Cost-effectiveness analysis of CYP3A5 genotype-guided tacrolimus dosing in solid organ transplantation using real-world data.

The objective of this study was to estimate the cost-effectiveness of CYP3A5 genotype-guided tacrolimus dosing in kidney, liver, heart, and lung transplant recipients relative to standard of care (SOC) tacrolimus dosing, from a US healthcare payer perspective. We developed decision-tree models to compare economic and clinical outcomes between CYP3A5 genotype-guided and SOC tacrolimus therapy in the first six months post-transplant. We derived inputs for CYP3A5 phenotype frequencies and physician use of genotype test results to inform clinical care from literature; tacrolimus exposure [high vs low tacrolimus time in therapeutic range using the Rosendaal algorithm (TAC TTR-Rosendaal)] and outcomes (incidences of acute tacrolimus nephrotoxicity, acute cellular rejection, and death) from real-world data; and costs from the Medicare Fee Schedule and literature. We calculated cost per avoided event and performed sensitivity analyses to evaluate the robustness of the results to changes in inputs. Incremental costs per avoided event for CYP3A5 genotype-guided vs SOC tacrolimus dosing were $176,667 for kidney recipients, $364,000 for liver recipients, $12,982 for heart recipients, and $93,333 for lung recipients. The likelihood of CYP3A5 genotype-guided tacrolimus dosing leading to cost-savings was 19.8% in kidney, 32.3% in liver, 51.8% in heart, and 54.1% in lung transplant recipients. Physician use of genotype results to guide clinical care and the proportion of patients with a high TAC TTR-Rosendaal were key parameters driving the cost-effectiveness of CYP3A5 genotype-guided tacrolimus therapy. Relative to SOC, CYP3A5 genotype-guided tacrolimus dosing resulted in a slightly greater benefit at a higher cost. Further economic evaluations examining intermediary outcomes (e.g., dose modifications) are needed, particularly in populations with higher frequencies of CYP3A5 expressers.

Comparison of proximal and minus lens autorefraction techniques to measure monocular accommodative amplitude.

SIGNIFICANCE: This study provides a faster method for objectively measuring accommodative amplitude with an open-field autorefractor in a research setting. PURPOSE: Objective measures of accommodative amplitude with an autorefractor take time because of the numerous stimulus demands tested. This study compares protocols using different amounts and types of demands to shorten the process. METHODS: One hundred participants were recruited for four age bins (5 to 9, 10 to 14, 15 to 19, and 20 to 24 years) and monocular amplitude measured with an autorefractor using three protocols: proximal, proximal-lens (letter), and proximal-lens (picture). For proximal, measurements were taken as participants viewed a 0.9 mm "E" placed at 13 demands (40 to 3.3 cm = 2.5 to 30 D). The other protocols used a target (either the "E" or a detailed picture) placed at 33 and 12.5 cm followed by 12.5 cm with a series of lenses (-2, -4, and -5.5 D). Adjustments were made for lens effectivity for the three lens conditions, which were thus 9.6, 11.1, and 12.0 D for individuals without additional spectacle lenses. Accommodative amplitude was defined as the greatest response measured with each technique. One-way analysis of variance was used to compare group mean amplitudes across protocols and differences between letter protocols by age bin. RESULTS: Amplitudes were significantly different between protocols (p < 0.001), with proximal having higher amplitudes (mean ± standard deviation, 8.04 ± 1.70 D) compared with both proximal-lens protocols (letter, 7.48 ± 1.42 D; picture, 7.43 ± 1.42 D) by post hoc Tukey analysis. Differences in amplitude between the proximal and proximal-lens (letter) protocol were different by age group (p = 0 .003), with the youngest group having larger differences (1.14 ± 1.58 D) than the oldest groups (0.17 ± 0.58 and 0.29 ± 0.48 D, respectively) by post hoc Tukey analysis. CONCLUSIONS: The proximal-lens protocols took less time and identified the maximum accommodative amplitude in participants aged 15 to 24 years; however, they may underestimate true amplitude in younger children.

Evaluation of the SpotChecks contrast sensitivity test in children.

