Real-world effectiveness, satisfaction, and optimization of ubrogepant for the acute treatment of migraine in combination with onabotulinumtoxinA: results from the COURAGE Study.

BACKGROUND: Individuals using onabotulinumtoxinA as a preventive migraine treatment often use acute treatments for breakthrough attacks. Data on real-world effectiveness of the small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist ubrogepant in combination with onabotulinumtoxinA are limited. METHODS: COURAGE, a prospective, multiple attack, observational study, evaluated the real-world effectiveness of ubrogepant (50 or 100 mg) for acute treatment of migraine in people receiving onabotulinumtoxinA, an anti-CGRP monoclonal antibody (mAb), or both. This analysis focused only on onabotulinumtoxinA users. The Migraine Buddy app was used to identify eligible participants and track response to treated attacks. For each ubrogepant-treated attack, meaningful pain relief (MPR) and return to normal function (RNF) at 2 and 4 h post-dose over 30 days was assessed. MPR was defined as a level of relief that is meaningful to the participant, usually occurring before the pain is all gone. After 30 days, satisfaction was reported on a 7-point scale and overall acute treatment optimization was evaluated using the migraine Treatment Optimization Questionnaire-4 (mTOQ-4). RESULTS: This analysis included 122 participants who received ubrogepant and onabotulinumtoxinA and reported on 599 ubrogepant-treated attacks. Following the first ubrogepant-treated attack, MPR was achieved in 53.3% of participants 2 h post-dose and in 76.2% of participants 4 h post-dose. RNF was achieved in 25.4% of participants 2 h post-dose and in 45.9% of participants 4 h post-dose. MPR and RNF results were similar across up to 10 ubrogepant-treated attacks. After 30 days, satisfaction with ubrogepant in combination with onabotulinumtoxinA was reported by 69.8% of participants and acute treatment optimization (defined as mTOQ-4 score ≥ 4) was achieved in 77.6%. CONCLUSIONS: In this prospective real-world effectiveness study, ubrogepant treatment in onabotulinumtoxinA users with self-identified migraine was associated with high rates of MPR and RNF at 2 and 4 h as well as satisfaction and acute treatment optimization. Although the lack of a contemporaneous control group limits causal inference, these findings demonstrate the feasibility of using a novel, app-based design to evaluate the real-world effectiveness and satisfaction of treatments.

Managing migraine on the frontline: Identifying disease, understanding burden, and incorporating CGRP pathway-targeting therapies in primary care.

Migraine is a common neurologic disorder with clinical phenotypes encompassing a variety of symptoms which all contribute to the burden felt by patients. In addition to negative impacts on a patient's quality of life, migraine has both direct medical costs and indirect costs related to missed work and decreased productivity that affect individuals as well as society at large. Unfortunately, migraine diagnoses are often missed, and many patients do not receive appropriate treatment. Primary care providers are in a key position to provide timely diagnosis and effectively manage migraine for many patients. This review aims to be a guide for improving migraine management in the primary care setting by providing strategies to overcome common challenges in migraine diagnosis; summarizing current knowledge on the mechanism of action, efficacy, and safety of calcitonin gene-related peptide (CGRP) pathway-targeting therapies; and reviewing approaches to incorporate traditional and emerging treatment options into a patient-centric migraine management strategy.

Cyclooxygenase-2 contributes to diabetic nephropathy through glomerular EP4 receptor.

Diabetic nephropathy (DN) is a major microvascular complication of diabetes and the leading cause of mortality in diabetic patients. Cyclooxygenase (COX) and COX-derived prostanoids are documented to participate in the pathogenesis of diabetic nephropathy. Herein, we found an increased COX2 expression level in diabetic kidneys of STZ-induced DBA mice. The COX2 inhibitor significantly attenuated albuminuria and histological lesions, accompanied by up-regulation of the renal angiopoietin-1/tie-2 system. This finding is consistent with the presence of an angiogenic signature in endothelial cells during the development of DN. Prostaglandin E2 (PGE2) is the most abundant prostanoid in the kidney, and its receptor EP4 is expressed in the glomerulus, as determined by in situ hybridization. To test the hypothesis that diabetes-associated COX2 overexpression induces renal PGE2 production and endothelial dysfunction by activating glomerular EP4 receptors, the effect of an EP4 antagonist on Akita/DBA mice was investigated. Our results showed that blockade of EP4 receptor significantly reduced albuminuria in diabetic mice. Owing to the established adverse effect of COX2 inhibitors, our study provided new insight into meaningful renal benefits for diabetic nephropathy by targeting the EP4 receptor.

