Optimized Aesthetic Outcomes When Treating Glabellar Lines with Botulinum Toxin Type A: GLO 3 + 2: A Precise Technique Based on Anatomy.

Good patient outcomes after treatment of the glabellar complex with botulinum toxin type A entail elimination of glabellar lines and maintenance of a natural eyebrow position. A precise injection technique that accurately targets the muscles that influence eyebrow position is required to reduce the risk of adverse aesthetic outcomes or unmasking an underlying eyelid ptosis. Here, we describe the glabellar lines optimization (GLO 3 + 2) injection anatomy technique, a precise five-point injection pattern that is based on current understanding of facial functional anatomy and which aims to minimize the risk of affecting nontargeted muscles. Injection sites above the brow or that do not target the precise location of the muscles in the glabellar complex are likely to inadvertently expose the frontalis to botulinum toxin type A and result in undesirable aesthetic outcomes. Because the frontalis is a strong determinant of aesthetic outcomes, it is important to consider the overall effects of the interactions between the eyebrow depressors and the opposing forces of the frontalis on brow outcomes in both the resting brow position and during dynamic brow movement.

Measurement of free fraction, total concentration and protein binding for testosterone, triiodothyronine and thyroxine.

Aims: Measuring the total and free concentrations of hormones is useful, but the technology to do this simultaneously is lacking. Methods: A new method offers the ability to measure these parameters concurrently for testosterone, thyroxine and triiodothyronine. Results: The free concentrations showed significant correlations with patients' vital statistics. Overall, 67% of correlations for total concentration showed that the new and classical methods had equal accuracy, or that comprehensive ultrafiltration was more accurate. The protein binding term was found to correlate significantly with the patients' luteinizing hormone, prostate-specific antigen and height. Conclusion: Comprehensive ultrafiltration for measuring the total concentration, free concentration and protein binding term uses less sample and is much faster than measuring these parameters with three separate methods.

A phase Ib study of interleukin-2 plus pembrolizumab for patients with advanced melanoma.

Introduction: High-dose interleukin-2 (HD IL-2) and pembrolizumab are each approved as single agents by the U.S. F.D.A. for the treatment of metastatic melanoma. There is limited data using the agents concurrently. The objectives of this study were to characterize the safety profile of IL-2 in combination with pembrolizumab in patients with unresectable or metastatic melanoma. Methods: In this Phase Ib study, patients received pembrolizumab (200 mg IV every 3 weeks) and escalating doses of IL-2 (6,000 or 60,000 or 600,000 IU/kg IV bolus every 8 hours up to 14 doses per cycle) in cohorts of 3 patients. Prior treatment with a PD-1 blocking antibody was allowed. The primary endpoint was the maximum tolerated dose (MTD) of IL-2 when co-administered with pembrolizumab. Results: Ten participants were enrolled, and 9 participants were evaluable for safety and efficacy. The majority of the evaluable participants (8/9) had been treated with PD-1 blocking antibody prior to enrollment. Patients received a median of 42, 22, and 9 doses of IL-2 in the low, intermediate, and high dose cohorts, respectively. Adverse events were more frequent with increasing doses of IL-2. No dose limiting toxicities were observed. The MTD of IL-2 was not reached. One partial response occurred in 9 patients (11%). The responding patient, who had received treatment with an anti-PD-1 prior to study entry, was treated in the HD IL-2 cohort. Discussion: Although the sample size was small, HD IL-2 therapy in combination with pembrolizumab appears feasible and tolerable. Clinical trial registration: ClinicalTrials.gov, identifier NCT02748564.

Impact of DaxibotulinumtoxinA for Injection on Brow Position and Frontalis Muscle Activity Following Treatment of Glabellar Lines.