PURPOSE: The purpose of this study was to determine intrasession repeatability of a worksheet style contrast sensitivity test (SpotChecks) in children and agreement with an established contrast sensitivity test (Pelli-Robson). METHODS: Forty-three children aged 4 to 12 years participated in this single visit study that included two administrations of the SpotChecks binocularly, a single administration of the Pelli-Robson test and other measures of visual performance such as high-contrast visual acuity. Test order was randomised, and participants wore their habitual correction (39 unaided, 4 wearing glasses) for testing. Bland-Altman plots were used to assess the test-retest repeatability of SpotChecks and its agreement with the Pelli-Robson test. Multiple linear regressions were performed to evaluate whether contrast sensitivity was related to participant characteristics such as age, sex and near binocular visual acuity. RESULTS: The mean difference in log contrast sensitivity (logCS) between two administrations of the SpotChecks was 0.01, with a coefficient of repeatability (1.96*SD of differences) of 0.14 logCS. The mean difference between SpotChecks and Pelli-Robson was 0.00 logCS with 95% limits of agreement of -0.19 to +0.20. For both tests, a statistically significant increase in logCS was associated with age (slopes were 0.02 logCS/year, p < 0.001 and 0.01 logCS/year, p = 0.02 for the SpotChecks and Pelli-Robson tests, respectively). CONCLUSIONS: The SpotChecks test shows good intrasession repeatability and excellent agreement with the Pelli-Robson test in children. Contrast sensitivity showed an increase in logCS with age in children for both tests.

Dioptric differences between clinically determined and metric-optimised refractions for adults with Down syndrome.

PURPOSE: Refractions based on the optimisation of single-value wavefront-derived metrics may help determine appropriate corrections for individuals with Down syndrome where clinical techniques fall short. This study compared dioptric differences between refractions obtained using standard clinical techniques and two metric-optimised methods: visual Strehl ratio (VSX) and pupil fraction tessellated (PFSt), and investigated characteristics that may contribute to the differences between refraction types. METHODS: Thirty adults with Down syndrome (age = 29 ± 10 years) participated. Three refractive corrections (VSX, PFSt and clinical) were determined and converted to vector notation (M, J0 , J45 ) to calculate the dioptric difference between pairings of each type using a mixed model repeated measures approach. Linear correlations and multivariable regression were performed to examine the relationship between dioptric differences and the following participant characteristics: higher order root mean square (RMS) for a 4 mm pupil diameter, spherical equivalent refractive error and Vineland Adaptive Behavior Scales (a measure of developmental ability). RESULTS: The least squares mean estimates (standard error) of the dioptric differences for each pairing were as follows: VSX versus PFSt = 0.51 D (0.11); VSX versus clinical = 1.19 D (0.11) and PFSt versus clinical = 1.04 D (0.11). There was a statistically significant difference in the dioptric differences between the clinical refraction and each of the metric-optimised refractions (p < 0.001). Increased dioptric differences in refraction were correlated with increased higher order RMS (R = 0.64, p < 0.001 [VSX vs. clinical] and R = 0.47, p < 0.001 [PFSt vs. clinical]) as well as increased myopic spherical equivalent refractive error (R = 0.37, p = 0.004 [VSX vs. clinical] and R = 0.51, p < 0.001 [PFSt vs. clinical]). CONCLUSIONS: The observed differences in refraction demonstrate that a significant portion of the refractive uncertainty is related to increased higher order aberrations and myopic refractive error. Methodology surrounding clinical techniques and metric-optimisation based on wavefront aberrometry may explain the difference in refractive endpoints.

Evaluation of an opioid pain teleconsultation service to address the opioid overdose epidemic in Colorado: A Health First Colorado demonstration project.

BACKGROUND: Since the mid-1990s, more than 500,000 deaths have been attributed to the opioid overdose epidemic, which has created a serious national crisis affecting public health and social and economic welfare. To mitigate these opioid-related overdoses and deaths, interventions targeted at both the patient and community level are needed. OBJECTIVE: This demonstration project sought to determine whether implementation of a provider-to-provider opioid pain teleconsultation service with a pain specialist was correlated with a reduction in inappropriate opioid use and improve health outcomes. METHODS: Individual-level claims data for Health First Colorado Medicaid members were collected between March 1, 2017, and September 30, 2021, for individuals who triggered a provider-to-provider pain management teleconsultation based on receipt of a prescription for an opioid where the member was receiving a high-dose opioid (n = 125) or was opioid-naive (n = 819). The primary outcome measures were a patient's opioid dose less than 200 morphine milligram equivalent (MME) by 6 months after the consult if consult was triggered for high-dose use or discontinuation of an opioid by 12 weeks after consult if the consult was triggered for opioid naivety. Secondary opioid-related health outcomes were also assessed. RESULTS: In the high-dose opioid cohort, 87% of the members had their monthly average MME reduced to less than 200 by 180 days after their consult. More than half of the opioid-naive group had discontinued their opioid by 90 days after their consult. CONCLUSION: Results indicate that provider-to-provider teleconsultation services with a pain specialist can be an effective intervention at reducing total inappropriate opioid use.

