Evolution of structural rearrangements in prostate cancer intracranial metastases.

Intracranial metastases in prostate cancer are uncommon but clinically aggressive. A detailed molecular characterization of prostate cancer intracranial metastases would improve our understanding of their pathogenesis and the search for new treatment strategies. We evaluated the clinical and molecular characteristics of 36 patients with metastatic prostate cancer to either the dura or brain parenchyma. We performed whole genome sequencing (WGS) of 10 intracranial prostate cancer metastases, as well as WGS of primary prostate tumors from men who later developed metastatic disease (n = 6) and nonbrain prostate cancer metastases (n = 36). This first whole genome sequencing study of prostate intracranial metastases led to several new insights. First, there was a higher diversity of complex structural alterations in prostate cancer intracranial metastases compared to primary tumor tissues. Chromothripsis and chromoplexy events seemed to dominate, yet there were few enrichments of specific categories of structural variants compared with non-brain metastases. Second, aberrations involving the AR gene, including AR enhancer gain were observed in 7/10 (70%) of intracranial metastases, as well as recurrent loss of function aberrations involving TP53 in 8/10 (80%), RB1 in 2/10 (20%), BRCA2 in 2/10 (20%), and activation of the PI3K/AKT/PTEN pathway in 8/10 (80%). These alterations were frequently present in tumor tissues from other sites of disease obtained concurrently or sequentially from the same individuals. Third, clonality analysis points to genomic factors and evolutionary bottlenecks that contribute to metastatic spread in patients with prostate cancer. These results describe the aggressive molecular features underlying intracranial metastasis that may inform future diagnostic and treatment approaches.

Drosophila Models Reveal Properties of Mutant Lamins That Give Rise to Distinct Diseases.

Mutations in the LMNA gene cause a collection of diseases known as laminopathies, including muscular dystrophies, lipodystrophies, and early-onset aging syndromes. The LMNA gene encodes A-type lamins, lamins A/C, intermediate filaments that form a meshwork underlying the inner nuclear membrane. Lamins have a conserved domain structure consisting of a head, coiled-coil rod, and C-terminal tail domain possessing an Ig-like fold. This study identified differences between two mutant lamins that cause distinct clinical diseases. One of the LMNA mutations encodes lamin A/C p.R527P and the other codes lamin A/C p.R482W, which are typically associated with muscular dystrophy and lipodystrophy, respectively. To determine how these mutations differentially affect muscle, we generated the equivalent mutations in the Drosophila Lamin C (LamC) gene, an orthologue of human LMNA. The muscle-specific expression of the R527P equivalent showed cytoplasmic aggregation of LamC, a reduced larval muscle size, decreased larval motility, and cardiac defects resulting in a reduced adult lifespan. By contrast, the muscle-specific expression of the R482W equivalent caused an abnormal nuclear shape without a change in larval muscle size, larval motility, and adult lifespan compared to controls. Collectively, these studies identified fundamental differences in the properties of mutant lamins that cause clinically distinct phenotypes, providing insights into disease mechanisms.

Implicit bias instruction across disciplines related to the social determinants of health: a scoping review.

One criticism of published curricula addressing implicit bias is that few achieve skill development in implicit bias recognition and management (IBRM). To inform the development of skills-based curricula addressing IBRM, we conducted a scoping review of the literature inquiring, "What interventions exist focused on IBRM in professions related to social determinants of health: education, law, social work, and the health professions inclusive of nursing, allied health professions, and medicine?"Authors searched eight databases for articles published from 2000 to 2020. Included studies: (1) described interventions related to implicit bias; and (2) addressed knowledge, attitude and/or skills as outcomes. Excluded were interventions solely focused on reducing/neutralizing implicit bias. Article review for inclusion and data charting occurred independently and in duplicate. Investigators compared characteristics across studies; data charting focused on educational and assessment strategies. Fifty-one full-text articles for data charting and synthesis, with more than 6568 learners, were selected. Educational strategies included provocative/engagement triggers, the Implicit Association Test, reflection and discussion, and various active learning strategies. Most assessments were self-report, with fewer objective measures. Eighteen funded studies utilized federal, foundation, institutional, and private sources. This review adds to the literature by providing tangible examples of curricula to complement existing frameworks, and identifying opportunities for further research in innovative skills-based instruction, learner assessment, and development and validation of outcome metrics. Continued research addressing IBRM would enable learners to develop and practice skills to recognize and manage their implicit biases during clinical encounters, thereby advancing the goal of improved, equitable patient outcomes.

