Preparing for the future of medical education: A case series of traditional and virtual clinical rotations in addiction medicine spanning the COVID pandemic.

Background: Substance use accounts for more than 400,000 deaths annually in the United States and overdose rates surged during the COVID pandemic. While the pandemic created increased pressure for better prepared providers, it simultaneously placed restrictions on medical training programs. The purpose of this educational case series is to assess the feasibility of a virtual addiction medicine training program and conduct a qualitative evaluation of medical student attitudes toward caring for people with substance use disorders, both before and after their addiction medicine training experience. Methods: We conducted a qualitative analysis related to course content focused on strengths and limitations of in-person and virtual training modalities. Individual quotes were evaluated and content themes were developed after a thorough review of all codes and detailed examination of interviewee quotes. Results: The primary themes that emerged were (1) Addiction medicine content is important to improve care of patients with substance disorders and is not fully addressed in undergraduate medical education (2) In-person and virtual training contain unique strengths and weaknesses and (3) Students perceived that both experiences provided positive and needed training in addiction medicine that shifted perspective and enhanced confidence to practice. Conclusions: Remote training via virtual lectures and patient visits may enhance training opportunities for students with limited exposure to addiction medicine patients and faculty with addiction medicine expertise. There is a need to further refine virtual care for patients with SUDs and virtual training to meet the needs of patients and learners across the country.

Supplemental estrogen and caloric restriction reduce obesity-induced periprostatic white adipose inflammation in mice.

Obesity is associated with an increased incidence of high-grade prostate cancer (PC) and worse prognosis for PC patients. Recently, we showed in men that obesity-related periprostatic white adipose tissue (WAT) inflammation, characterized by macrophages surrounding dead or dying adipocytes forming crown-like structures, was associated with high-grade PC. Possibly, interventions that suppress periprostatic WAT inflammation will improve outcomes for men with PC. Here, we tested the hypothesis that supplemental 17ß-estradiol (E2) could decrease periprostatic WAT inflammation in obese male mice. Mice were fed a high-fat diet to induce periprostatic WAT inflammation before being treated with supplemental E2. E2 supplementation suppressed caloric intake, induced weight loss, decreased periprostatic WAT inflammation and downregulated the expression of genes linked to inflammation including Cd68, Mcp1 and Tnf. Similar to the effects of E2 supplementation, treatment with diethylstilbestrol, a synthetic estrogen, also suppressed caloric intake and reduced periprostatic WAT inflammation. To determine whether the observed effects of supplemental estrogen could be reproduced by caloric restriction (CR) alone, obese mice were put on a 30% CR diet. Like estrogen treatment, CR was effective in reducing body weight, periprostatic WAT inflammation and the expression of pro-inflammatory genes. Transcriptomic analyses of periprostatic fat showed that obesity was associated with enrichment in inflammatory response pathways, which were normalized by both supplemental E2 and CR. Taken together, these findings strengthen the rationale for future efforts to determine whether either CR or supplemental estrogen will decrease periprostatic WAT inflammation and thereby improve outcomes for men with PC.

Obesity alters the lung myeloid cell landscape to enhance breast cancer metastasis through IL5 and GM-CSF.

Obesity is associated with chronic, low-grade inflammation, which can disrupt homeostasis within tissue microenvironments. Given the correlation between obesity and relative risk of death from cancer, we investigated whether obesity-associated inflammation promotes metastatic progression. We demonstrate that obesity causes lung neutrophilia in otherwise normal mice, which is further exacerbated by the presence of a primary tumour. The increase in lung neutrophils translates to increased breast cancer metastasis to this site, in a GM-CSF- and IL5-dependent manner. Importantly, weight loss is sufficient to reverse this effect, and reduce serum levels of GM-CSF and IL5 in both mouse models and humans. Our data indicate that special consideration of the obese patient population is critical for effective management of cancer progression.

Menopause Is a Determinant of Breast Aromatase Expression and Its Associations With BMI, Inflammation, and Systemic Markers.