Longitudinal Assessment of Multimorbidity Medication Patterns among Smokers in the COPDGene Cohort.

Background and objectives: Chronic obstructive pulmonary disease (COPD) is usually comorbid with other chronic diseases. We aimed to assess the multimorbidity medication patterns and explore if the patterns are similar for phase 1 (P1) and 5-year follow-up phase 2 (P2) in the COPDGene cohort. Materials and Methods: A total of 5564 out of 10,198 smokers from the COPDGene cohort who completed 2 visits, P1 and P2 visits, with complete medication use history were included in the study. We conducted latent class analysis (LCA) among the 27 categories of chronic disease medications, excluding COPD treatments and cancer medications at P1 and P2 separately. The best number of LCA classes was determined through both statistical fit and interpretation of the patterns. Results: We found four classes of medication patterns at both phases. LCA showed that both phases shared similar characteristics in their medication patterns: LC0: low medication; LC1: hypertension (HTN) or cardiovascular disease (CVD)+high cholesterol (Hychol) medication predominant; LC2: HTN/CVD+type 2 diabetes (T2D) +Hychol medication predominant; LC3: Hychol medication predominant. Conclusions: We found similar multimorbidity medication patterns among smokers at P1 and P2 in the COPDGene cohort, which provides an understanding of how multimorbidity medication clustered and how different chronic diseases combine in smokers.

Dynamic Risk Prediction of Response to Ursodeoxycholic Acid Among Patients with Primary Biliary Cholangitis in the USA.

BACKGROUND: Ursodeoxycholic acid (UDCA) remains the first-line therapy for primary biliary cholangitis (PBC); however, inadequate treatment response (ITR) is common. The UK-PBC Consortium developed the modified UDCA Response Score (m-URS) to predict ITR (using alkaline phosphatase [ALP] > 1.67 times the upper limit of normal [*ULN]) at 12 months post-UDCA initiation). Using data from the US-based Fibrotic Liver Disease Consortium, we assessed the m-URS in our multi-racial cohort. We then used a dynamic modeling approach to improve prediction accuracy. METHODS: Using data collected at the time of UDCA initiation, we assessed the m-URS using the original formula; then, by calibrating coefficients to our data, we also assessed whether it remained accurate when using Paris II criteria for ITR. Next, we developed and validated a dynamic risk prediction model that included post-UDCA initiation laboratory data. RESULTS: Among 1578 patients (13% men; 8% African American, 9% Asian American/American Indian/Pacific Islander; 25% Hispanic), the rate of ITR was 27% using ALP > 1.67*ULN and 45% using Paris II criteria. M-URS accuracy was "very good" (AUROC = 0.87, sensitivity = 0.62, and specificity = 0.82) for ALP > 1.67*ULN and "moderate" (AUROC = 0.74, sensitivity = 0.57, and specificity = 0.70) for Paris II. Our dynamic model significantly improved accuracy for both definitions of ITR (ALP > 1.67*ULN: AUROC = 0.91; Paris II: AUROC = 0.81); specificity approached 100%. Roughly 9% of patients in our cohort were at the highest risk of ITR. CONCLUSIONS: Early identification of patients who will not respond to UDCA treatment using a dynamic prediction model based on longitudinal, repeated risk factor measurements may facilitate earlier introduction of adjuvant treatment.

Visual Acuity Outcomes in a Randomized Trial of Wavefront Metric-optimized Refractions in Adults with Down Syndrome.