Emergency Department Visits Increase in Transition-Age Patients Empaneled in a Primary Care Network at a Major Academic Medical Center.

PURPOSE: The aim of this study is to identify important predictors of emergency department (ED) utilization within a population of transition-aged patients empaneled within a primary care network, particularly with high-risk chronic conditions of childhood (HRC). METHODS: We analyzed cross-sectional data of patients aged 12-29 within a primary care network (n = 19,989). We used negative binomial regression modeling to identify important predictors of ED visits in the last year. RESULTS: Nearly 10% (n = 1,975) of the patients had one or more identified HRCs. Our final adjusted model showed that, among others, age 18-23 years (incidence rate ratio [IRR] 1.94, 95% confidence interval [CI] 1.74-2.15), presence of a high-risk condition (IRR 1.74, 95% CI 1.54-1.96]), transfer between two primary care providers in system (IRR 1.43, 95% CI 1.18-1.72), presence of care manager (IRR 2.19, 95% CI 1.68-1.72), and public insurance status (IRR 2.85, 95% CI 2.62-3.10) were all independent predictors of higher ED utilization. Conditions associated with a high incidence of ED utilization included sickle cell anemia (IRR 5.41, 95% CI 2.78-10.54), history of transplant (IRR 2.53, 95% CI 1.11-5.80), type 1 diabetes (IRR 2.12, 95% CI 1.42-3.15), and seizure disorder (IRR 2.01, 95% CI 1.61-2.51). We estimated that for each added chronic condition, the IRR increased 1.23-fold (95% CI 1.00-1.51). CONCLUSIONS: Our results demonstrate significantly greater use of high-cost healthcare services for patients in the 18- to 23-year age group and for patients with multiple complex medical conditions. These findings prompt a call for systems-wide processes to improve the pediatric-to-adult transition process.

In Silico and In Vivo Analysis of Amino Acid Substitutions That Cause Laminopathies.

Mutations in the LMNA gene cause diseases called laminopathies. LMNA encodes lamins A and C, intermediate filaments with multiple roles at the nuclear envelope. LMNA mutations are frequently single base changes that cause diverse disease phenotypes affecting muscles, nerves, and fat. Disease-associated amino acid substitutions were mapped in silico onto three-dimensional structures of lamin A/C, revealing no apparent genotype-phenotype connections. In silico analyses revealed that seven of nine predicted partner protein binding pockets in the Ig-like fold domain correspond to sites of disease-associated amino acid substitutions. Different amino acid substitutions at the same position within lamin A/C cause distinct diseases, raising the question of whether the nature of the amino acid replacement or genetic background differences contribute to disease phenotypes. Substitutions at R249 in the rod domain cause muscular dystrophies with varying severity. To address this variability, we modeled R249Q and R249W in Drosophila Lamin C, an orthologue of LMNA. Larval body wall muscles expressing mutant Lamin C caused abnormal nuclear morphology and premature death. When expressed in indirect flight muscles, R249W caused a greater number of adults with wing posturing defects than R249Q, consistent with observations that R249W and R249Q cause distinct muscular dystrophies, with R249W more severe. In this case, the nature of the amino acid replacement appears to dictate muscle disease severity. Together, our findings illustrate the utility of Drosophila for predicting muscle disease severity and pathogenicity of variants of unknown significance.

Implicit Bias Recognition and Management in Interpersonal Encounters and the Learning Environment: A Skills-Based Curriculum for Medical Students.

Introduction: Students desire instruction in skill development to address both their own implicit biases and bias perceived in the learning environment. Curricula to date achieve strategy identification through reflection and discussion but do not provide opportunity for personally relevant skill development and practice in implicit bias recognition and management. To address this gap, we developed and evaluated a skills-based elective in implicit bias recognition and management focused on learners' own interpersonal interactions, including patient encounters, and perceived bias in the learning environment. Method: Fifteen first-year medical students completed the nine-session elective over three annual offerings. Each session lasted 1.5 hours. Curriculum development was informed by published frameworks and transformative learning theory. Direct observation of student performances in role-plays and other active learning exercises constituted the formative assessment. Program evaluation focused on the impact of instruction through pre- and posttests, along with analysis of notes taken by the investigative team, including notes on formative assessments. Results: Students engaged with all aspects of instruction, including role-plays. Pretest/posttest results demonstrated increased self-reported knowledge and comfort in addressing perceived bias. Formative assessment demonstrated students' skill development in safely and respectfully addressing perceived bias in the learning environment without endangering their relationships with supervisors. Discussion: Skills developed-addressing bias in interpersonal encounters and perceived bias in clinical and teaching encounters-are relevant to learners throughout their careers. This course is relevant to medical students and trainees at various experience levels and could serve as a template for novel, skills-based curricula across health professions.