Factors Predictive of Publication Among Medical Students Participating in School-Sponsored Research Programs.

INTRODUCTION: Publishing research is an important component of medical students' career development and becoming a more competitive residency applicant. Many medical schools offer structured programs to enable students to participate in research during their preclinical and clinical years, but the majority of student-mentor partnerships do not culminate in publication across a variety of institutions and medical specialties. The primary objective of this study is to determine if any factors associated with mentee-mentor partnerships are predictive of publication from two school-sponsored research programs at a single US medical school. METHODS: The PubMed-indexed publications of all student-mentor pairings from a summer internship (after year 1 of medical school) or research elective (during year 4 of medical school) at a single institution from 2008 to 2018 were retrospectively reviewed. Student/mentor demographic information was associated with the probability of publication. RESULTS: A total of 124 students participated in the summer internship with 32 (26%) achieving publication. The publication was significantly more likely for students that were from highly ranked undergraduate institutions (p = 0.04; likelihood ratio (LR) = 5.788), were future Alpha Omega Alpha (AOA) members (p = 0.03; LR = 4.597), or worked with a mentor focused on clinical rather than basic science research (p = 0.02; LR = 5.662). Forty-four students participated in the fourth-year elective with 11 (25%) achieving publication. The publication was more likely if the student worked with a mentor without a Doctor of Medicine (MD)/Doctor of Osteopathic Medicine (DO) degree (p = 0.001; LR = 7.051), with a PhD degree (p = 0.002; LR = 7.820), or a mentor with prior publication(s) with prior mentee(s) (p = 0.03; LR = 5.368). CONCLUSION: Only one-quarter of mentor-mentee research pairings resulted in publication, with student-related factors more predictive for publication from the internship and mentor-related factors more predictive of publication from the elective. Approaches to promote successful completion of medical student research projects should be considered to yield the greatest value from students' work and strengthen the development of future physician-scientists.

Coronavirus Disease Contact Tracing Outcomes and Cost, Salt Lake County, Utah, USA, March-May 2020.

Outcomes and costs of coronavirus disease (COVID-19) contact tracing are limited. During March-May 2020, we constructed transmission chains from 184 index cases and 1,499 contacts in Salt Lake County, Utah, USA, to assess outcomes and estimate staff time and salaries. We estimated 1,102 staff hours and $29,234 spent investigating index cases and contacts. Among contacts, 374 (25%) had COVID-19; secondary case detection rate was ≈31% among first-generation contacts, ≈16% among second- and third-generation contacts, and ≈12% among fourth-, fifth-, and sixth-generation contacts. At initial interview, 51% (187/370) of contacts were COVID-19-positive; 35% (98/277) became positive during 14-day quarantine. Median time from symptom onset to investigation was 7 days for index cases and 4 days for first-generation contacts. Contact tracing reduced the number of cases between contact generations and time between symptom onset and investigation but required substantial resources. Our findings can help jurisdictions allocate resources for contact tracing.

Barriers and Facilitators of Adverse Event Reporting by Adolescent Patients and Their Families.

OBJECTIVES: The objectives were (1) to describe barriers and facilitators of adverse event reporting by adolescent patients and parents in a pediatric hospital and (2) to identify characteristics the participants wished to have in a formal reporting system of adverse events. METHODS: We used a qualitative design in which 6 focus groups, 3 with parents and 3 with adolescents, were conducted. The transcripts of audio recordings, notes of team debriefings, and written field notes of group behaviors were analyzed using NVivo software for qualitative data analysis. RESULTS: Participants reported that the quality of the experience with the health care system, type of communication with health care providers, and degree of personal self-confidence in communication within the health care system were 3 interacting factors influencing willingness to report adverse events. Preferred reporting mechanisms were different for different participants and included face-to-face meetings with hospital representatives, Web sites, smart phone capability, phone calls from a human, and paper mail. Reporting systems should be easy to use, ensure confidentiality, and provide user feedback. CONCLUSIONS: Experience, communication, and confidence are 3 factors that can engage an adolescent patient and parents in their health care. Confident adolescent patients and parents in turn have a possibility of reporting an adverse safety event given an opportunity.

"Who's Been Putting Socks in My Drawer?" Narrative Case Study of an Elder Role Model.

