Unsupervised restoration of a complex learned behavior after large-scale neuronal perturbation.

Reliable execution of precise behaviors requires that brain circuits are resilient to variations in neuronal dynamics. Genetic perturbation of the majority of excitatory neurons in HVC, a brain region involved in song production, in adult songbirds with stereotypical songs triggered severe degradation of the song. The song fully recovered within 2 weeks, and substantial improvement occurred even when animals were prevented from singing during the recovery period, indicating that offline mechanisms enable recovery in an unsupervised manner. Song restoration was accompanied by increased excitatory synaptic input to neighboring, unmanipulated neurons in the same brain region. A model inspired by the behavioral and electrophysiological findings suggests that unsupervised single-cell and population-level homeostatic plasticity rules can support the functional restoration after large-scale disruption of networks that implement sequential dynamics. These observations suggest the existence of cellular and systems-level restorative mechanisms that ensure behavioral resilience.

Olanzapine within steroid-sparing antiemetic regimen to prevent chemotherapy-induced nausea and vomiting in patients with acute leukemia receiving multi-day intensive chemotherapy.

INTRODUCTION: Olanzapine use for chemotherapy-induced nausea and vomiting (CINV) in hematological malignancies, for multi-day chemotherapy, and with a steroid-sparing antiemetic strategy is poorly understood. This study investigated if olanzapine is associated with improved prevention of CINV when added to a steroid-sparing antiemetic regimen in patients with acute leukemia receiving intensive, moderately emetogenic, multi-day chemotherapy. METHODS: This was a single-center, retrospective cohort study in patients with acute leukemia. Patients who received olanzapine for CINV prevention were compared to those who did not. All patients received a 5-HT3 antagonist. Adult patients receiving moderately emetogenic, multi-day, intensive chemotherapy for acute leukemia were included. Patients were excluded if they received steroids greater than physiological doses during the study period. The primary endpoint was the complete response of CINV (no emesis or rescue antiemetic usage). RESULTS: This study included 58 patients, 12 patients received olanzapine and 46 patients were in the control group. Baseline demographics were similar. In the study population, 89.7% had acute myeloid leukemia, median age was 54 (interquartile range 42-63) years, 34.5% were female, 27.6% had prior CINV. Complete response of CINV was similar between groups, 4 (33.3%) and 15 (32.6%) patients in the olanzapine and control groups, respectively. Safety events were similar between groups. CONCLUSION: Patients with acute leukemia receiving multi-day intensive chemotherapy are at high risk for CINV. The limited data in this study suggests that olanzapine use within a steroid-sparing antiemetic regimen was well tolerated and associated with similar incidence and severity of CINV compared to the control group.

Impact of pegaspargase dose capping on incidence of pegaspargase-related adverse events in adults.

INTRODUCTION: Asparaginase derivatives are essential components of the treatment of acute lymphoblastic leukemia in adolescent and young adult patients. However, their associated toxicities limit wider use in older populations. This study seeks to determine if the practice of capping the pegaspargase dose at 3750 units reduces the risk of related adverse events in adults. METHODS: Adverse event data were retrospectively collected 28 days following each administration of pegaspargase in a single center. Doses were categorized as either capped (≤3750 units) (n = 57, 47.5%) or non-capped (>3750 units) (n = 63, 52.5%). The primary endpoint of this study was the composite incidence of serious pegaspargase-related adverse events, defined as grade 3 or higher. RESULTS: Of the 120 doses administered, 47 (39.2%) were administered to patients > 39 years. For the primary endpoint, 26 doses (45.6%) in the dose capped group versus 22 doses (34.9%) in the non-dose capped group were associated with serious pegaspargase-related adverse events (p = 0.23). Isolated laboratory abnormalities accounted for all hepatotoxicity and pancreatic toxicity events, while venous thromboembolism and bleeding occurred after 8.3% and 13.3% of doses, respectively. Multivariate analysis of the primary outcome to adjust for differences in baseline characteristics found no difference between groups (OR 2.56 (0.84, 7.77, p = 0.098)). CONCLUSIONS: The incidence of serious clinical toxicities was low in this study, particularly pegaspargase-related venous thromboembolism. This suggests that the practice of capping pegaspargase doses at 3750 units, coupled with vigilant monitoring and prophylaxis for pegaspargase-related adverse events, can allow for the inclusion of this drug in the treatment of older individuals.