BACKGROUND: Botulinum toxin type A (BoNTA) injections for the treatment of facial lines may lead to pleasant or undesirable changes in eyebrow height and position. OBJECTIVES: The aim of this study was to evaluate the impact of glabellar injection of DaxibotulinumtoxinA for Injection (DAXI), a novel BoNTA formulation, on eyebrow position and frontalis activity. METHODS: This study involved the post hoc analysis of adult patients from the Phase 2a forehead lines (FHL, N = 60) and open-label safety (OLS, N = 175) studies who received a single dose of DAXI 40 U to the glabella and for whom facial photographs were taken at rest and at maximum eyebrow elevation. Median vertical and horizontal displacement of the brows and median forehead strain (an objective quantitative assessment of frontalis activity) from baseline to 2 weeks after glabellar DAXI injection were measured. RESULTS: Two weeks after glabellar DAXI injection, vertical eyebrow movement (at rest) of the lateral brow was observed. In both studies, vertical movement was greatest in the lateral (0.6-0.9 mm) and mid (0.5-0.7 mm) brow regions; movement in the medial brow was negligible (0-0.23 mm). In both studies, a graded reduction in forehead strain was observed 2 weeks post glabellar DAXI injection, with the greatest reduction being in the lower segment (FHL, -73%; OLS, -82%). Treatment with DAXI showed improvements in FHL wrinkle severity. CONCLUSIONS: Glabellar injection of DAXI showed a positive reduction in dynamic frontalis activity that maintained or had a positive effect on eyebrow position. Vertical movement of the brow was suggestive of an improved eyebrow shape with a mild lateral arch.

A Natural Language Processing and Machine Learning Approach to Identification of Incidental Radiology Findings in Trauma Patients Discharged from the Emergency Department.

STUDY OBJECTIVE: Patients undergoing diagnostic imaging studies in the emergency department (ED) commonly have incidental findings, which may represent unrecognized serious medical conditions, including cancer. Recognition of incidental findings frequently relies on manual review of textual radiology reports and can be overlooked in a busy clinical environment. Our study aimed to develop and validate a supervised machine learning model using natural language processing to automate the recognition of incidental findings in radiology reports of patients discharged from the ED. METHODS: We performed a retrospective analysis of computed tomography (CT) reports from trauma patients discharged home across an integrated health system in 2019. Two independent annotators manually labeled CT reports for the presence of an incidental finding as a reference standard. We used regular expressions to derive and validate a random forest model using open-source and machine learning software. Final model performance was assessed across different ED types. RESULTS: The study CT reports were divided into derivation (690 reports) and validation (282 reports) sets, with a prevalence of incidental findings of 22.3%, and 22.7%, respectively. The random forest model had an area under the curve of 0.88 (95% confidence interval [CI], 0.84 to 0.92) on the derivation set and 0.92 (95% CI, 0.88 to 0.96) on the validation set. The final model was found to have a sensitivity of 92.2%, a specificity of 79.4%, and a negative predictive value of 97.2%. Similarly, strong model performance was found when stratified to a dedicated trauma center, high-volume, and low-volume community EDs. CONCLUSION: Machine learning and natural language processing can classify incidental findings in CT reports of ED patients with high sensitivity and high negative predictive value across a broad range of ED settings. These findings suggest the utility of natural language processing in automating the review of free-text reports to identify incidental findings and may facilitate interventions to improve timely follow-up.

Bayesian local exchangeability design for phase II basket trials.

We propose an information borrowing strategy for the design and monitoring of phase II basket trials based on the local multisource exchangeability assumption between baskets (disease types). In our proposed local-MEM framework, information borrowing is only allowed to occur locally, that is, among baskets with similar response rate and the amount of information borrowing is determined by the level of similarity in response rate, whereas baskets not considered similar are not allowed to share information. We construct a two-stage design for phase II basket trials using the proposed strategy. The proposed method is compared to competing Bayesian methods and Simon's two-stage design in a variety of simulation scenarios. We demonstrate the proposed method is able to maintain the family-wise type I error rate at a reasonable level and has desirable basket-wise power compared to Simon's two-stage design. In addition, our method is computationally efficient compared to existing Bayesian methods in that the posterior profiles of interest can be derived explicitly without the need for sampling algorithms. R scripts to implement the proposed method are available at https://github.com/yilinyl/Bayesian-localMEM.

Incidental Radiology Findings on Computed Tomography Studies in Emergency Department Patients: A Systematic Review and Meta-Analysis.