BACKGROUND AND OBJECTIVES: This article presents a narrative-based case study about vital involvement in an elder role model, exploring the dimensions of this man's current vital involvement and identifying its lifelong expressions that appear, in older adulthood, to have enabled him to become such an exemplar. This case was chosen from a larger study of "Elder Roles Models", that explores: (i) What about these particular older adults (identified by colleagues, friends, program directors, and service providers) constitutes their "elder role model-hood"; and (ii) How, developmentally, they got to be this way in older adulthood. This case study addresses the first of these questions by identifying five dimensions of vital involvement. RESEARCH DESIGN AND METHODS: Case study data were collected through five, semi-structured life-history interviews conducted over the 3 months. Interviews (90-120 minutes, each) were transcribed and analyzed using a thematic analysis approach. FINDINGS: Five dimensions emerged as constituting this man's vital involvement in older adulthood: (i) enacting personal values and strengths; (ii) person-environment reciprocity; (iii) using environmental supports; (iv) enriching the environment; and (v) experience-based perspective. DISCUSSION AND IMPLICATIONS: Dimensions are contextualized in terms of gerontological and life-cycle research, theory, and practice. A fundamental principle of Erikson's theory of lifelong psychosocial development, the vital involvement dynamic, is suggested as an "umbrella concept" for integrating disparate gerontological practices, theories, and research, and for conceptualizing older adulthood in the context of the life cycle as a whole.

Family Involvement in Adult Chronic Disease Care: Reviewing the Systematic Reviews.

Health care providers, policy makers, and investigators are dependent upon the quality and accuracy of published research findings to inform and guide future practice and research in their field. Systematic reviews, the synthesis of outcomes across studies are increasingly more common in the family literature; however, published review reports often lack information on strategies reviewers used to insure dependability of findings, and minimize methodological bias in the review. In this article, we summarize findings from systematic reviews of interventions and outcomes from family involvement in adult chronic disease care published between 2007 and 2016. In addition, we explore procedures reviewers used to insure the quality and methodologic rigor of the review. Our discussion provides guidance and direction for future studies of family involvement in chronic disease care.

Nonselective Cyclooxygenase Inhibition Retards Cyst Progression in a Murine Model of Autosomal Dominant Polycystic Kidney Disease.

Aim: Autosomal dominant polycystic kidney disease is one of the most common genetic renal diseases. Cyclooxygenase plays an important role in epithelial cell proliferation and may contribute to the mechanisms underlying cyst formation. The aim of the present study was to evaluate the role of cyclooxygenase inhibition in the cyst progression in polycystic kidney disease. Method: Pkd2WS25/- mice, a murine model which harbors a compound cis-heterozygous mutation of the Pkd2 gene were used. Cyclooxygenase expression was assessed in both human and murine kidney specimens. Pkd2WS25/- mice were treated with Sulindac (a nonselective cyclooxygenase inhibitor) or vehicle for 8 months starting at three weeks age, and then renal cyst burden was assessed by kidney weight and volume. Results: Cyclooxygenase-2 expression was up-regulated compared to control kidneys as shown by RNase protection in human polycystic kidneys and immunoblot in mouse Pkd2WS25/- kidneys. Cyclooxygenase-2 expression was up-regulated in the renal interstitium as well as focal areas of the cystic epithelium (p<0.05). Basal Cyclooxygenase-1 levels were unchanged in both immunohistochemistry and real-time PCR. Administration of Sulindac to Pkd2WS25/- mice and to control mice for 8 months resulted in reduced kidney weights and volume in cystic mice. Renal function and electrolytes were not significantly different between groups. Conclusion: Thus treatment of a murine model of polycystic kidney disease with Sulindac results in decreased kidney cyst burden. These findings provide additional implications for the use of Cyclooxygenase inhibition as treatment to slow the progression of cyst burden in patients with polycystic kidney disease.

Hyperspectral Imaging and K-Means Classification for Histologic Evaluation of Ductal Carcinoma In Situ.