Recovery of a learned behavior despite partial restoration of neuronal dynamics after chronic inactivation of inhibitory neurons.

Maintaining motor skills is crucial for an animal's survival, enabling it to endure diverse perturbations throughout its lifespan, such as trauma, disease, and aging. What mechanisms orchestrate brain circuit reorganization and recovery to preserve the stability of behavior despite the continued presence of a disturbance? To investigate this question, we chronically silenced a fraction of inhibitory neurons in a brain circuit necessary for singing in zebra finches. Song in zebra finches is a complex, learned motor behavior and central to reproduction. This manipulation altered brain activity and severely perturbed song for around two months, after which time it was precisely restored. Electrophysiology recordings revealed abnormal offline dynamics, resulting from chronic inhibition loss, some aspects of which returned to normal as the song recovered. However, even after the song had fully recovered, the levels of neuronal firing in the premotor and motor areas did not return to a control-like state. Single-cell RNA sequencing revealed that chronic silencing of interneurons led to elevated levels of microglia and MHC I, which were also observed in normal juveniles during song learning. These experiments demonstrate that the adult brain can overcome extended periods of abnormal activity, and precisely restore a complex behavior, without recovering normal neuronal dynamics. These findings suggest that the successful functional recovery of a brain circuit after a perturbation can involve more than mere restoration to its initial configuration. Instead, the circuit seems to adapt and reorganize into a new state capable of producing the original behavior despite the persistence of some abnormal neuronal dynamics.

Dopamine neurons evaluate natural fluctuations in performance quality.

Many motor skills are learned by comparing ongoing behavior to internal performance benchmarks. Dopamine neurons encode performance error in behavioral paradigms where error is externally induced, but it remains unknown whether dopamine also signals the quality of natural performance fluctuations. Here, we record dopamine neurons in singing birds and examine how spontaneous dopamine spiking activity correlates with natural fluctuations in ongoing song. Antidromically identified basal ganglia-projecting dopamine neurons correlate with recent, and not future, song variations, consistent with a role in evaluation, not production. Furthermore, maximal dopamine spiking occurs at a single vocal target, consistent with either actively maintaining the existing song or shifting the song to a nearby form. These data show that spontaneous dopamine spiking can evaluate natural behavioral fluctuations unperturbed by experimental events such as cues or rewards.

Increased body mass index is a risk factor for acute promyelocytic leukemia.

Introduction: Obesity has become increasingly prevalent worldwide and is a risk factor for many malignancies. We studied the correlation between body mass index (BMI) and the incidence of acute promyelocytic leukemia (APL), non-APL acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and control hospitalized patients without leukemia in the same community. Methods: Multi-center, retrospective analysis of 71,196 patients: APL (n=200), AML (n=437), ALL (n=103), non-leukemia hospitalized (n=70,456) admitted to University of Maryland and Johns Hopkins Cancer Centers, and University of Maryland Medical Center. Results: Patients with APL had a significantly higher unadjusted mean and median BMI (32.5 kg/m2 and 30.3 kg/m2) than those with AML (28.3 kg/m2 and 27.1 kg/m2), ALL (29.3 kg/m2 and 27.7 kg/m2), and others (29.3 kg/m2 and 27.7 kg/m2) (p<0.001). Log-transformed BMI multivariable models demonstrated that APL patients had a significantly higher adjusted mean BMI by 3.7 kg/m2 (p<0.001) or approximately 10% (p<0.01) compared to the other groups, when controlled for sex, race, and age. Conclusions: This study confirms that when controlled for sex, age, and race there is an independent association of higher BMI among patients with APL compared to patients with ALL, AML, and hospitalized individuals without leukemia in the same community.

Venous thromboembolism incidence and risk factors in adults with acute lymphoblastic leukemia treated with and without pegylated E. coli asparaginase-containing regimens.