STUDY OBJECTIVE: An incidental finding is defined as a newly discovered mass or lesion detected on imaging performed for an unrelated reason. The identification of an incidental finding may be an opportunity for the early detection of a serious medical condition, including a malignancy. However, little is known about the prevalence of incidental findings in the emergency department (ED) setting and the strategies that can be used to mitigate the risk associated with them in the ED. This study aimed to estimate the overall prevalence of incidental findings and to summarize the currently described measures to mitigate the risks associated with incidental findings. METHODS: On November 22, 2020, a systematic literature search of PubMed, EMBASE, and Scopus was performed for studies that were published in peer-reviewed journals and reported the prevalence of incidental findings in computed tomography (CT) scans in patients in the ED. Patients who received CT scans that included the head, neck, chest, or abdomen/pelvis were included. The study characteristics, overall prevalence of incidental findings, prevalence of incidental findings by body region, and prespecified subgroups were extracted. The criteria used for risk stratification within individual studies were also extracted. Pooled estimates were calculated using a random-effects meta-analysis. RESULTS: A total of 1,385 studies were identified, and 69 studies met the inclusion criteria. The included studies represented 147,763 ED encounters or radiology reports across 16 countries, and 83% of studies were observational, cross-sectional studies. A total of 35 studies (50.7%) were in trauma patients. A large degree of heterogeneity was observed across the included studies. The overall pooled prevalence estimate for any incidental finding was 31.3% (95% confidence interval 24.4% to 39.1%). We found great variation in the methods described to mitigate the risk associated with incidental findings, including a lack of standardized risk stratification, inconsistent documentation practices, and only a small subset of studies describing prospective interventions aimed at improving the recognition and management of incidental findings from the ED. CONCLUSION: In patients in the ED receiving CT scans, incidental findings are commonly encountered across a broad range of ED chief complaints. This review highlights the existence of great heterogeneity in the definitions used to classify incidental findings. Future studies are needed to determine a clinically feasible categorization standard or terminology for commonly encountered incidental findings in the ED setting to standardize classification and documentation.

Predictors of Medical Students' Perceptions About Medical Cannabis.

BACKGROUND: There has been a recent uptick in interest regarding the therapeutic properties of cannabis. Evidence exists to support the role of medical cannabis (MC) in chronic illness management for conditions such as posttraumatic stress, pain, and cancer. The majority of physicians in the United States report not knowing how to prescribe or answer questions about MC and receive minimal education about it during training. As MC becomes more socially acceptable with federal legalization in process, new physicians will encounter patients looking for information on the utility and safety of MC. The goal of this research was thus to assess the perceived knowledge, beliefs, and perceptions of medical students towards MC, and to obtain a better understanding of factors that may influence their attitudes. METHODS: A descriptive, cross-sectional study design was used to investigate the medical students' knowledge, attitudes, and perceptions regarding MC. Quantitative data were collected from 526 medical students (years one to four) via an anonymous, online, 32-item questionnaire to determine if perceived knowledge, concerns about the potential negative effects of cannabis, and certain beliefs would significantly contribute to their attitudes toward MC. Hypothesis testing was conducted using Spearman-rank order correlation and multivariate linear regression analyses. RESULTS: A statistically significant regression equation was found: (F(4, 428)=114.826, p<.001 with an R2 =0.518 [adjusted R2 =0.513]) indicating greater perception of knowledge about MC, lower concern for possible negative effects of MC use, greater belief in federal legalization of MC, and greater belief in the federal legalization of recreational cannabis significantly contributed to a higher score on positive attitudes and perceptions toward MC. Moreover, while many participants reported physicians should be able to prescribe MC, they reported that little if any MC education had been provided. CONCLUSIONS: This study identified the knowledge, concerns, and perceptions of medical students regarding MC as well as several factors contributing to their attitudes about it. Favorable attitudes toward MC among patients exist and as its popularity and acceptance among patients continue, more may be asking their physicians about symptomatic and curative treatment with cannabis-based products. Results from this research have the potential to assist medical educators in understanding students' perceptions about MC to help guide innovative and contemporary curricular advances as a public health imperative.

Bayesian basket trial design with false-discovery rate control.