Hyperspectral imaging (HSI) is a non-invasive optical imaging modality that shows the potential to aid pathologists in breast cancer diagnoses cases. In this study, breast cancer tissues from different patients were imaged by a hyperspectral system to detect spectral differences between normal and breast cancer tissues. Tissue samples mounted on slides were identified from 10 different patients. Samples from each patient included both normal and ductal carcinoma tissue, both stained with hematoxylin and eosin stain and unstained. Slides were imaged using a snapshot HSI system, and the spectral reflectance differences were evaluated. Analysis of the spectral reflectance values indicated that wavelengths near 550 nm showed the best differentiation between tissue types. This information was used to train image processing algorithms using supervised and unsupervised data. The K-means method was applied to the hyperspectral data cubes, and successfully detected spectral tissue differences with sensitivity of 85.45%, and specificity of 94.64% with true negative rate of 95.8%, and false positive rate of 4.2%. These results were verified by ground-truth marking of the tissue samples by a pathologist. In the hyperspectral image analysis, the image processing algorithm, K-means, shows the greatest potential for building a semi-automated system that could identify and sort between normal and ductal carcinoma in situ tissues.

Methods of Academic Course Planning for Cancer Biology PhD Students to Enhance Knowledge of Clinical Oncology.

Little is known about how clinical oncology concepts are taught to PhD students or the most effective methods of doing so. In this study, electronic surveys were sent to faculty and students at PhD training programs, assessing their institution's methods of clinical oncology education and their perspective on optimal approaches to clinical oncology education. Only 40.0% of students reported any clinical oncology component to their institution's training, and only 26.5% had a clinician on their graduate advisory committee. Forty-three percent of students believed that they had a good understanding for translating basic science research into clinical practice, and 77.2% of all participants believed dual degree MD/PhD students were superior to PhD students in this regard. Lectures on clinical oncology research topics were the most valuable type of experience for all participants and were also the most common type of experience utilized. Working with a clinician to develop a clinical trial with correlative endpoints was also highly valued, but was only utilized by approximately 10% of programs. Faculty rated the value of nearly all types of clinical oncology exposure significantly lower than did students. Inclusion of the approaches identified in this study is likely to enhance PhD training in oncology-related disciplines. Cancer Res; 77(18); 4741-4. ©2017 AACR.

Essential Components of Cancer Education.

Modern cancer therapy/care involves the integration of basic, clinical, and population-based research professionals using state-of-the-art science to achieve the best possible patient outcomes. A well-integrated team of basic, clinical, and population science professionals and educators working with a fully engaged group of creative junior investigators and trainees provides a structure to achieve these common goals. To this end, the structure provided by cancer-focused educational programs can create the integrated culture of academic medicine needed to reduce the burden of cancer on society. This summary outlines fundamental principles and potential best practice strategies for the development of integrated educational programs directed at achieving a work force of professionals that broadly appreciate the principals of academic medicine spanning the breadth of knowledge necessary to advance the goal of improving the current practice of cancer care medicine.

The Interactions of Obesity, Inflammation and Insulin Resistance in Breast Cancer.

Obese postmenopausal women have an increased breast cancer risk, the principal mechanism for which is elevated estrogen production by adipose tissue; also, regardless of menstrual status and tumor estrogen dependence, obesity is associated with biologically aggressive breast cancers. Type 2 diabetes has a complex relationship with breast cancer risk and outcome; coexisting obesity may be a major factor, but insulin itself induces adipose aromatase activity and estrogen production and also directly stimulates breast cancer cell growth and invasion. Adipose tissue inflammation occurs frequently in obesity and type 2 diabetes, and proinflammatory cytokines and prostaglandin E2 produced by cyclooxygenase-2 in the associated infiltrating macrophages also induce elevated aromatase expression. In animal models, the same proinflammatory mediators, and the chemokine monocyte chemoattractant protein-1, also stimulate tumor cell proliferation and invasion directly and promote tumor-related angiogenesis. We postulate that chronic adipose tissue inflammation, rather than body mass index-defined obesity per se, is associated with an increased risk of type 2 diabetes and postmenopausal estrogen-dependent breast cancer. Also, notably before the menopause, obesity and type 2 diabetes, or perhaps the associated inflammation, promote estrogen-independent, notably triple-negative, breast cancer development, invasion and metastasis by mechanisms that may involve macrophage-secreted cytokines, adipokines and insulin.

High-Fat, High-Calorie Diet Enhances Mammary Carcinogenesis and Local Inflammation in MMTV-PyMT Mouse Model of Breast Cancer.