Context: Most estrogen-dependent breast cancers occur after menopause, despite low levels of circulating estrogens. Breast expression of the estrogen-biosynthetic enzyme, aromatase, is proposed to drive breast cancer development after menopause. However, the effects of menopause on breast aromatase expression are unknown. Objective: To determine the effect of menopause on breast aromatase expression in relation to body mass index (BMI), white adipose tissue inflammation (WATi), and systemic markers of metabolic dysfunction. Design, Setting, and Participants: Cross-sectional study of 102 premenopausal (age 27 to 56) and 59 postmenopausal (age 45 to 74) women who underwent mastectomy for breast cancer treatment/prevention. Outcome: Breast tissue was assessed for the presence of crown-like structures and the expression and activity of aromatase. Systemic markers examined include interleukin (IL)-6, insulin, glucose, leptin, adiponectin, high-sensitivity C-reactive protein (hsCRP), cholesterol, and triglycerides. Multivariable analysis was performed for aromatase messenger RNA (mRNA) in relation to BMI, WATi, and blood markers. Results: Postmenopausal women had higher BMI and more breast WATi than premenopausal women. Fasting levels of IL-6, glucose, leptin, hsCRP, and homeostatic model assessment 2 insulin resistance score were higher in the postmenopausal group. BMI was positively correlated with aromatase mRNA in both pre- and postmenopausal women. Aromatase levels were higher in breast tissue of postmenopausal women, with levels being higher in inflamed vs noninflamed, independent of BMI. Adipocyte diameter and levels of leptin, hsCRP, adiponectin, and high-density lipoprotein cholesterol were more strongly correlated with aromatase in postmenopausal than premenopausal women. Conclusions: Elevated aromatase in the setting of adipose dysfunction provides a possible mechanism for the higher incidence of hormone-dependent breast cancer in obese women after menopause.

Metabolic Obesity, Adipose Inflammation and Elevated Breast Aromatase in Women with Normal Body Mass Index.

Obesity is associated with breast white adipose tissue (WAT) inflammation, elevated levels of the estrogen biosynthetic enzyme, aromatase, and systemic changes that have been linked to the pathogenesis of breast cancer. Here, we determined whether metabolic obesity, including changes in breast biology and systemic effects, occurs in a subset of women with normal body mass index (BMI). Breast WAT and fasting blood were collected from 72 women with normal BMI (<25 kg/m2) undergoing mastectomy for breast cancer risk reduction or treatment. WAT inflammation was defined by the presence of crown-like structures of the breast (CLS-B) which are composed of dead or dying adipocytes surrounded by macrophages. Severity of inflammation was measured as CLS-B/cm2 The primary objective was to determine whether breast WAT inflammation is associated with aromatase expression and activity. Secondary objectives included assessment of circulating factors and breast adipocyte size. Breast WAT inflammation was present in 39% of women. Median BMI was 23.0 kg/m2 (range, 18.4-24.9 kg/m2) in women with breast WAT inflammation versus 21.8 kg/m2 (range, 17.3-24.6 kg/m2) in those without inflammation (P = 0.04). Breast WAT inflammation was associated with elevated aromatase expression and activity, which increased with severity of inflammation (P < 0.05). Breast WAT inflammation correlated with larger adipocytes (P = 0.01) and higher circulating levels of C-reactive protein, leptin, insulin, and triglycerides (P ≤ 0.05). A subclinical inflammatory state associated with elevated aromatase in the breast, adipocyte hypertrophy, and systemic metabolic dysfunction occurs in some normal BMI women and may contribute to the pathogenesis of breast cancer. Cancer Prev Res; 10(4); 235-43. ©2017 AACRSee related article by Berger, p. 223-25.

Public- and Private-Sector Contributions to the Research and Development of the Most Transformational Drugs in the Past 25 Years: From Theory to Therapy.

BACKGROUND: With available funding from the public sector decreasing while medical needs and scientific complexity increase, private-sector collaborations with academia and government have become increasingly key in furthering medical innovation. Nonetheless, some skeptics diminish the contribution of the private sector to the discovery and development of truly innovative drugs on the one hand, while on the other hand they assert that research and development (R&D) of new medicines could and should be exclusively within control (at least financially) of the government. This begs the question, How much government funding would be needed to replace industry new drug R&D spending? METHODS: We address the respective roles of the private and public sectors in drug development by examining a diverse array of evidentiary materials on the history of 19 individual drugs, 6 drug classes, and 1 drug combination identified as the most transformative drugs in health care over the past 25 years by a survey of over 200 physicians. RESULTS: Only 4 of the individual drugs appear to have been almost completely researched and developed by one sector. One sector or the other, however, did dominate particular phases of the R&D continuum. For example, 54% of basic science milestones were achieved predominantly by the public sector and 27% by the private sector. For discovery milestones, it was 15% by the public sector and 58% by the private sector. The private sector was also dominant in achieving the major milestones for both the production and drug development phases (81% and 73% of the drugs reviewed, respectively). For 19% to 27% of the case histories for the various categories, dominance of one sector versus the other could not be determined. On the question of replacing industry's spending on the R&D of medicines, we estimate quite conservatively that the amount that would have to be spent by government would be nearly double the budget of the National Institutes of Health just to maintain the flow of the most innovative drug approvals and would have to increase nearly 2.5 times that level to maintain the development of all new drugs. CONCLUSIONS: Our analysis indicates that industry's contributions to the R&D of innovative drugs go beyond development and marketing and include basic and applied science, discovery technologies, and manufacturing protocols, and that without private investment in the applied sciences there would be no return on public investment in basic science.