BACKGROUND: Recent advances in developing "tumor agnostic" oncology therapies have identified molecular targets that define patient subpopulations in a manner that supersedes conventional criteria for cancer classification. These successes have produced effective targeted therapies that are administered to patients regardless of their tumor histology. Trials have evolved as well with master protocol designs. By blending translational and clinical science, basket trials in particular are well-suited to investigate and develop targeted therapies among multiple cancer histologies. However, basket trials intrinsically involve more complex design decisions, including issues of multiple testing across baskets, and guidance for investigators is needed. METHODS: The sensitivity of the multisource exchangeability model to prior specification under differing degrees of response heterogeneity is explored through simulation. Then, a multisource exchangeability model design that incorporates control of the false-discovery rate is presented and a simulation study compares the operating characteristics to a design where the family-wise error rate is controlled and to the frequentist approach of treating the baskets as independent. Simulations are based on the original design of a real-world clinical trial, the SUMMIT trial, which investigated Neratinib treatment for a variety of solid tumors. The methods studied here are specific to single-arm phase II trials with binary outcomes. RESULTS: Values of prior probability of exchangeability in the multisource exchangeability model between 0.1 and 0.3 provide the best trade-offs between gain in precision and bias, especially when per-basket sample size is below 30. Application of these calibration results to a re-analysis of the SUMMIT trial showed that the breast basket exceeded the null response rate with posterior probability of 0.999 while having low posterior probability of exchangeability with all other baskets. Simulations based on the design of the SUMMIT trial revealed that there is meaningful improvement in power even in baskets with small sample size when the false-discovery rate is controlled as opposed to the family-wise error rate. For example, when only the breast basket was active, with a sample size of 25, the power was 0.76 when the false-discovery rate was controlled at 0.05 but only 0.56 when the family-wise error rate was controlled at 0.05, indicating that impractical sample sizes for the phase II setting would be needed to achieve acceptable power while controlling the family-wise error rate in this setting of a trial with 10 baskets. CONCLUSION: Selection of the prior exchangeability probability based on calibration and incorporation of false-discovery rate control result in multisource exchangeability model designs with high power to detect promising treatments in the context of phase II basket trials.

A phase I study of veliparib with cyclophosphamide and veliparib combined with doxorubicin and cyclophosphamide in advanced malignancies.

PURPOSE: Veliparib (V), an oral poly(ADP-ribose) polymerase (PARP) inhibitor, potentiates effects of alkylating agents and topoisomerase inhibitors in preclinical tumor models. We conducted a phase I trial of V with iv cyclophosphamide (C) and V plus iv doxorubicin (A) and C. METHODS: Objectives were to establish the maximum tolerated dose (MTD) of the combinations, characterize V pharmacokinetics (PK) in the presence and absence of C, measure PAR in peripheral blood mononuclear cells (PBMCs) and γH2AX in circulating tumor cells (CTCs). In Group 1, dose escalations of V from 10 to 50 mg every 12 h Days 1-4 plus C 450 to 750 mg/m2 Day 3 in 21-day cycles were evaluated. In Group 2, V doses ranged from 50 to 150 mg every 12 h Days 1-4 with AC (60/600 mg/m2) Day 3 in 21-day cycles. In Group 3, patients received AC Day 1 plus V Days 1-7, and in Group 4, AC Day 1 plus V Days 1-14 was given in 21-day cycles to evaluate effects on γH2AX foci. RESULTS: Eighty patients were enrolled. MTD was not reached for V and C. MTD for V and AC was V 100 mg every 12 h Days 1-4 with AC (60/600 mg/m2) Day 3 every 21 days. V PK appears to be dose-dependent and has no effect on the PK of C. Overall, neutropenia and anemia were the most common adverse events. Objective response in V and AC treated groups was 22% (11/49). Overall clinical benefit rate was 31% (25/80). PAR decreased in PBMCs. Percentage of γH2AX-positive CTCs increased after treatment with V and AC. CONCLUSION: V and AC can be safely combined. Activity was observed in patients with metastatic breast cancer.

Genome-wide enhancer maps link risk variants to disease genes.

