Optimizing twin-screw melt granulation: The role of overflight clearance on granulation behavior.

Twin-screw melt granulation (TSMG) relies on the dispersive and distributive mixing at the kneading zone for granule growth to happen highlighting the critical role played by the kneading elements in TSMG. Despite extensive research conducted on the impact of screw geometry in melt compounding, there is not enough literature for TSMG. Disc width for the kneading elements was 2 mm, contrary to the standard 5 mm. The objective of this study was to evaluate if varying overflight clearance (OC) can alter the paradigm for TSMG. The new elements reduce the peak shear at kneading zone however a higher barrel temperature and degree of fill (DoF) is required to compensate to attain similar granule attributes. The change in DoF was achieved through a combination of modified screw configuration to pre-densify powders before kneading and processing at a lower screw speed. Despite the higher barrel temperature, process optimization of thermally unstable gabapentin was carried out. Using the new elements, compressible granules (Tensile strength > 2 MPa) with low % GABA-L content were manufactured despite increasing OC to 0.4 mm. Granule stability at 40 °C, ambient humidity for 6 months indicated gabapentin was stable (% GABA-L ≪0.4 %) despite a high barrel temperature of 120 °C.

The presence of busulfan metabolites and pharmacometabolomics in plasma drawn immediately before allograft infusion in hematopoietic cell transplant recipients.

Busulfan is hepatically metabolized through glutathione (GSH) conjugation; in vitro, this process depletes hepatocyte GSH stores and generates the cytotoxic metabolite γ-glutamyldehydroalanylglycine, which is too unstable to be quantitated in vivo. We sought to evaluate if pre-graft (i.e., immediately before allograft infusion) concentrations of busulfan metabolites' and of endogenous metabolomic compounds (EMCs) representing the glutathione pathway were associated with clinical outcomes in hematopoietic cell transplant (HCT) recipients receiving busulfan. The clinical outcomes evaluated were relapse, acute graft versus host disease (GVHD), chronic GVHD, non-relapse mortality, and neutrophil nadir. In pre-graft samples obtained from patients immediately before allograft infusion, our objectives were to evaluate for: (1) the presence of busulfan and its metabolites tetrahydrothiophenium ion (THT+), tetrahydrothiophene 1-oxide, sulfolane, and 3-hydroxysulfolane (N = 124); (2) EMCs using a global metabolomics assay (N = 77); and (3) the association of the busulfan metabolites and the EMCs with clinical outcomes. In the pre-graft samples, busulfan and THT+ could not be detected. THT 1-oxide, sulfolane, and 3-hydroxysulfolane were quantitated in 9.6%, 26%, and 58% of pre-graft samples; their concentrations were not associated with clinical outcomes. Four pre-graft EMCs were statistically significantly associated with the neutrophil nadir. The pre-graft EMCs were not associated with the other clinical outcomes. In conclusion, busulfan's metabolites are present in patients' plasma immediately before allograft infusion; the neutrophil nadir is associated with pre-graft EMCs. Future research should investigate the association of clinical outcomes with the concentrations of busulfan's metabolites and EMCs in the pre-graft plasma from allogeneic HCT recipients.

The U.S. Equity-First Vaccination Initiative: Impacts and Lessons Learned.

The one-year U.S. Equity-First Vaccination Initiative (EVI), launched in April 2021, aimed to reduce racial inequities in coronavirus disease 2019 (COVID-19) vaccination across five demonstration cities (Baltimore, Chicago, Houston, Newark, and Oakland) and over the longer term strengthen the United States' public health system to achieve more-equitable outcomes. This initiative comprised nearly 100 community-based organizations (CBOs), who led hyper-local work to increase vaccination access and confidence in communities of individuals who identify as Black, Indigenous, and People of Color. In this study, the second of two on the initiative, the authors examine the results of the EVI. They look at the initiative's activities, effects, and challenges, and provide recommendations for how to support and sustain this hyper-local community-led approach and strengthen the public health system in the United States.

Prediction of Busulfan Clearance by Predose Plasma Metabolomic Profiling.