PURPOSE: Asparaginases, key agents in treatment of acute lymphoblastic leukemia (ALL), are associated with venous thromboembolism (VTE). While risks of short-acting asparaginase-related VTE is well-known, we studied VTE incidence and risk factors in adult ALL patients treated with and without long-acting pegylated asparaginase (PegA). METHODS: Single-center, retrospective analysis of 89 ALL patients treated with (n = 61) or without (n = 28) PegA at Greenebaum Comprehensive Cancer Center. Reviewed patient and disease characteristics, treatment, and VTE incidence. RESULTS: VTE during treatment occurred in 31 patients (35%), and was associated with PegA (p = 0.001) and Philadelphia chromosome negativity (p = 0.002). Among PegA recipients, VTE was associated with a significantly higher mean body mass index (BMI) of 31.3 kg/m2 (p = 0.037), and was more common with pre-T/T cell compared to pre-B/B cell ALL (68.2% vs. 33.3%, p = 0.009). Antithrombin-III (ATIII) levels were measured for 26 patients; 16 (61.5%) were < 50%. Of those, 8 (50%) experienced VTE, while 3 of 10 (30%) patients with ATIII levels ≥ 50% experienced VTE. VTE occurred in 7 of 13 (54%) of patients who received ATIII repletion. There was a trend toward a higher incidence of VTE in the PegA group among patients with non-O compared to O blood type (55.9% vs. 33.3%, p = 0.079) as well as those with a higher hemoglobin at diagnosis (9.3 vs 8.1 g/dL, p = 0.056). CONCLUSION: This study confirms PegA as a risk factor for VTE in patients with ALL. Risk factors among those receiving PegA include higher BMI and pre-T/T cell ALL. ATIII repletion was not shown to be protective against VTE. There was a higher incidence of VTE in patients who received PegA with non-O compared to O blood type, but the precise correlation is uncertain.

Meeting the challenge: Implementation of a collaborative quality improvement initiative for a multi-site pharmacy residency and fellowship program.

INTRODUCTION: The American Society of Health-System Pharmacists (ASHP) accreditation standards for postgraduate training programs require a continuous improvement plan as a method of quality improvement (QI). The University of Maryland (UM) Residency and Fellowship Program offers several residency and fellowship programs. The primary objective of this QI project was to assess the perceived effectiveness of the UM's training program in preparing trainees for their desired career goals. A secondary objective was to acquire suggestions from graduates to assist in QI. METHODS: A 12-question electronic survey was sent to UM residents and fellows who graduated between 2012 and 2016. Survey questions addressed the graduate's perception of their training experience. Graduates were also asked how well certain skills were taught based on core ASHP requirements. Participation was voluntary and responses were anonymous. RESULTS: Seventy-five graduates were identified for potential inclusion, and 43 (57%) completed the survey. Findings revealed 88% of graduates were practicing in a position that matched their training and 95% indicated that their program prepared them adequately for their current job. CONCLUSIONS: The ASHP accreditation standards for pharmacy residency programs require an ongoing process of QI. This study provides support for use of an electronic survey as a helpful tool to assess effectiveness of a residency program.

Use of active learning and simulation to teach pharmacy students order verification and patient education best practices with oral oncolytic therapies.

INTRODUCTION: The primary objective of this study was to describe the incorporation of the flipped classroom model and use of real-life oncology patients to facilitate student learning of oral oncolytic best safety practices and patient counseling. The secondary objective was to assess the impact of the flipped classroom learning activity on students' perceived confidence. METHODS: This study was a prospective, single center, flipped classroom learning activity and pre/post assessment survey administered to third year doctor of pharmacy students enrolled in the Oncology Pharmacotherapy didactic elective in 2016 and 2017. A pre/post survey was used to assess student's perceived confidence with oral oncolytic best practice competencies. RESULTS: Ten students participated in the flipped classroom learning activity and survey. Five students completed both the pre- and postsurvey. The overall change in student's mean scores for their confidence of oral oncolytic competencies improved significantly from 3 to 4.1 on a 6-point Likert Scale (p = 0.03) following the learning activity. Students perceived confidence in performing oral oncolytic order verification increased following the implementation of a flipped classroom learning activity and use of real-life cancer oncology patients. CONCLUSION: This study describes the development and implementation of a flipped classroom learning activity and use of real-life patients with cancer that can be implemented at other institutions of higher education in a didactic or experiential learning environment. Additionally, this study demonstrated a potential benefit in student learning.

Comparison of High-Dose Cytarabine, Mitoxantrone, and Pegaspargase (HAM-pegA) to High-Dose Cytarabine, Mitoxantrone, Cladribine, and Filgrastim (CLAG-M) as First-Line Salvage Cytotoxic Chemotherapy for Relapsed/Refractory Acute Myeloid Leukemia.

