceous Carcinoma of the Wrist in an Elderly Woman: A Case Report.

Sebaceous carcinoma is a rare, aggressive cutaneous malignancy most commonly arising from the periocular area. Extraocular locations of sebaceous carcinomas, particularly outside of the head and neck region, are rare and not well-described. We report a case of an 89-year-old Caucasian female with sebaceous carcinoma of the right wrist. She initially presented with a 1.2-centimeter friable nodule on the right wrist. Initial shave biopsy and subsequent pathologic evaluation revealed a basaloid neoplasm with sebaceous differentiation, atypia, and frequent mitoses, consistent with sebaceous carcinoma. The presented case reviews common clinical features and the pertinent histopathology of ocular and extraocular sebaceous carcinoma and provides a literature review of diagnosis, prognosis, and treatment.

Reliability of urine drug testing among patients on buprenorphine transdermal patch.

BACKGROUND: Urine drug testing (UDT) plays a significant role in monitoring patients on chronic opioid therapy (COT) for non-medical opioid use (NMOU). UDT, at times, can be inconsistent and misleading. We present a case where a patient on a buprenorphine patch had false negative results. CASE DESCRIPTION: A female in her 70s with metastatic breast cancer presented with uncontrolled pain from a T6 compression fracture. She had no relief with tramadol 50 mg every 6 hours as needed. Due to an allergic reaction to hydromorphone, our team prescribed a buprenorphine patch of 5 µg/h. Subsequently, she expressed excellent pain control, and the clinician confirmed the patch placement on examination. She underwent a UDT during the visit. The UDT was negative for both buprenorphine and its metabolites. The literature review showed that false negative UDT results are relatively common among patients with low-dose buprenorphine patches. The combination of a thorough physical examination, a review of the Prescription Drug Monitoring Program, and reassuring scores on screening tools placed her at low risk for NMOU. DISCUSSION: Buprenorphine has a ceiling effect on respiratory depression and a lower risk for addiction. However, when used in low doses, the drug might not have enough metabolites in the urine, leading to a false negative UDT. Such results might affect patient-physician relationships. CONCLUSION: In addition to the UDT, a thorough history, screening for NMOU, physical exam, a review of PDMP, and a good understanding of opioid metabolism are necessary to help guide pain management.

Impact of an Institution-Wide Goals of Care Program on the Timing of Referrals to Outpatient Palliative Care.

CONTEXT: Palliative care has received increased interest since the COVID-19 pandemic due to its role in guiding goals of care (GOC) discussions. OBJECTIVES: We assessed the change in the timing of outpatient palliative care referrals before and after implementing an institution-wide multicomponent interdisciplinary GOC (myGOC) program. METHODS: We reviewed 200 random supportive care center (SCC) consult visits each from June to November 2019 (before myGOC) and June to November 2020 (after myGOC). Data regarding Edmonton Symptom Assessment Scale (ESAS) scores, time from hospital registration to SCC visit, SCC visit until death/last follow-up, and advance care planning (ACP) notes were collected. Kaplan-Meier curves were used to evaluate overall survival (OS). RESULTS: The median OS from the SCC consult visit was 15.2 months (95% CI:11.7-19.7) before and 14.0 months (95% CI:10.8-17.9) after the myGOC program (P = 0.646). There were no significant differences in the median time between the SCC consult visit to death/last follow-up (11.95 vs. 12.0 months after myGOC; P = 0.841) and the first visits to our cancer center and SCC (6.1 vs. 5.29 months after myGOC; P = 0.689). Patients seen after myGOC had significantly lower ESAS symptom scores, better performance status (2 [1-2] vs. 2 [1-3]; P = 0.018], and more ACP notes composed by medical oncology teams (25.5% vs. 4.5%; P < 0.001). CONCLUSION: There were no significant differences in OS among patients seen in the SCC before and after myGOC, likely related to a ceiling effect. More oncologists had ACP discussions with patients, and patients had lower symptom scores on ESAS after myGOC, likely indicating that more patients were referred for GOC discussions and ACP rather than for symptom distress.