Intravenous busulfan doses are often personalized to a target plasma exposure (targeted busulfan) using an individual's busulfan clearance (BuCL). We evaluated whether BuCL could be predicted by a predose plasma panel of 841 endogenous metabolomic compounds (EMCs). In this prospective cohort of 132 hematopoietic cell transplantation (HCT) patients, all had samples collected immediately before busulfan administration (preBU) and 96 had samples collected 2 weeks before busulfan (2-week-preBU). BuCL was significantly associated with 37 EMCs after univariate linear regression analysis and controlling for false discovery (< 0.05) in the 132 preBU samples. In parallel, with preBU samples, we included all 841 EMCs in a least absolute shrinkage and selection operator-penalized regression which selected 13 EMCs as predominantly associated with BuCL. Then, we constructed a prediction model by estimating coefficients for these 13 EMCs, along with sex, using ordinary least-squares. When the resulting linear prediction model was applied to the 2-week-preBU samples, it explained 40% of the variation in BuCL (adjusted R2  = 0.40). Pathway enrichment analysis revealed 18 pathways associated with BuCL. Lysine degradation followed by steroid biosynthesis, which aligned with the univariate analysis, were the top two pathways. BuCL can be predicted before busulfan administration with a linear regression model of 13 EMCs. This pharmacometabolomics method should be prioritized over use of a busulfan test dose or pharmacogenomics to guide busulfan dosing. These results highlight the potential of pharmacometabolomics as a precision medicine tool to improve or replace pharmacokinetics to personalize busulfan doses.

Effectiveness of internet-based behavioral activation on quality of life among young adult survivors of childhood brain tumor: a randomized controlled trial.

PURPOSE: Diagnosis and treatment of childhood brain tumor have detrimental effects on physical, neurocognitive, psychological, and social functioning that lasts into adulthood and effects quality of life (QOL). To address diminished QOL, an Internet-based behavioral activation (BA) intervention was developed. Behavioral activation aims to increase activities and behaviors likely to improve thoughts, mood, and QOL. METHODS: Participants included 127 young adult survivors of childhood brain tumor (SCBT) randomized into the experimental group (n= 64) or the waitlist control group (n= 63). The dependent variables included: life satisfaction, stress, and activation and were assessed with a two-way mixed analysis of variance (ANOVA). RESULTS: Results revealed a significant interaction between the intervention and time on life satisfaction, F(1, 125)=4.793, p = 0.03. There were no significant main effects over time for perceived stress and activation. CONCLUSIONS: Findings offer initial evidence that BA can be delivered over the internet and that Internet-delivered BA can have a positive effect on the QOL of young adult SCBT. Internet-based BA interventions can serve as a resource for young adult SCBT who desire to boost their mood and QOL.Implications for rehabilitationBehavioral activation (BA) is aimed at increasing positively reinforcing overt behaviors that are likely to promote improved thoughts, mood, and quality of life (QOL).Results indicated study participants in the experimental group demonstrated a significant gain in life satisfaction compared to the control group after receiving the Internet-based BA intervention; and provides support that the intervention was associated with positive changes across time.Findings offer initial evidence that BA can be delivered over the internet and that Internet-delivered BA can have a positive effect on the QOL of young adult survivors of childhood brain tumor (SCBT).Internet-based BA interventions can serve as a resource for young adult SCBT who desire to boost their mood and QOL.

Racial And Ethnic Disparities In COVID-19 Booster Uptake.

We investigated racial and ethnic disparities in COVID-19 vaccine uptake, using data from the Centers for Disease Control and Prevention. As of March 29, 2022, uptake of the first dose was higher among Hispanic and Asian people than among White and Black people. In contrast, uptake rates of the booster were higher among Asian and White people than among Black and Hispanic people.

Relations among gratitude, adaptation to disability, and flourishing among adults with disabilities: A longitudinal mediation model.

PURPOSE/OBJECTIVE: Flourishing, a primary outcome of rehabilitation psychology, is understudied among adults with disabilities. Gratitude has emerged as an individual strength that is both malleable and robust in predicting flourishing and adaptation to disability. The purpose of this study was to assess the influence of gratitude on flourishing over time and to analyze the potential mediating role of adaptation to disability on this relationship for a group of adults with disabilities. RESEARCH METHOD/DESIGN: Data were collected at 3 time points over 21 months (N = 429). A single mediator model with external demographic variables was tested to determine the relationship of gratitude (Time 1) with adaptation to disability (Time 2) and flourishing (Time 3). Approximately 40% of the initial sample was retained across all time points. RESULTS: Gratitude predicted later flourishing and adaptation to disability accounted for a significant portion of this relationship, accounting for 27% of the total effect. CONCLUSIONS/IMPLICATIONS: Results of this single mediator model indicate that adaptation to disability serves as a partial mediator of the relationship between gratitude and flourishing, with both gratitude and adaptation to disability having a significantly positive influence on flourishing. Understanding gratitude's influence on later adaptation and flourishing provides data to inform rehabilitation psychology interventions. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Physicochemical changes and chemical degradation of gliclazide during twin-screw melt granulation.

