Citations

Hypertension is a common bevacizumab‐induced toxicity. No markers are available to predict patients at risk of developing hypertension. We hypothesized that genetic risk of essential hypertension, as measured by a blood pressure polygenic risk score (PRS), would be associated with risk of severe bevacizumab‐induced hypertension. PRSs were calculated for 1,027 bevacizumab‐treated patients of European descent with cancer from four clinical trials (Alliance for Clinical Trials in Oncology (Alliance) / Cancer and Leukemia Group B (CALGB) 80303, 40503, 90401, 40502) using summary systolic blood pressure (SBP) and diastolic blood pressure (DBP) genome‐wide association results obtained from 757,601 individuals of European descent. The association between PRS and grade 3 bevacizumab‐induced hypertension (Common Toxicity Criteria for Adverse Events version 3) in each trial was performed by multivariable logistic regression. Fixed‐effect meta‐analyses odds ratios (ORs) per standard deviation (SD) of the association of PRS (quantitative) and hypertension across trials were estimated by inverse‐variance weighting. PRSs were additionally stratified into quintiles, with the bottom quintile as the referent group. The OR of the association between hypertension and each quintile vs. the referent group was determined by logistic regression. The most significant PRS (quantitative)‐hypertension association included up to 67 single‐nucleotide variants (SNPs) associated with SBP (P = 0.0077, OR per SD = 1.31, 95% confidence interval (CI), 1.07–1.60), and up to 53 SNPs associated with DBP (P = 0.0209, OR per SD = 1.27, 95% CI, 1.04–1.56). Patients in the top quintile had a higher risk of developing bevacizumab‐induced hypertension compared with patients in the bottom quintile using SNPs associated with SBP (P = 4.75 × 10−4, OR = 3.72, 95% CI, 1.84–8.16) and DBP (P = 0.076, OR = 1.83, 95% CI, 0.95–3.64). Genetic variants associated with essential hypertension, mainly SBP, increase the risk of severe bevacizumab‐induced hypertension.

Abstract A discussion and debate on the American Medical Informatics Association’s (AMIA) Ethical, Legal, and Social Issues (ELSI) Working Group listserv in 2021 raised important issues related to a forthcoming conference in Texas. Texas had recently enacted a restrictive abortion law and restricted voting rights. Several AMIA members advocated for a boycott of the state and the scheduled conference. The discussion led the AMIA Board of Directors to request that the organization’s Ethics Committee provide general guidance for principle-based venue selection. This document recommends overarching principles for the venue selection for future AMIA events and conferences. Discussions by the AMIA Board, the Ethics Committee, and the ELSI Working Group informed these recommendations, and this document on guiding principles was approved by the AMIA Board of Directors in April 2022.

The therapeutic activities elicited by mesenchymal stem cells (MSC) are in part mediated through paracrine action by the release of extracellular vesicles (EV) and secreted proteins. Collectively, these MSC-derived factors, referred to as the secretome product (SP), are intrinsically therapeutic and represent an attractive alternative to cell-based therapies. Herein, we developed a lyopreservation protocol to extend the shelf-life of the MSC-SP without compromising the structural or functional integrity of the vesicular components. The SP isolated from normoxia- and anoxia-exposed MSC elicited protective effects in an in vitro model of oxidative injury and the bioactivity was retained in the lyophilized samples. Three separate formulations of MSC-SP were isolated by tangential flow filtration using sucrose, trehalose, and mannitol as lyoprotectant agents. The MSC-SPs were lyophilized using a manifold protocol and the structural and functional integrity were assessed. The trehalose formulation of SP exhibited the highest EV and protein recovery after manifold-based lyophilization. To facilitate development as a therapeutic, a shelf lyophilization protocol was developed which markedly enhanced the recovery of EV and proteins. In conclusion, lyophilization represents an efficient method to preserve the structural and functional integrity of the MSC-SP and can be used to develop an off-the-shelf therapeutic.

Background: A composite metric for the quality of glycemia from continuous glucose monitor (CGM) tracings could be useful for assisting with basic clinical interpretation of CGM data. Methods: We assembled a data set of 14-day CGM tracings from 225 insulin-treated adults with diabetes. Using a balanced incomplete block design, 330 clinicians who were highly experienced with CGM analysis and interpretation ranked the CGM tracings from best to worst quality of glycemia. We used principal component analysis and multiple regressions to develop a model to predict the clinician ranking based on seven standard metrics in an Ambulatory Glucose Profile: very low–glucose and low-glucose hypoglycemia; very high–glucose and high-glucose hyperglycemia; time in range; mean glucose; and coefficient of variation. Results: The analysis showed that clinician rankings depend on two components, one related to hypoglycemia that gives more weight to very low-glucose than to low-glucose and the other related to hyperglycemia that likewise gives greater weight to very high-glucose than to high-glucose. These two components should be calculated and displayed separately, but they can also be combined into a single Glycemia Risk Index (GRI) that corresponds closely to the clinician rankings of the overall quality of glycemia (r = 0.95). The GRI can be displayed graphically on a GRI Grid with the hypoglycemia component on the horizontal axis and the hyperglycemia component on the vertical axis. Diagonal lines divide the graph into five zones (quintiles) corresponding to the best (0th to 20th percentile) to worst (81st to 100th percentile) overall quality of glycemia. The GRI Grid enables users to track sequential changes within an individual over time and compare groups of individuals. Conclusion: The GRI is a single-number summary of the quality of glycemia. Its hypoglycemia and hyperglycemia components provide actionable scores and a graphical display (the GRI Grid) that can be used by clinicians and researchers to determine the glycemic effects of prescribed and investigational treatments.