SIGNIFICANCE: This study reports visual acuity outcomes from a clinical trial investigating an objective refraction strategy that may provide a useful tool for practitioners needing additional strategies to identify refractive corrections for adults with intellectual disability. PURPOSE: Determining refractions for individuals with Down syndrome is challenging because of the presence of elevated refractive error, optical aberrations, and cognitive impairment. This randomized clinical trial evaluated the performance of spectacle corrections determined using clinical techniques and objective refractions derived from wavefront aberration measures. METHODS: Thirty adults with Down syndrome had a clinical refraction determined by a single expert examiner using pre-dilation and post-dilation techniques appropriate for this population. Objective refractions were determined from dilated wavefront aberration measures that were processed post-visit to identify refractions that optimized each of two image quality metrics: pupil fraction tessellated and visual Strehl ratio in the spatial domain. The three refractions were dispensed in random order and worn for 2 months each. The primary outcome measure, binocular visual acuity, was obtained by a masked examiner administering a distance logMAR acuity test. To compare treatment types, mean acuity was compared using a two-sided type 3 F test of the treatment effect in a linear mixed-effects regression model, where the final model included fixed effects for treatment, period (1, 2, or 3), and first-order carryover effects. RESULTS: The 2-month estimated least square means in binocular visual acuity (logMAR) were 0.34 (95% confidence interval [CI], 0.25 to 0.39) for clinical refractions, 0.31 (95% CI, 0.25 to 0.36) for pupil fraction tesselated refractions, and 0.33 (95% CI, 0.27 to 0.38) for visual Strehl ratio refractions. No statistically significant treatment effect was observed (F = 1.10, P = .34). CONCLUSIONS: Objective refractions derived from dilated wavefront aberration measures resulted in acuity similar to expert clinician-derived refractions, suggesting that the objective method may be a suitable alternative for patients with Down syndrome.

Ciliary muscle thickness in adults with Down syndrome.

PURPOSE: The relationship between ciliary muscle thickness (CMT), age and refractive error was investigated to determine if CMT, like other anterior ocular anatomy, differs in adults with Down syndrome (DS). METHODS: The CMT of 33 adults with DS was imaged using anterior segment optical coherence tomography. Images from the right eye obtained 45 minutes after cycloplegia (1% tropicamide, 2.5% phenylephrine) were analysed to calculate thickness at 1, 2 and 3 mm posterior to the scleral spur (CMT1, CMT2, CMT3), maximum thickness (CMTMAX) and apical thickness (AT = CMT1 - CMT2). Spherical equivalent refractive error was determined by clinical refraction using both non-dilated and dilated measures. Multivariate regression analysis evaluated the relationship between CMT and refractive error while controlling for subject age. RESULTS: Images were analysed from 26 subjects (mean age (SD) 29 years; mean refractive error (SD): -0.90 (5.03) D, range: -15.75 to +5.13D). Mean (SD) CMT decreased with posterior position (CMT1: 804 (83) µm; CMT2: 543 (131) µm; CMT3: 312 (100) µm). Mean (SD) CMTMAX and AT was 869 (57) µm and 260 (84) µm, respectively. There was a significant linear correlation indicating thinning CMT with increasing age for CMT1 and CMT2 (p ≤0.05). CMT2 and CMT3 had a significant negative correlation (thicker muscle with increasing myopic refractive error) (p ≤0.01). AT had a significant positive correlation (thicker muscle with increasing hyperopic refractive error) (p <0.01). CONCLUSIONS: Ciliary muscle thickness in participants with DS was found to be in a similar range with similar refractive error trends to previous reports of individuals without DS. However, it is important to note that the refractive error trends were driven by individuals with moderate to high levels of myopia.

A Randomized Trial of Objective Spectacle Prescriptions for Adults with Down Syndrome: Baseline Data and Methods.

SIGNIFICANCE: It is difficult to determine the most efficacious refractive correction for individuals with Down syndrome using routine clinical techniques. New objective methods that optimize spectacle corrections for this population may reduce limitations on daily living by improving visual quality. PURPOSE: This article describes the methods and baseline characteristics of study participants in a National Eye Institute-sponsored clinical trial to evaluate objectively derived spectacle corrections in adults with Down syndrome. Intersession repeatability of the primary outcome measure (distance visual acuity) is also reported. METHODS: Adults with Down syndrome were enrolled into a nine-visit study to compare clinically derived spectacle corrections and two different objective spectacle corrections derived from wavefront aberration data. Spectacle corrections were randomized and dispensed for 2 months each. Distance visual acuity was measured with a Bailey-Lovie-style chart. Intersession repeatability of acuity was established by performing difference versus mean analysis from binocular acuity measures obtained through habitual corrections at visits 1 and 2. RESULTS: Thirty adults (mean ± standard deviation age, 29 ± 10 years) with a large range of refractive errors were enrolled. Presenting visual acuity at visit 1 was reduced (right eye, 0.47 ± 0.20 logMAR; left eye, 0.42 ± 0.17 logMAR). The mean difference between visits 1 and 2 was 0.02 ± 0.06 logMAR, with a coefficient of repeatability (1.96 × within-subject standard deviation) of 0.12 logMAR. CONCLUSIONS: This study seeks to investigate new strategies to determine optical corrections that may reduce commonly observed visual deficits in individuals with Down syndrome. The good intersession repeatability of acuity found in this study (six letters) indicates that, despite the presence of reduced acuity, adults with Down syndrome performed the outcome measure for this clinical trial reliably.