Currently, no standard of care exists for the treatment of relapsed or refractory acute myeloid leukemia (AML). We present our institutional experience with using either CLAG-M or HAM-pegA, a novel regimen that includes pegaspargase. This is a retrospective comparison of 34 patients receiving CLAG-M and 10 receiving HAM-pegA as first salvage cytotoxic chemotherapy in the relapsed or refractory setting. Composite complete response rates were 47.1% for CLAG-M and 90% for HAM-pegA (p = 0.027). Event-free survival was significantly different in favor of HAM-pegA (p = 0.045), though overall survival was similar between groups. There were no significant differences in toxicities experienced by patients treated with the two regimens, including adverse events of special interest related to pegaspargase (venous thromboembolism, hemorrhage, hepatotoxicity, pancreatitis, and hypersensitivity reactions). HAM-pegA is a novel regimen for relapsed or refractory AML that resulted in improved response rates and similar toxicities compared to CLAG-M.

Optimizing pegylated asparaginase use: An institutional guideline for dosing, monitoring, and management.

The incorporation of L-asparaginase and pegylated asparaginase into pediatric-inspired regimens has conferred a survival advantage in treatment of adults with acute lymphoblastic leukemia. Use of asparaginase products requires careful prevention, monitoring, and management of adverse effects including hypersensitivity, hepatotoxicity, pancreatitis, coagulopathy, and thrombosis. Currently, there is limited published literature to offer guidance on management of these toxicities. At the University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, a standard of practice guideline was created to prevent and manage asparaginase-related adverse events. By sharing our long-term experience with asparaginase products and clinical management of asparaginase-induced toxicities, this article aims to improve patient safety and optimize treatment outcomes.

Real-world experience managing blinatumomab toxicities in adults with relapsed/refractory acute lymphoblastic leukemia.

PURPOSE: The purpose of this study was to determine the effect of blinatumomab toxicities on drug therapy modifications in an intended 28-day course of blinatumomab therapy. METHODS: Patients with acute lymphoblastic leukemia who received blinatumomab at the University of Maryland Marlene & Stewart Greenebaum Comprehensive Cancer Center from March 1, 2015 to April 30, 2018 were included. The primary objective of this study was to identify the frequency and severity of blinatumomab toxicities that led to drug therapy modifications; secondary objectives were to identify the frequency and duration of modifications and the total dose and duration of therapy received. RESULTS: This study included 23 patients. Seventy-eight percent of patients experienced cytokine release syndrome and/or neurotoxicity. Eighteen drug therapy modifications occurred due to toxicity with a median interruption time of nine hours. Drug therapy was continued for the majority of grade 1 or 2 events and discontinued during grade 3 or 4 neurotoxicity. The median number of days of therapy delivered was 28 days (range, 27-35). A median of 2 h (range, 0-16) of therapy or 0.2% (range, 0-2.4) of a total 28-day cycle was lost due to transition of care. CONCLUSION: This retrospective study demonstrates a single center experience with blinatumomab toxicity management and appropriate delivery of drug during transitions of care. Overall, these results support to the importance of institutional guidelines in place to facilitate safe and effective delivery of blinatumomab.

Student confidence with oncology pharmacy competencies.

OBJECTIVE: The purpose of this study was to assess the change in student confidence to perform oncology pharmacy competencies before and after completing oncology didactic instruction using a flipped classroom approach. METHODS: First year doctor of pharmacy students completed a survey prior to the Applied Science and Therapeutics (AST) oncology module (pre-survey) and the same survey following the completion of the oncology module (post-survey). The survey consisted of questions addressing prior oncology pharmacy experience related to employment (research or patient care) and education, level of interest in oncology pharmacy, and level of confidence to perform thirteen oncology pharmacy competencies. RESULTS: One-hundred sixteen students completed the pre-survey and 35 completed the post-survey. Students completing both surveys reported greater confidence in all oncology pharmacy competencies (p < 0.0001) after instruction. The greatest increases in student confidence were related to chemotherapy dose calculations, patient education, and drug-drug interactions. CONCLUSIONS: The delivery of oncology content using flipped classroom instruction in the AST course successfully increased student confidence in ability to perform oncology pharmacy competencies. Cancer screening, cancer risk factors, and the preparation and dispensing of chemotherapy were competencies identified as needing greater emphasis in classroom instruction. Future studies are needed to assess student's knowledge and application of oncology pharmacy competencies in both the experiential and classroom settings.