Cultured cardiac fibroblasts and myofibroblasts express Sushi Containing Domain 2 and assemble a unique fibronectin rich matrix.

Cardiac fibroblasts and myofibroblasts assemble and maintain extracellular matrix during normal development and following injury. Culture expansion of these cells yield a bioengineered matrix that could lead to intriguing therapeutic opportunities. For example, we reported that cultured rat cardiac fibroblasts form a matrix that can be used to delivery therapeutic stem cells. Furthermore, we reported that matrix derived from cultured human cardiac fibroblasts/myofibroblasts converted monocytes into macrophages that express interesting anti-inflammatory and pro-angiogenic properties. Expanding these matrix investigations require characterization of the source cells for quality control. In these efforts, we observed and herein report that Sushi Containing Domain 2 (SUSD2) is a novel and consistent marker for cultured human cardiac fibroblast and myofibroblasts.

It Can Be Done! A Skills-Based Elective in Implicit Bias Recognition and Management for Preclinical Medical Students.

PURPOSE: Students perceive bias in learning environments. Curricula targeting implicit bias recognition and management increase student awareness and achieve strategy identification, but fall short of actual skill development to address bias. In light of this gap, the authors developed and evaluated a skills-based elective to recognize and manage implicit bias in the learning environment. METHOD: Nine 1.5-hour sessions were delivered to 15 first-year medical students from 2017 to 2019. An evidence-based conceptual framework and transformative learning theory informed the instructional design; it incorporated active learning exercises. Skills assessment occurred through direct observation of student performances in role-play exercises. Using thematic analysis, the authors conducted a program evaluation based on focus groups with students and data from notes taken by the investigative team. RESULTS: Students engaged with all aspects of instruction, including role-plays. Authors identified 3 themes from the program evaluation: (1) Student engagement can be enhanced, (2) Instruction is empowering, and (3) It (addressing bias in one's own and witnessed encounters) can be done! Analysis additionally highlighted opportunities for improvement and lessons learned. CONCLUSIONS: This innovative course achieved skill development and practice for medical students in implicit bias recognition and management as it pertains to 3 facets of clinical care present at every stage of a health professional's career. These include interpersonal encounters, advocating for patients when bias is perceived in witnessed encounters with peers and supervisors, and addressing comments made by others within the learning environment. Outcomes could inform novel, skills-based curricula across the spectrum of health professions training and practice.

Development and pilot testing of a text message vaccine reminder system for use during an influenza pandemic.

In an influenza pandemic, two vaccine doses administered 21 days apart may be needed for individuals of all ages to achieve seroprotection. Achieving dose-series completion can be challenging even for routinely recommended vaccines. To prepare for a two-dose influenza pandemic vaccine campaign and promote dose-series completion and correct dosing intervals, CDC and its partners developed a text message-based vaccine reminder system to remind persons who receive a first dose of pandemic influenza vaccine to receive the second dose. Taking advantage of the high prevalence of cell phones in the United States, the system sent second-dose text message reminders and hyperlinks to educational information. The system was pilot tested from November 2015 to April 2016 among graduate public health students enrolled at four United States universities. Universities were selected based on convenience, and each university used a different recruitment method. Among 59 volunteers who pilot tested the system and completed a survey, 57 (92%) felt the system would be helpful during a pandemic. Forty (68%) respondents felt the information included in the messages was informative. Volunteers recommended including actionable ways to stay healthy during a pandemic, though specific suggestions varied. With further development, text reminder systems could be used to promote adherence to a two-dose regimen in a future pandemic, although audience-specific messaging and other complementary systems will likely be needed. Public and private partners can adapt and implement this tool in conjunction with their routine patient information systems to improve dose-series completion and ensure optimal protection during an influenza pandemic.