Ursodeoxycholic Acid Treatment Preferentially Improves Overall Survival Among African Americans With Primary Biliary Cholangitis.

BACKGROUND: We used data from the Fibrotic Liver Disease Consortium to evaluate the impact of ursodeoxycholic acid (UDCA) treatment across race/ethnicity, gender, and clinical status among patients with primary biliary cholangitis. METHODS: Data were collected from "index date" (baseline) through December 31, 2016. Inverse Probability of Treatment Weighting was used to adjust for UDCA treatment selection bias. Cox regression, focusing on UDCA-by-risk factor interactions, was used to assess the association between treatment and mortality and liver transplant/death. RESULTS: Among 4,238 patients with primary biliary cholangitis (13% men; 8% African American, 7% Asian American/American Indian/Pacific Island [ASINPI]; 21% Hispanic), 78% had ever received UDCA. The final multivariable model for mortality retained age, household income, comorbidity score, total bilirubin, albumin, alkaline phosphatase, and interactions of UDCA with race, gender, and aspartate aminotransferase/alanine aminotransferase ≥1.1. Among untreated patients, African Americans and ASINPIs had higher mortality than whites (adjusted hazard ratio [aHR] = 1.34, 95% confidence interval [CI] 1.08-1.67 and aHR = 1.40, 95% CI 1.11-1.76, respectively). Among treated patients, this relationship was reversed (aHR = 0.67, 95% CI 0.51-0.86 and aHR = 0.88, 95% CI 0.67-1.16). Patterns were similar for liver transplant/death. UDCA reduced the risk of liver transplant/death in all patient groups and mortality across all groups except white women with aspartate aminotransferase/alanine aminotransferase ≥1.1. As compared to patients with low-normal bilirubin at baseline (≤0.4 mg/dL), those with high-normal (1.0 > 0.7) and mid-normal bilirubin (0.7 > 0.4) had significantly higher liver transplant/death and all-cause mortality. DISCUSSION: African American and ASINPI patients who did not receive UDCA had significantly higher mortality than white patients. Among African Americans, treatment was associated with significantly lower mortality. Regardless of UDCA treatment, higher baseline bilirubin, even within the normal range, was associated with increased mortality and liver transplant/death compared with low-normal levels.

The landscape of pharmacogenetic testing in a US managed care population.

PURPOSE: Little is known about how many insured patients receive pharmacogenetic testing. We describe trends of single-gene pharmacogenetic testing in a US managed care population, and demographic and clinical characteristics of patients who received a test. METHODS: We leveraged a random sample of nearly 11 million patients from a data set of paid medical and pharmacy claims to identify patients with at least one claim indicating receipt of at least one of these single-gene pharmacogenetic tests: CYP2C19, CYP2D6, CYP2C9, VKORC1, UGT1A1, and HLA class 1 typing. RESULTS: From 1 January 2013 to 30 September 2017, 5712 patients received at least one pharmacogenetic test (55% female; mean age = 43 years). The median number of tests per patient was 3 (mean = 2.7, max = 12); 54% were processed through Managed Medicare/Medicaid, while 45% were processed through commercial insurance. The total number of pharmacogenetic tests received more than doubled from 2013 (n = 1955) to 2015 (n = 4192), then decreased slightly in 2016 (n = 3946). The most common test was CYP2C19 (n = 4719), and "long-term (current) use of other medications" was the most common diagnosis. CONCLUSION: Pharmacogenetic testing through patients' insurance was low, but more than doubled from 2013 to 2016. This study highlights the need to better understand utilization patterns and insurance coverage for pharmacogenetic tests.