Equipotent doses of daunorubicin and idarubicin for AML: a meta-analysis of clinical trials versus in vitro estimation.

In the treatment of acute myeloid leukemia (AML), the "7 + 3"-based strategy, combining cytarabine 100-200 mg/m2 for 7 days with an anthracycline for 3 days, remains the standard of care for younger and medically fit patients. Daunorubicin (DNR) and idarubicin (IDA) are the two anthracyclines most commonly used. DNR and IDA are used interchangeably with different conversion factors, as there is no high-level evidence on the equipotency of these two agents for AML treatment. To determine the equipotent doses of DNR and IDA, we first systematically reviewed studies directly comparing the clinical outcomes of AML induction therapy utilizing DNR and IDA. We found 15 articles that met our inclusion criteria and compared time-to-event survival end points as well as complete remission rates post-induction. The DNR:IDA equipotency ratio was estimated at 5.90 with 95% confidence interval (CI) 1.7-20.7. To validate the estimate from our meta-analysis biologically, we conducted in vitro tests comparing anti-AML activity of DNR and IDA against six AML cell lines and two primary AML cells from patients with different cytogenetic and molecular characteristics. Based on these in vitro data, the equipotency dose ratio between DNR and IDA was 4.06 with 95% CI 3.64-4.49. Combining the estimates from the meta-analysis and the in vitro data using inverse-variance weighting, the current best estimate of the DNR:IDA equipotent ratio is 4.1 with 95% CI 3.9-4.3. This estimate, however, is largely driven by the in vitro chemo-sensitivity data. Given clinical studies demonstrating the safety of IDA at higher doses, our work implies that dose intensification of IDA could be investigated in future clinical trials in AML.

Variation in sequence dynamics improves maintenance of stereotyped behavior in an example from bird song.

Performing a stereotyped behavior successfully over time requires both maintaining performance quality and adapting efficiently to environmental or physical changes affecting performance. The bird song system is a paradigmatic example of learning a stereotyped behavior and therefore is a good place to study the interaction of these two goals. Through a model of bird song learning, we show how instability in neural representation of stable behavior confers advantages for adaptation and maintenance with minimal cost to performance quality. A precise, temporally sparse sequence from the premotor nucleus HVC is crucial to the performance of song in songbirds. We find that learning in the presence of sequence variations facilitates rapid relearning after shifts in the target song or muscle structure and results in decreased error with neuron loss. This robustness is due to the prevention of the buildup of correlations in the learned connectivity. In the absence of sequence variations, these correlations grow, due to the relatively low dimensionality of the exploratory variation in comparison with the number of plastic synapses. Our results suggest one would expect to see variability in neural systems executing stereotyped behaviors, and this variability is an advantageous feature rather than a challenge to overcome.

A single center retrospective analysis of a protocol for high-dose methotrexate and leucovorin rescue administration.

BACKGROUND: Methotrexate has a wide dosing range. High-dose methotrexate is a dose of 1000 mg/m2 or greater. In the 1970s, the incidence of mortality associated with High-dose methotrexate ranged from 4.6 to 6%. In 2012, the University of Maryland Medical Center implemented a standardized high-dose methotrexate protocol. The purpose of this study was to evaluate whether the institution followed recommendations based on the Bleyer nomogram for the administration of high-dose methotrexate more closely after the implementation of the protocol. METHODS: In this retrospective chart review, 37 patients received 119 cycles of high-dose methotrexate before the protocol implementation (1 January 2009 through 31 December 2010) and 45 patients received 106 cycles of high-dose methotrexate after protocol implementation (1 January 2013 through 31 December 2014). Patient characteristics, protocol data, and complications were analyzed. RESULTS: Protocol implementation significantly reduced the deviation of methotrexate level timing at 24, 48, and 72 h: median 7.47 vs. 1.46 h, 7.23 vs. 1.35 h, and 7.00 vs. 1.52 h before and after implementation, respectively (p < 0.0001 for each). The protocol significantly reduced deviation of the first dose of leucovorin administration: median 5.2 vs. 0.675 h before and after implementation, respectively (p<0.0001). After protocol implementation, there was an increase in the use of leucovorin prescriptions written appropriately for patients discharged before methotrexate levels reached a value of ≤0.05 µmol/L. CONCLUSIONS: Implementation of a protocol for the administration of high-dose methotrexate improved the adherence to consensus recommendations. Further analysis is needed to assess clinical pharmacist involvement and the cost savings implications within this protocol.