Guanfacine is a selective alpha-2a adrenoreceptor agonist that with overdose can cause symptoms ranging from mild sedation to coma, respiratory depression, hyporeflexia, hypotonia, bradycardia, and hypotension. Despite a well-defined and predictable toxidrome, variations can be seen based on multiple factors including age, quantity ingested, organ functions, coingestions, time since ingestion, and specific dosage form. Here, we describe two cases of delayed presentation of extended release guanfacine toxicity and highlight the variations encountered in the toxidrome presentation. These cases bring to attention the importance of maintaining a high suspicion for such atypical presentations, keeping in mind the limitations of managing these complications on an inpatient psychiatric unit.

AbstractObjectivesPersistent functional impairment is common in bipolar disorder (BD) and is influenced by a number of demographic, clinical, and cognitive features. The goal of this project was to estimate and compare the influence of key factors on community function in multiple cohorts of well‐characterized samples of individuals with BD.MethodsThirteen cohorts from 7 countries included n = 5882 individuals with BD across multiple sites. The statistical approach consisted of a systematic uniform application of analyses across sites. Each site performed a logistic regression analysis with empirically derived “higher versus lower function” as the dependent variable and selected clinical and demographic variables as predictors.ResultsWe found high rates of functional impairment, ranging from 41 to 75%. Lower community functioning was associated with depressive symptoms in 10 of 12 of the cohorts that included this variable in the analysis. Lower levels of education, a greater number of prior mood episodes, the presence of a comorbid substance use disorder, and a greater total number of psychotropic medications were also associated with low functioning.ConclusionsThe bipolar clinical research community is poised to work together to characterize the multi‐dimensional contributors to impairment and address the barriers that impede patients' complete recovery. We must also identify the core features which enable many to thrive and live successfully with BD. A large‐scale, worldwide, prospective longitudinal study focused squarely on BD and its heterogeneous presentations will serve as a platform for discovery and promote major advances toward optimizing outcomes for every individual with this illness.

Introduction: Studying the clinical nature of myocarditis on a broad scale across age and sex groups is required to investigate risk factors and patterns of disease. This study aimed to examine patient- and hospital-centered characteristics of patients being hospitalized for myocarditis. Hypothesis: Sex differences in myocarditis prevalence are dependent on age. Methods and Results: We included all patients being hospitalized in three tertiary care centers between 1999 and 2021 with a diagnosis of acute or chronic myocarditis. We utilized Chi-square, T-test, Fisher exact or Wilcoxon-Mann-Whitney U tests. 7,031 patients with acute or chronic myocarditis were included in total. 231 (3.3%) were of pre-pubescent age (<13 years if male, <11 years if female), 410 (5.8%) were adolescent patients (<18 years), 2,089 (29.7%) young adults (18-35 years), 2,535 (36.1%) middle-aged adults (35-54 years) and 1,766 (25.1%) patients were over 54 years (post-menopausal age). The diagnosis of myocarditis was confirmed by endomyocardial biopsy in 1,337 patients (19%), while it was based on clinical parameters and/or magnetic resonance imaging in the remaining patients. Adolescent patients had the highest levels of procalcitonin (6.98 ±44.6 μg/l), troponin T (450 ±1,550 ng/l) and creatine kinase (360 ±677U/l), while pre-pubescent patients had the highest levels of anti-streptolysin antibody (320 ±470 kU/l) and NT-proBNP (14,000 ±20,800ng/l) compared to all other age groups. Left-ventricular ejection fraction decreased over age groups from 60 ±4% in adolescent patients to 44.0 ±16% in senior patients. The strongest sex difference in myocarditis frequency was observed in young (608 female vs. 1,481 male; P<0.001) and middle-aged adults (1,025 female vs. 1,510 male; P<0.001) (see Figure 1). Conclusion: Strong sex differences in myocarditis prevalence were particularly observed in young and middle-aged patients. Sex hormones may determine the risk of developing myocarditis.

Abstract Chronic noncancer pain in children and adolescents can be impairing and results in substantial health care costs. Intensive interdisciplinary pain treatment (IIPT), an inpatient or day hospital treatment delivered by a team of 3 or more health professionals, may be an effective intervention for these children and adolescents. Based on previous reviews and meta-analyses, we updated findings regarding the description of available treatments and estimated the effectiveness of IIPT, overcoming methodological shortcomings of previous work by requesting and analyzing individual participant data. On June 26, 2021, we searched 5 literature databases (PubMed, PsycINFO, Web of Science, Cochrane Library, and PubPsych) for studies examining the effectiveness of IIPT. Included studies used a pre–post design, assessed patients younger than 22 years, and presented their results in English, German, French, or Spanish. We used standard methodological procedures expected by Cochrane to pool treatment effects and assess risk of bias. We identified 13 different treatment sites with similar treatment inclusion criteria and treatment components, but the descriptions of those treatments varied widely. Regarding treatment effectiveness, IIPT may result in large improvements in the mean pain intensity (g = −1.28), disability (g = −1.91), and number of missed school days at the 12-month follow-up (g = −0.99), as well as moderate improvements in anxiety (g = −0.77) and depression (g = −0.76). The certainty of the evidence, however, was graded from very low to low. We recommend that future researchers use more scientific rigor to increase the certainty of the evidence for IIPT and standardize treatment outcomes for children and adolescents with chronic pain.