Increased Odds of Ventricular Arrhythmias Associated with Selective Serotonin Reuptake Inhibitor Use among the Pediatric and Young Adult Population: A Case-Control Study.

OBJECTIVE: To measure the association between selective serotonin reuptake inhibitor (SSRI) use and out-of-hospital ventricular arrhythmia among the pediatric and young adult population. STUDY DESIGN: Case-control study using US claims data from 2007 to 2018. Cases were subjects with at least 1 event between ages 2 and 24 years. Controls (matched 10:1 on index date, age, sex, and continuous enrollment) had no events during study period. Independent association between current SSRI use (prescription fill with continuous exposure ending on, or after, the index date) and incident out-of-hospital ventricular arrhythmia (hospitalization or emergency room encounter with primary diagnostic code for ventricular arrhythmia) was estimated using multivariable conditional logistic regression. Separate analyses were performed for pediatric (2-17 years of age) vs young adult (18-24 years of age) subjects and between citalopram/escitalopram vs other SSRIs. RESULTS: During the study period, 237 eligible cases were identified with 2370 matched controls. Cases were more likely to have government insurance and have a mental health, cardiac, or other complex chronic condition. Thirteen cases (5%) and 15 controls (<1%) had current SSRI exposure. After adjustment for mental health and chronic conditions, there was an increased odds of current SSRI use among cases compared with controls (OR 5.11, 95% CI 1.22-21.37). No difference was observed between pediatric and young adult ages, nor between citalopram/escitalopram and other SSRIs. CONCLUSIONS: These findings demonstrate increased odds of out-of-hospital ventricular arrhythmia associated with SSRI use in the pediatric and young adult population, suggesting a need for heightened awareness and ongoing monitoring of this potential adverse effect.

A Quasi-Experimental Analysis of Lethal Means Assessment and Risk for Subsequent Suicide Attempts and Deaths.

BACKGROUND: Counseling on access to lethal means is highly recommended for patients with suicide risk, but there are no formal evaluations of its impact in real-world settings. OBJECTIVE: Evaluate whether lethal means assessment reduces the likelihood of suicide attempt and death outcomes. DESIGN: Quasi-experimental design using an instrumental variable to overcome confounding due to unmeasured patient characteristics that could influence provider decisions to deliver lethal means assessment. SETTING: Kaiser Permanente Colorado, an integrated health system serving over 600,000 members, with comprehensive capture of all electronic health records, medical claims, and death information. PARTICIPANTS: Adult patients who endorsed suicide ideation on the Patient Health Questionnaire-9 (PHQ-9) depression screener administered in behavioral health and primary care settings from 2010 to 2016. INTERVENTIONS: Provider documentation of lethal means assessment in the text of clinical notes, collected using a validated Natural Language Processing program. MEASUREMENTS: Main outcome was ICD-9 or ICD-10 codes for self-inflicted injury or suicide death within 180 days of index PHQ-9 event. RESULTS: We found 33% of patients with suicide ideation reported on the PHQ-9 received lethal means assessment in the 30 days following identification. Lethal means assessment reduced the risk of a suicide attempt or death within 180 days from 3.3 to 0.83% (p = .034, 95% CI = .069-.9). LIMITATIONS: Unmeasured suicide prevention practices that co-occur with lethal means assessment may contribute to the effects observed. CONCLUSIONS: Clinicians should expand the use of counseling on access to lethal means, along with co-occurring suicide prevention practices, to all patients who report suicide ideation.

National survey of physicians' perspectives on pharmacogenetic testing in solid organ transplantation.

INTRODUCTION: Our objective was to evaluate physicians' perspectives on the clinical utility of pharmacogenetic (PGx) testing in kidney, liver, heart, and lung transplantation (KLHL-Tx). METHODS: A 36-question web-based survey was developed and administered to medical and surgical directors of US KLHL-Tx centers. RESULTS: There were 82 respondents (10% response rate). The majority were men (78%), non-Hispanic whites (70%), medical directors (72%), and kidney transplant physicians (35%). Although 78% of respondents reported having some PGx education, most reported lack of confidence in their PGx knowledge and ability to apply a PGx test. Participants reported mixed views about the clinical utility of PGx testing-most agreed with the efficacy of PGx testing, but not the benefits relative to the risks or standard of care. While 55% reported that testing was available at their institution, only 38% ordered a PGx test in the past year, most commonly thiopurine-S-methyltransferase. Physician-reported barriers to PGx implementation included uncertainty about the clinical value of PGx testing and patient financial burden. CONCLUSION: Together, our findings suggest prospective PGx research and pilot implementation programs are needed to elucidate the clinical utility and value of PGx in KLHL-Tx. These initiatives should include educational efforts to inform the use of PGx testing.