Epidemiological studies provide strong evidence that obesity and the associated adipose tissue inflammation are risk factors for breast cancer; however, the molecular mechanisms are poorly understood. We evaluated the effect of a high-fat/high-calorie diet on mammary carcinogenesis in the immunocompetent MMTV-PyMT murine model. Four-week old female mice (20/group) were randomized to receive either a high-fat (HF; 60% kcal as fat) or a low-fat (LF; 16% kcal) diet for eight weeks. Body weights were determined, and tumor volumes measured by ultrasound, each week. At necropsy, the tumors and abdominal visceral fat were weighed and plasma collected. The primary mammary tumors, adjacent mammary fat, and lungs were preserved for histological and immunohistochemical examination and quantification of infiltrating macrophages, crown-like structure (CLS) formation, and microvessel density. The body weight gains, visceral fat weights, the primary mammary tumor growth rates and terminal weights, were all significantly greater in the HF-fed mice. Adipose tissue inflammation in the HF group was indicated by hepatic steatosis, pronounced macrophage infiltration and CLS formation, and elevations in plasma monocyte chemoattractant protein-1 (MCP-1), leptin and proinflammatory cytokine concentrations. HF intake was also associated with higher tumor-associated microvascular density and the proangiogenic factor MCP-1. This study provides preclinical evidence in a spontaneous model of breast cancer that mammary adipose tissue inflammation induced by diet, enhances the recruitment of macrophages and increases tumor vascular density suggesting a role for obesity in creating a microenvironment favorable for angiogenesis in the progression of breast cancer.

Finding the New Normal: Accepting Changes After Combat-Related Mild Traumatic Brain Injury.

INTRODUCTION: More than 300,000 soldiers have returned from Southwest Asia (i.e., Iraq and Afghanistan) with combat-related mild traumatic brain injuries (mTBIs). Despite less visible physical injuries, these soldiers demonstrate various physical and cognitive symptoms that impact their ability to reintegrate post-mTBI. This study explores family reintegration experiences, as described by married dyads, following a combat-related mTBI. METHODS: Nine soldiers with mTBI and their spouses participated, and a total of 27 interviews, both joint and individual, were conducted. Strauss and Corbin's grounded theory methodology and semistructured interviews were used to collect participants' perceptions and analyze the data. FINDINGS: The overarching theme of the reintegration experience is described as finding the "new normal." A new normal was defined by participants as the couple's new, post-mTBI expectation of the family unit or family routine. Some participants indicated that they had accepted the post-mTBI changes and were working toward this new normal, whereas others indicated these changes were unacceptable and continued their efforts to return to pre-injury functioning. CONCLUSIONS: Individuals with mTBI and their families may benefit from interventions that directly address mismatched expectations and promote the acceptance of a new normal.

Loss of Adipocyte VEGF Impairs Endurance Exercise Capacity in Mice.

PURPOSE: Reducing vascular endothelial growth factor (VEGF) in adipose tissue alters adipose vascularity and metabolic homeostasis. We hypothesized that this would also affect metabolic responses during exercise-induced stress and that adipocyte-specific VEGF-deficient (adipoVEGF-/-) mice would have impaired endurance capacity. METHODS: Endurance exercise capacity in adipoVEGF-/- (n = 10) and littermate control (n = 11) mice was evaluated every 4 wk between 6 and 24 wk of age using a submaximal endurance run to exhaustion at 20 m·min(-1) at 10° incline. Maximal running speed, using incremental increases in speed at 30-s intervals, was tested at 25 and 37 wk of age. RESULTS: White and brown adipose tissue capillarity were reduced by 40% in adipoVEGF-/-, and no difference in skeletal muscle capillarity was observed. Endurance run time to exhaustion was 30% lower in adipoVEGF-/- compared with that in controls at all time points (P < 0.001), but no difference in maximal running speed was observed between the groups. After exercise (1 h at 50% maximum running speed), adipoVEGF-/- mice displayed lower circulating insulin (P < 0.001), lower glycerol (P < 0.05), and tendency for lower blood glucose (P = 0.06) compared with controls. There was no evidence of altered oxidative damage or changes in carnitine palmitoyltransferase-1ß expression in skeletal muscle of adipoVEGF-/- mice. CONCLUSIONS: These data suggest that VEGF-mediated deficits in adipose tissue blunt the availability of lipid substrates during endurance exercise, which likely reduced endurance performance. Surprisingly, we also found an unchanged basal blood glucose despite lower circulating insulin in adipoVEGF-/- mice, suggesting that loss of adipocyte VEGF can blunt insulin release and/or increase basal insulin sensitivity.