Case report of capecitabine toxicity and use of uridine triacetate.

Fluorouracil and capecitabine are fluoropyrimidine chemotherapy agents that are commonly used for various cancers. These agents are generally well tolerated at standard doses; however, it has been reported that 31-34% of patients develop dose-limiting toxicities. Dihydropyrimidine dehydrogenase and thymidylate synthase play a major role in fluorouracil and capecitabine activity and toxicity. Uridine triacetate has shown promising results for the emergency treatment of patients who either receive an overdose of the cancer treatment fluorouracil or capecitabine or to treat patients who exhibit early-onset, severe, or life-threatening toxicity. We describe a case of a patient who developed capecitabine toxicity and was unsuccessfully treated with uridine triacetate.

Addressing Administration Challenges Associated With Blinatumomab Infusions: A Multidisciplinary Approach.

Blinatumomab has shown great potential for patients with chemotherapy-resistant B-cell acute lymphocytic leukemia. Blinatumomab's toxicity profile includes central nervous system toxicities, as well as cytokine release syndrome. Although neurological toxicities associated with blinatumomab are almost always reversible, early detection and intervention of these toxicities is vital to ensure that patients continue their full course of treatment. Guidelines for the preparation and administration of blinatumomab in both inpatient and outpatient settings, as well as a standardized neurological nursing assessment, were developed to ensure safe and effective administration of blinatumomab.

Combination of Blinatumomab and Vincristine Sulfate Liposome Injection for Treatment of Relapsed Philadelphia Chromosome Positive B-cell Acute Lymphoblastic Leukemia.

Relapsed Philadelphia chromosome (Ph) positive Acute Lymphoblastic Leukemia (ALL) is an aggressive lymphoid malignancy with a poor prognosis and no randomized studies demonstrating superiority of any single salvage regimen. We present the case of a 33-year-old woman with relapsed Ph positive precursor (pre) B-cell ALL with rapidly rising peripheral blasts while on blinatumomab monotherapy initially, but ultimately responded with the addition of Vincristine Sulfate Liposome Injection (VSLI). Ponatinib was added later when it became available for the patient, and she ultimately achieved a complete remission. Further study is warranted to explore mechanisms of potential synergy, and the safety and efficacy of the combination of blinatumomab and VSLI.

Facilitating Home Hospice Transitions of Care in Oncology: Evaluation of Clinical Pharmacists' Interventions, Hospice Program Satisfaction, and Patient Representation Rates.

BACKGROUND: The importance of medication reconciliation and the pharmacist's role within the interdisciplinary team at the point of transition to home hospice is understudied. A transitions of care pilot initiative was developed to streamline the transition for patients at end of life from inpatient cancer center care to home hospice. The initiative consisted of using a hospice discharge checklist, pharmacist-led discharge medication reconciliation in consultation with the primary team responsible for inpatient care, review of discharge prescriptions, and facilitation of bedside delivery of discharge medications. METHODS: This was a single-center, prospective, pilot initiative. The objectives of this study were to characterize pharmacist interventions at the time of transition, to assess changes in hospice organizations' perceptions of discharge readiness, and to evaluate differences in representation rates with the implementation of the pilot discharge process. RESULTS: Fifteen patients in the preimplementation period and 12 patients in the postimplementation period were included. One hundred eleven pharmacist interventions were captured, an average of 9.3 interventions per patient, with an acceptance rate of 82.9% by providers. There was a statistically significant ( P = .035) improvement in hospice organizations' perceptions of discharge readiness. There was no difference in 30-day representation rates postdischarge ( P = 1). CONCLUSION: This well-received pilot initiative demonstrated an improvement in local hospice's perception of patient readiness for discharge and a high percentage of accepted pharmacist interventions during discharge medication reconciliation. A larger sample size of patients and longer follow-up period may be needed to demonstrate statistically significant improvements in representation rates postintervention.