Genome-wide association studies (GWAS) have identified thousands of noncoding loci that are associated with human diseases and complex traits, each of which could reveal insights into the mechanisms of disease1. Many of the underlying causal variants may affect enhancers2,3, but we lack accurate maps of enhancers and their target genes to interpret such variants. We recently developed the activity-by-contact (ABC) model to predict which enhancers regulate which genes and validated the model using CRISPR perturbations in several cell types4. Here we apply this ABC model to create enhancer-gene maps in 131 human cell types and tissues, and use these maps to interpret the functions of GWAS variants. Across 72 diseases and complex traits, ABC links 5,036 GWAS signals to 2,249 unique genes, including a class of 577 genes that appear to influence multiple phenotypes through variants in enhancers that act in different cell types. In inflammatory bowel disease (IBD), causal variants are enriched in predicted enhancers by more than 20-fold in particular cell types such as dendritic cells, and ABC achieves higher precision than other regulatory methods at connecting noncoding variants to target genes. These variant-to-function maps reveal an enhancer that contains an IBD risk variant and that regulates the expression of PPIF to alter the membrane potential of mitochondria in macrophages. Our study reveals principles of genome regulation, identifies genes that affect IBD and provides a resource and generalizable strategy to connect risk variants of common diseases to their molecular and cellular functions.

Management of type 2 diabetes with oral semaglutide: Practical guidance for pharmacists.

PURPOSE: To provide pharmacists with information on counseling patients with type 2 diabetes (T2D) receiving oral semaglutide. SUMMARY: Oral semaglutide, the first oral glucagon-like peptide 1 (GLP-1) receptor agonist (GLP-1RA), was approved for the treatment of adults with T2D by the US Food and Drug Administration in September 2019. Semaglutide has been coformulated with the absorption enhancer sodium N-(8-[2-hydroxybenzoyl] amino) caprylate to improve bioavailability of semaglutide following oral administration. Oral semaglutide has been shown to have efficacy and safety profiles similar to those of other GLP-1RAs. Many patients with T2D have a complex oral medication regimen to manage their T2D and concomitant chronic comorbid conditions. Therefore, it is important that patients follow the dose administration instructions closely: oral semaglutide should be taken on an empty stomach upon waking with a sip (≤120 mL) of plain water and at least 30 minutes before the first food, beverage, or other oral medications of the day. The most common adverse effects of oral semaglutide are gastrointestinal (typically nausea, diarrhea, and vomiting). It is important for pharmacists to counsel patients prescribed oral semaglutide about optimal oral dosing, why correct dosing conditions are necessary, expected therapeutic response, and effective strategies to mitigate potential gastrointestinal adverse events. CONCLUSION: Information and practical strategies provided by pharmacists may facilitate initiation and maintenance of oral semaglutide therapy and ensure that each patient achieves an optimal therapeutic response.

Programmed Cell Death-1 Monoclonal Antibody Therapy and Type 1 Diabetes Mellitus: A Review of the Literature.

Two Food and Drug Administration-approved programmed cell death-1 (PD-1) inhibitors, nivolumab (Opdivo®), and pembrolizumab (Keytruda®), are indicated for treatment-resistant malignancies. Inhibition of PD-1 also inhibits T-cell peripheral tolerance, enhancing autoimmunity. Various autoimmune conditions have been reported with the use of these agents, including type 1 diabetes mellitus (T1DM). This article reviews literature regarding the development of T1DM in patients treated with PD-1 inhibitors and identifies strategies for the appropriate identification, monitoring, and follow-up of these patients. Published cases of T1DM related to PD-1 inhibitor therapy were identified using PubMed. Eighty-three identified publications were reviewed, of which 37 publications involving 42 cases of anti-PD-1 therapy-induced T1DM were identified. The average age of patients at presentation was 62 years and 59.5% were male. The mean number of PD-1 inhibitor doses received was 5, with a mean time to presentation of 11 weeks. Initial presentation of diabetic ketoacidosis was reported in 69% of cases, with an average blood glucose of 660 mg/dL and an average HbA1c of 8.7%. The exact mechanism PD-1 inhibitor therapy-induced T1DM is unknown. Blood glucose monitoring is recommended for all patients receiving anti-PD-1 therapy. Further research is needed to delineate the frequency of this adverse effect, as well as to evaluate potential risk factors and ideal management strategies.