Advance Care Planning conversations: What constitutes best practice and the way forward: Advance Care Planning-Gespräche: Was Best Practice ausmacht und wie es weitergehen kann.

BACKGROUND: Advance Care Planning (ACP) conversations are a cornerstone of modern health care and need to be supported. However, research indicates that the uptake thereof is limited, regardless of various campaigns. ACP conversations are complex and specific elements thereof should be discussed at various timepoints during the illness trajectory. OBJECTIVE: This narrative review delineates what ACP conversation should entail, and a way forward. METHODS: A PEO (Population, Exposure, Outcome) search was performed using relevant keywords, and 615 articles were identified. Through screening and coding, this number was reduced to 24 articles. All the authors were involved in the final selection of the articles. RESULTS: Various themes developed throughout the review which include timing early on in the disease trajectory; incorporating beliefs and culturally relevant contexts; conversations needing to be iterative and short; involving surrogates and family; applying various media formats. DISCUSSION: ACP conversations are relevant. ACP is not static and needs to be dynamic as patients' illness trajectories and goals change. The care team needs to guard themselves against having ACP conversations to satisfy a metric and should instead be guided by the patient's expressed values and wishes. A system-wide operational plan will help alleviate common barriers in having appropriate ACP conversations.

ADCC's Improving Goal Concordant Care Initiative: Implementing Primary Palliative Care Principles.

BACKGROUND: High-quality, timely goals of care communication (GOCC) may improve patient and caregiver outcomes and promote care that is consistent with patient preferences. PROBLEM: Cancer patients, and their loved ones, appreciate GOCC; however, oncologists often lack formal communication training, institutional support and structures necessary to promote the delivery, documentation, and longitudinal follow-up of GOCC. PROPOSED SOLUTION: The Alliance of Dedicated Cancer Centers (ADCC), representing 10 U.S. academic cancer hospitals, undertook the Improving Goal Concordant Care Initiative (IGCC). This national, 3-year implementation initiative was designed in Fall 2019 by a workgroup of quality, oncology, and palliative care leaders, as well as patient and family advisory committee members (PFAC). IGCC addresses systemic gaps by requiring four core components for participation: 1) Implementation of a formal communication skills training (CST) program, 2) Structured GOCC documentation in the electronic medical record that is visible to all clinicians, 3) Expectations regarding the timing and patient populations for GOCC, and 4) Implementation of a measurement framework. METHOD: Dyads of palliative and oncology leaders committed to attend regularly scheduled, ADCC-led, virtual meetings during the design and implementation phase, incorporating PFAC feedback at every stage. Using the RE-AIM framework, we describe process and outcome evaluation measures defined by implementation and measures workgroups and collected routinely, including: CST completion; trainee evaluation response rate, trainee-reported quality of CST, trainee changes in self-efficacy and distress; percent of high-priority patients participating in GOCC, and patient-reported response to the "Heard and Understood" scale (HU). IGCC's impact will be assessed using claims-based utilization metrics near the end of life (EOLM) and followed longitudinally. Qualitative evaluations near the completion of IGCC will provide insight into perceived barriers, enabling factors, and sustainability. OUTCOMES: Implementation of all IGCC components has begun at all sites. ADCC-wide, 35% of MD/DOs have completed CST (range by site: 8%-100%). CST is highly rated; in Quarter 3, 2022, 93%-100%, 90%-100% and 87%-100% of respondents reported above average to excellent CST quality, likelihood to use the skills and likelihood to recommend CST to others, respectively. Clinician self-efficacy and distress ratings are expected in late 2023. All sites have identified patient populations and continue to refine automated triggers and timelines; uptake of GOCC documentation has been slow. Eight of 10 sites have submitted patient-reported HU data. EOLM data are expected for all sites in early 2024. LESSONS LEARNED: Flexibility in implementation with shared definitions, measures, and learnings about approaches optimizes the ability of all centers to collaborate and make progress in improving GOCC. Flexibility adds to the complexity of understanding intervention effectiveness, the critical intervention components and the fidelity necessary to achieve specific outcomes.