Histopathology-guided mass spectrometry differentiates benign nevi from malignant melanoma.

PURPOSE: Distinguishing benign nevi from malignant melanoma using current histopathological criteria may be very challenging and is one the most difficult areas in dermatopathology. The goal of this study was to identify proteomic differences, which would more reliably differentiate between benign and malignant melanocytic lesions. METHODS: We performed histolpathology - guided mass spectrometry (HGMS) profiling analysis on formalin-fixed, paraffin embedded tissue samples to identify differences at the proteomic level between different types of benign nevi and melanomas. A total of 756 cases, of which 357 cases of melanoma and 399 benign nevi, were included in the study. The specimens originated from both biopsies (376 samples) and tissue microarray (TMA) cores (380 samples). After obtaining mass spectra from each sample, classification models were built using a training set of biopsy specimens from 111 nevi and 100 melanomas. The classification algorithm developed on the training data set was validated on an independent set of 288 nevi and 257 melanomas from both biopsies and TMA cores. RESULTS: In the melanoma cohort, 239/257 (93%) cases classified correctly in the validation set, 3/257 (1.2%) classified incorrectly, and 15/257 (5.8%) classified as indeterminate. In the cohort of nevi, 282/288 (98%) cases classified correctly, 1/288 (0.3%) classified incorrectly, and 5/288 (1.7%) were indeterminate. HGMS showed a sensitivity of 98.76% and specificity of 99.65% in determining benign vs malignant. CONCLUSION: HGMS proteomic analysis is an objective and reliable test with minimal tissue requirements, which can be a helpful ancillary test in the diagnosis of challenging melanocytic lesions.

Validity of administrative claims-based algorithms for ventricular arrhythmia and cardiac arrest in the pediatric population.

PURPOSE: Identify administrative claims-based algorithms for capturing out-of-hospital ventricular arrhythmias (VA) and cardiac arrests (CA) due to cardiac causes in the pediatric population with high positive-predictive value (PPV). METHODS: Within a single pediatric center, a retrospective cohort of patients hospitalized or seen in the emergency room for VA or CA were identified from the electronic health records. Eligible encounters were blindly reviewed and linked to administrative data, including ICD-9/ICD-10 codes. Test characteristics, including PPV, for different diagnostic and procedure codes were generated using a 50% training sample. The gold standard was definite or suspected out-of-hospital VA or CA due to cardiac cause verified based on clinical criteria. Algorithms with the highest PPV were then applied to a 50% validation sample to validate performance. RESULTS: From 2004-2017, 598 encounters met eligibility criteria. 174 (29%) had an outcome of interest, with remainder being an inpatient event or CA due to other cause. Within the training sample (n = 263), VA codes in primary position had a PPV 94% (95%CI 81%-99%) with low sensitivity (44%, 95%CI 33%-56%). CA codes in any position or VA codes in nonprimary positions had low PPV (18%-19%, 31% respectively). Applying the top three performing algorithms to the validation sample (n = 252) yielded similar PPV values. CONCLUSIONS: Contrary to adults, algorithms including a CA code do not perform well for identifying out-of-hospital VA and CA due to cardiac cause in the pediatric populations. Researchers should be aware of the potential implications for future pediatric drug safety studies for these outcomes.

Placement of Reveal LINQ Device in the Left Anterior Axillary Position.

Implantable loop recorders (ILR) are utilized for long-term rhythm monitoring. Typical placement of the Medtronic Reveal LINQ along the left parasternal border may compromise the quality and/or feasibility of future imaging studies. We sought to evaluate the utility of placing an ILR in the left anterior axillary position and the impact on the quality of cardiac imaging. We reviewed patients from May 2017 to June 2018 who had placement of a Reveal LINQ device in the left anterior axillary position. Demographic, procedural, and clinical data were collected via retrospective review. Cardiac magnetic resonance imaging (MRI) studies were reviewed for image quality after ILR placement. Eight patients met inclusion criteria for this study (median age 6 years, 50% female). Six patients (75%) had an ILR placed in the operating room, while all others were placed in the electrophysiology lab. All patients demonstrated acceptable R waves for diagnostic evaluation (median = 0.85 mV, range 0.24-1.7 mV). Cardiac MRI was obtained in 7 patients following ILR placement with diagnostic image quality and no adverse events. One device was explanted 28 days after placement due to concern for possible infection. No other devices required removal or revision (median follow up duration 11 months, IQR 8-13.5). ILR placement in the left anterior axillary position can record adequate signals in pediatric patients. In addition, axillary ILR device position may allow for completion of cardiac imaging, particularly cardiac MRI, without significant artifacts which is critical for patients with congenital heart disease.