Using a miscible model formulation consisting of 80% gliclazide (GLZ) and 20% hydroxypropyl cellulose, we investigate how the twin-screw melt granulation process affects the chemical stability and process-induced physicochemical changes of the drug. No degradation was observed in the conveying section that leads to kneading element. Approximately 1/3 of the GLZ degradant was generated at the kneading section, while the remaining 2/3 was generated in the conveying section post-kneading and during cooling outside the barrel. A strong correlation was observed between the overall degradation and the temperature of the granules at the barrel exit. In the kneading section, the degradant content correlates best with the specific mechanical energy. With higher specific mechanical energies, the size of the GLZ crystals was reduced further, resulting in more surface defects. In the section post-kneading element, GLZ degradation correlates best with the granule temperature measured at the kneading section. This knowledge of drug degradation during twin-screw melt granulation can be used to develop processing strategies to maintain drug stability during and post processing.

Impact of childhood maltreatment on psychosomatic outcomes among men and women with disabilities.

PURPOSE: This project examined the impact of childhood maltreatment types on psychosomatic outcomes among adults with a range of self-reported disabilities. MATERIALS AND METHODS: Participants (n = 643) were recruited using Amazon Mechanical Turk and Cloud Research. Single-item questions assessed sociodemographic information. The Childhood Trauma Questionnaire measured childhood maltreatment types (emotional, physical, and sexual abuse, and emotional and physical neglect) and the RAND-36 Item Health Survey evaluated physical functioning, pain, and energy/fatigue. Logistic regressions determined associations between childhood trauma and psychosomatic outcomes; stratified models compared men and women. RESULTS: Multivariate-adjusted models indicated physical abuse was positively associated with poor physical functioning (OR: 2.03; 95%CI: 1.35-3.06) with this relationship being stronger for men (OR: 3.25; 95%CI: 1.42-7.43) than women (OR: 1.91; 95%CI: 1.17-3.13). Adjusted models showed that physical neglect was protective against fatigue (OR: 0.58; 95% CI: 0.36-0.94), while emotional neglect increased the risk of fatigue (OR: 1.74; 95%CI: 1.02-2.95). Lastly, physical abuse was positively associated with pain (OR: 1.53; 95%CI: 1.01-2.33). This relationship was stronger in men (OR: 4.99; 95%CI: 1.91-12.99). CONCLUSIONS: Results improve our understanding of risk factors for poor physical health outcomes and can guide the development of trauma-sensitive rehabilitation services.Implications for RehabilitationIndividuals with disabilities who report childhood maltreatment may experience poor psychosomatic outcomes in adulthood.Consequences of experiencing childhood maltreatment may manifest differently between men and women over the course of the lifespan.It is essential to integrate trauma-informed principles into treatment plans for individuals with poor psychosomatic health.Rehabilitation professionals should screen for abuse and refer individuals to the appropriate mental and physical health services.

Tutorial: The Speech-Language Pathologist's Role in Return to Work for Adults With Traumatic Brain Injury.

PURPOSE: Return to work (RTW) is a major life participation metric used for persons with a traumatic brain injury (TBI). Speech-language pathologists (SLPs) have clinical expertise in the cognitive-communication aspects of TBI. This clinical focus article aims to support the clinical practice of SLPs by summarizing key interprofessional vocational rehabilitation (VR) models and illustrating the role of the SLP throughout the RTW process with a case study. METHOD: This clinical focus article was written by the Academy of Neurologic Communication Disorders and Sciences TBI Research Group along with a VR expert. Authors engaged in deliberative, agenda-based discussions beginning with a literature review based on previous systematic studies. Discussions explored relevant VR and SLP practices. RESULTS: This clinical focus article presents key VR models in parallel with SLP assessment and treatment to illustrate best practice patterns in an RTW field with a dearth of SLP-specific literature. We summarize general VR approaches and four evidence-supported VR models for adults with TBI. We highlight how a model of interprofessional assessment can assist with planning and communication of important work-related concerns. We illustrate how the chronological model of work return can assist with developing goals and planning treatment. CONCLUSIONS: SLPs play an important role in identifying, managing, and collaborating with an RTW team following TBI. A working knowledge of VR models can assist with improving the dialogue between SLPs and VR professionals and can inform practice when working with persons with TBI who have work return as a goal.

Development and validation of the social motivation scale in people with disabilities.

OBJECTIVE: Social effectiveness is key to success in the labor market. For decades, social motivation has been empirically studied as both a presumed cause and consequence of social effectiveness. Yet, few direct measures of social motivation exist, and even fewer have been validated with a disability population. This study provides the measurement structure and psychometric properties of a newly created measure of social motivation tested with a general disability population. RESEARCH DESIGN: Participants included 1,013 US adults with disabilities. Exploratory factor analysis (EFA) and Confirmatory Factor Analysis (CFA) were implemented to validate the measure. RESULTS: Results of the EFA suggest that a reduced 26-item inventory exhibits a 5-factor structure in a general population of people with disabilities. These results were confirmed with the CFA. Concurrent validity analysis revealed that most factors were significantly associated with relevant psychosocial variables in the expected directions. CONCLUSIONS: The Social Motivation Inventory provides a useful tool for enhancing understanding of social motivation in rehabilitation psychology and rehabilitation counseling research and practice. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Glove and instrument changing to prevent bacterial contamination in infected wound debridement and closure procedures: A prospective observational study.

Many surgeons use a single table of instruments for both excisional debridement and coverage/closure of infected wounds. This study investigates the effectiveness of a two-table set-up of sterile instruments, in addition to glove exchange, to reduce instrument cross-contamination during these procedures. This is a prospective, single-site, institutional review board-approved observational study of surgical debridements of infected wounds over a 17-month period. Two separate sterile surgical tables were used for each case: Table A for initial wound debridement (debridement set-up) and Table B for wound coverage/closure (clean set-up). Swabs of each table and its respective instruments were taken after debridement but prior to coverage/closure. The primary outcome of interest was bacterial growth at 48 hours. There were 72 surgical cases included in this study. Culture results of Table A demonstrated bacterial growth in 23 of 72 (32%) cases at 48 hours compared with 5of 72 (7%) from Table B (P = .001). These data suggest that there is significant bacterial contamination of surgical instruments used for debridement of infected wounds. Use of a two-table set-up reduced instrument cross-contamination by 78%, suggesting avoidable re-contamination of the wound.

Company Characteristics, Disability Inclusion Practices, and Employment of People with Disabilities in the Post COVID-19 Job Economy: A Cross Sectional Survey Study.

Purpose In the post coronavirus disease 2019 (COVID-19) recession economy, rehabilitation counselors, transition specialists, and other disability service providers must redouble their efforts to connect with employers to create employment opportunities for people with physical and mental impairments. The purpose of the present study was to investigate company characteristics and effective disability inclusion practices that are related to employment of people with disabilities. Methods Four hundred sixty-six employers completed a demographic questionnaire and the Disability Inclusion Profiler. Results Results indicated company characteristics and disability practices were positively related to employment of people with disabilities. Conclusions Findings of the present study can be used by transition specialists, rehabilitation counselors, and other disability service providers to engage and connect with employers to increase employment opportunity for people with disabilities in the post COVID-19 economy. Future research and practice implications are provided.

Prediction of Kidney Drug Clearance: A Comparison of Tubular Secretory Clearance and Glomerular Filtration Rate.