Bacillus thuringiensis Cry1Da_7 and Cry1B.868 Protein Interactions with Novel Receptors Allow Control of Resistant Fall Armyworms, Spodoptera frugiperda (J.E. Smith).

Two new modified Bacillus thuringiensis (Bt) proteins, Cry1Da_7 and Cry1B.868, with activity against fall armyworms (FAW), Spodoptera frugiperda (J.E. Smith), were evaluated for their potential to bind new insect receptors compared to proteins currently deployed as plant-incorporated protectants (PIPs) in row crops. Results from resistant insect bioassays, disabled insecticidal protein (DIP) bioassays, and cell-based assays using insect cells expressing individual receptors demonstrate that receptor utilizations of the newly modified Cry1Da_7 and Cry1B.868 proteins are distinct from each other and from those of commercially available Bt proteins such as Cry1F, Cry1A.105, Cry2Ab, and Vip3A. Accordingly, these two proteins target different insect proteins in FAW midgut cells and when pyramided together should provide durability in the field against this economically important pest.IMPORTANCE There is increased concern with the development of resistance to insecticidal proteins currently expressed in crop plants, especially against high-resistance-risk pests such as fall armyworm (FAW), Spodoptera frugiperda, a maize pest that already has developed resistance to Bacillus thuringiensis (Bt) proteins such as Cry1F. Lepidopteran-specific proteins that bind new insect receptors will be critical in managing current Cry1F-resistant FAW and delaying future resistance development. Results from resistant insect assays, disabled insecticidal protein (DIP) bioassays, and cell-based assays using insect cells expressing individual receptors demonstrate that target receptors of the Cry1Da_7 and Cry1B.868 proteins are different from each other and from those of commercially available Bt proteins such as Cry1F, Cry1A.105, Cry2Ab, and Vip3A. Therefore, pyramiding these two new proteins in maize will provide durable control of this economically important pest in production agriculture.

Comparison of Dynamic Retinoscopy and Autorefraction for Measurement of Accommodative Amplitude.

SIGNIFICANCE: This study promotes the use of dynamic retinoscopy to obtain objective measures of accommodative amplitude (AA) in the clinical setting in lieu of the subjective push-up technique. PURPOSE: This study compared the agreement between open-field autorefraction and a modified dynamic retinoscopy for the objective measurement of AA. METHODS: Accommodative amplitude was measured using two objective techniques for subjects aged 5 to 60 years. Test order was randomized and monocular AA was measured as subjects viewed printed letters 0.9 mm in height with their dominant eye and distance refraction. For retinoscopy, subjects held a near rod and viewed the target at the nearest (most proximal) point of clear vision. The examiner then performed dynamic retinoscopy along the horizontal meridian and identified the physical location of neutrality of the reflex, which was converted to AA in diopters. Autorefraction was performed obtaining repeated measures of refraction beginning from a target demand of 2.5 D and increasing in discrete steps until there was no subsequent increase in accommodative response. Refractions were converted to power in the horizontal meridian and expressed as accommodation in diopters with the maximal value termed the AA. Distance overrefractions were measured for both techniques to adjust AA for any uncorrected refractive error. Difference versus mean analysis was used to compare agreement between tests. RESULTS: The 95% limits of agreement between techniques were calculated after removal of two young outliers who responded poorly to one of the techniques. The overall mean difference for 95 subjects was 0.02 ± 0.97 D, with limits of agreement spanning -1.87 to 1.92 D. No significant linear relationship between the magnitude of the AA and the differences between techniques was observed. CONCLUSIONS: Agreement between dynamic retinoscopy and open-field autorefraction was less than 2 D with no systematic bias, suggesting that dynamic retinoscopy may be a suitable clinical technique to measure objective AA.