BACKGROUND: Although proximal tubular secretion is the primary mechanism of kidney drug elimination, current kidney drug dosing strategies are on the basis of eGFR. METHODS: In a dedicated pharmacokinetic study to compare GFR with tubular secretory clearance for predicting kidney drug elimination, we evaluated stable outpatients with eGFRs ranging from 21 to 140 ml/min per 1.73 m2. After administering single doses of furosemide and famciclovir (metabolized to penciclovir), we calculated their kidney clearances on the basis of sequential plasma and timed urine measurements. Concomitantly, we quantified eight endogenous secretory solutes in plasma and urine using liquid chromatography-tandem mass spectrometry and measured GFR by iohexol clearance (iGFR). We computed a summary secretion score as the scaled average of the secretory solute clearances. RESULTS: Median iGFR of the 54 participants was 73 ml/min per 1.73 m2. The kidney furosemide clearance correlated with iGFR (r=0.84) and the summary secretion score (r=0.86). The mean proportionate error (MPE) between iGFR-predicted and measured furosemide clearance was 30.0%. The lowest MPE was observed for the summary secretion score (24.1%); MPEs for individual secretory solutes ranged from 27.3% to 48.0%. These predictive errors were statistically indistinguishable. Penciclovir kidney clearance was correlated with iGFR (r=0.83) and with the summary secretion score (r=0.91), with similar predictive accuracy of iGFR and secretory clearances. Combining iGFR with the summary secretion score yielded only modest improvements in the prediction of the kidney clearance of furosemide and penciclovir. CONCLUSIONS: Secretory solute clearance measurements can predict kidney drug clearances. However, tight linkage between GFR and proximal tubular secretory clearance in stable outpatients provides some reassurance that GFR, even when estimated, is a useful surrogate for predicting secretory drug clearances in such patients.

A Modified Delphi Study to Prioritize Content for a Simulation-based Pediatric Curriculum for Emergency Medicine Residency Training Programs.

OBJECTIVES: Pediatric training is an essential component of emergency medicine (EM) residency. The heterogeneity of pediatric experiences poses a significant challenge to training programs. A national simulation curriculum can assist in providing a standardized foundation of pediatric training experience to all EM trainees. Previously, a consensus-derived set of content for a pediatric curriculum for EM was published. This study aimed to prioritize that content to establish a pediatric simulation-based curriculum for all EM residency programs. METHODS: Seventy-three participants were recruited to participate in a three-round modified Delphi project from 10 stakeholder organizations. In round 1, participants ranked 275 content items from a published set of pediatric curricular items for EM residents into one of four categories: definitely must, probably should, possibly could, or should not be taught using simulation in all residency programs. Additionally, in round 1 participants were asked to contribute additional items. These items were then added to the survey in round 2. In round 2, participants were provided the ratings of the entire panel and asked to rerank the items. Round 3 involved participants dichotomously rating the items. RESULTS: A total of 73 participants participated and 98% completed all three rounds. Round 1 resulted in 61 items rated as definitely must, 72 as probably should, 56 as possibly could, 17 as should not, and 99 new items were suggested. Round 2 resulted in 52 items rated as definitely must, 91 as probably should, 120 as possibly could, and 42 as should not. Round 3 resulted in 56 items rated as definitely must be taught using simulation in all programs. CONCLUSIONS: The completed modified Delphi process developed a consensus on 56 pediatric items that definitely must be taught using simulation in all EM residency programs (20 resuscitation, nine nonresuscitation, and 26 skills). These data will serve as a targeted needs assessment to inform the development of a standard pediatric simulation curriculum for all EM residency programs.

Myxedema Coma: A Life-Threatening Condition in Patients Using Pembrolizumab.

The advent of immune checkpoint inhibitors has significantly improved the prognosis of patients with advanced malignancies. As we begin to understand these medications, multiple immune-related adverse effects (irAEs) have been found with these drugs, including endocrinopathies. Understanding the treatment-related adverse events of these medications is critical for clinical practice. Thyroid-related adverse effects usually occur within the first three months of treatment and rarely after eight months. It can manifest as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by a rapid transition to hypothyroidism, requiring long-term levothyroxine substitution. We present a case in which our patient was found unresponsive, hypothermic, and with respiratory failure almost after completing a year of treatment with pembrolizumab. He had an initial mild elevation in thyroid-stimulating hormone (TSH) of 6.52, although with normal free thyroxine (T4) of 1.06, in his first three months of starting treatment which then rapidly progressed to a true myxedema coma. The infrequency with which this occurs makes it a diagnostic challenge.

The American Society of Shoulder and Elbow Therapists' consensus statement on rehabilitation for anatomic total shoulder arthroplasty.

Anatomic total shoulder arthroplasty is the gold standard shoulder replacement procedure for patients with an intact rotator cuff and sufficient glenoid bone to accommodate prosthetic glenoid implant and offers reliable patient satisfaction, excellent implant longevity, and a low incidence of complications. Disparity exists in the literature regarding rehabilitation strategies following anatomic total shoulder arthroplasty. This article presents a consensus statement from experts in the field on rehabilitation following anatomic total shoulder arthroplasty. The goal of this consensus statement is to provide a current evidence-based foundation to inform the rehabilitation process after anatomic total shoulder arthroplasty. These guidelines apply to anatomic total shoulder arthroplasty (replacement of the humeral head and glenoid), hemiarthroplasty (replacing only the humeral head), and hemiarthroplasty with glenoid reaming or resurfacing. The consensus statement integrates an extensive literature review, as well as survey results of the practice patterns of members of the American Society of Shoulder and Elbow Therapists and the American Shoulder and Elbow Surgeons. Three stages of recovery are proposed, which initially protect and then gradually load soft tissue affected by the surgical procedure, such as the subscapularis, for optimal patient outcomes. The proposed guidelines should be used in collaboration with surgeon preferences and patient-specific factors.

Dexmedetomidine Pharmacokinetics in Neonates with Hypoxic-Ischemic Encephalopathy Receiving Hypothermia.

Dexmedetomidine is a promising sedative and analgesic for newborns with hypoxic-ischemic encephalopathy (HIE) undergoing therapeutic hypothermia (TH). Pharmacokinetics and safety of dexmedetomidine were evaluated in a phase I, single-center, open-label study to inform future trial strategies. We recruited 7 neonates ≥36 weeks' gestational age diagnosed with moderate-to-severe HIE, who received a continuous dexmedetomidine infusion during TH and the 6 h rewarming period. Time course of plasma dexmedetomidine concentration was characterized by serial blood sampling during and after the 64.8 ± 6.9 hours of infusion. Noncompartmental analysis yielded descriptive pharmacokinetic estimates: plasma clearance of 0.760 ± 0.155 L/h/kg, steady-state distribution volume of 5.22 ± 2.62 L/kg, and mean residence time of 6.84 ± 3.20 h. Naive pooled and population analyses according to a one-compartment model provided similar estimates of clearance and distribution volume. Overall, clearance was either comparable or lower, distribution volume was larger, and mean residence time or elimination half-life was longer in cooled newborns with HIE compared to corresponding estimates previously reported for uncooled (normothermic) newborns without HIE at comparable gestational and postmenstrual ages. As a result, plasma concentrations in cooled newborns with HIE rose more slowly in the initial hours of infusion compared to predicted concentration-time profiles based on reported pharmacokinetic parameters in normothermic newborns without HIE, while similar steady-state levels were achieved. No acute adverse events were associated with dexmedetomidine treatment. While dexmedetomidine appeared safe for neonates with HIE during TH at infusion doses up to 0.4 µg/kg/h, a loading dose strategy may be needed to overcome the initial lag in rise of plasma dexmedetomidine concentration.

Interrogation of CYP2D6 Structural Variant Alleles Improves the Correlation Between CYP2D6 Genotype and CYP2D6-Mediated Metabolic Activity.

The cytochrome P450 2D6 (CYP2D6) gene locus is challenging to accurately genotype due to numerous single nucleotide variants and complex structural variation. Our goal was to determine whether the CYP2D6 genotype-phenotype correlation is improved when diplotype assignments incorporate structural variation, identified by the bioinformatics tool Stargazer, with next-generation sequencing data. Using CYP2D6 activity measured with substrates dextromethorphan and metoprolol, activity score explained 40% and 34% of variability in metabolite formation rates, respectively, when diplotype calls incorporated structural variation, increasing from 36% and 31%, respectively, when diplotypes did not incorporate structural variation. We also investigated whether the revised Clinical Pharmacogenetics Implementation Consortium (CPIC) recommendations for translating genotype to phenotype improve CYP2D6 activity predictions over the current system. Although the revised recommendations do not improve the correlation between activity score and CYP2D6 activity, perhaps because of low frequency of the CYP2D6*10 allele, the correlation with metabolizer phenotype group was significantly improved for both substrates. We also measured the function of seven rare coding variants: one (A449D) exhibited decreased (44%) and another (R474Q) increased (127%) activity compared with reference CYP2D6.1 protein. Allele-specific analysis found that A449D is part of a novel CYP2D6*4 suballele, CYP2D6*4.028. The novel haplotype containing R474Q was designated CYP2D6*138 by PharmVar; another novel haplotype containing R365H was designated CYP2D6*139. Accuracy of CYP2D6 phenotype prediction is improved when the CYP2D6 gene locus is interrogated using next-generation sequencing coupled with structural variation analysis. Additionally, revised CPIC genotype to phenotype translation recommendations provides an improvement in assigning CYP2D6 activity.