Ang-2/VEGF bispecific antibody reprograms macrophages and resident microglia to anti-tumor phenotype and prolongs glioblastoma survival.

Inhibition of the vascular endothelial growth factor (VEGF) pathway has failed to improve overall survival of patients with glioblastoma (GBM). We previously showed that angiopoietin-2 (Ang-2) overexpression compromised the benefit from anti-VEGF therapy in a preclinical GBM model. Here we investigated whether dual Ang-2/VEGF inhibition could overcome resistance to anti-VEGF treatment. We treated mice bearing orthotopic syngeneic (Gl261) GBMs or human (MGG8) GBM xenografts with antibodies inhibiting VEGF (B20), or Ang-2/VEGF (CrossMab, A2V). We examined the effects of treatment on the tumor vasculature, immune cell populations, tumor growth, and survival in both the Gl261 and MGG8 tumor models. We found that in the Gl261 model, which displays a highly abnormal tumor vasculature, A2V decreased vessel density, delayed tumor growth, and prolonged survival compared with B20. In the MGG8 model, which displays a low degree of vessel abnormality, A2V induced no significant changes in the tumor vasculature but still prolonged survival. In both the Gl261 and MGG8 models A2V reprogrammed protumor M2 macrophages toward the antitumor M1 phenotype. Our findings indicate that A2V may prolong survival in mice with GBM by reprogramming the tumor immune microenvironment and delaying tumor growth.

Development of Light-Activated CRISPR Using Guide RNAs with Photocleavable Protectors.

The ability to remotely trigger CRISPR/Cas9 activity would enable new strategies to study cellular events with greater precision and complexity. In this work, we have developed a method to photocage the activity of the guide RNA called "CRISPR-plus" (CRISPR-precise light-mediated unveiling of sgRNAs). The photoactivation capability of our CRISPR-plus method is compatible with the simultaneous targeting of multiple DNA sequences and supports numerous modifications that can enable guide RNA labeling for use in imaging and mechanistic investigations.

Satisfaction with a meal kit delivery program and feasibility of a phase I trial in the intervening in food insecurity to reduce and mitigate (InFoRM) childhood obesity study.

BACKGROUND: Food and nutrition security interventions have been demonstrated to optimize health, prevent and treat chronic diseases among adult populations. Despite the increasing prevalence and intersection of food insecurity and childhood obesity in the United States, there are few food and nutrition security interventions targeted to children and families. OBJECTIVES: The primary purpose of this phase I randomized, crossover trial was to assess the safety, acceptability and satisfaction of a meal kit delivery program among children with obesity living in households with food insecurity. Secondarily, we assessed the feasibility of our study design, recruitment and retention to inform future larger scale trials. METHODS: We delivered 6 weeks of healthy meal kits, which included fresh pre-portioned ingredients and simple picture-based recipes (two recipes/week) in English or Spanish to prepare one-pot, under 30-min meals (after preparation ~ 10 servings/week). RESULTS: Caregivers received and prepared the meal kits and reported overall satisfaction with the meal kit delivery program. CONCLUSION: A meal kit delivery intervention for children with obesity and food insecurity is acceptable and a phase I randomized, crossover trial is feasible.

Managing the Unpredictable: Recommendations to Improve Trainee Safety During Global Health Away Electives.

Background: For institutions offering global health programs, the safety of trainees during clinical rotations at international sites is paramount. Current guidelines for global health electives recommend pre-departure training and safety-net resources, yet their advice on managing unanticipated problems is limited. Objective: This report illustrates critical safety considerations requiring additional guidance for programs and students and highlights approaches that may improve trainee safety while abroad. Methods: We present a series of five cases adapted from the experiences of students traveling to and from the Yale School of Medicine between the years of 2011-2021. These cases include instances of personal injury, mental health challenges following trauma, sexual harassment, political instability, and natural disaster. For each case, we recommend ways in which programs and their participants may approach the challenges and we highlight issues requiring additional analysis. Findings: We categorized the types of trainee safety issues into three groups: personal health emergencies, individual-level stressors, and large-scale crises. Conclusion: Ultimately, we recommend that rather than solely emphasizing a universal policy, programs and trainees should also be educated on the tools and resources available for addressing unexpected emergencies.

Mothers' Perceptions of the Cardboard Box as a Potential Sleep Space.

OBJECTIVE: Due to increasing popularity, our hospital began considering distributing cardboard boxes combined with safe sleep education to new mothers. As a first step in studying the impact of this intervention on bedsharing in our community, we sought to understand mothers' perceptions of the cardboard box. METHODS: We recruited primarily low-income, English- or Spanish-speaking mothers of infants aged 2 to 16 weeks during routine primary care visits. Participants responding to a cross-sectional survey about infant sleep practices were invited to participate in in-depth interviews about the cardboard box. We used a grounded theory approach and the constant comparative method until saturation was reached. RESULTS: Of 120 participants in the survey, 50 (42%) participated in the qualitative study. Participants were mothers of infants aged ≤4 weeks (46%), 4 to 8 weeks (32%), and 16 weeks (22%). Of 50 participants, 52% said they would use the cardboard box for their infant to sleep in, if provided, compared with 42% who said they would not and 6% were unsure. Three themes emerged from the data: (1) safety of the cardboard box; (2) appearance, and (3) variation in planned use. Some participants planned to place the cardboard box in their bed. CONCLUSIONS: Participants in our study were divided about whether they would use the cardboard box for their infant to sleep in. If distributed, hospital staff should advise families to not place the cardboard box in their bed. Next steps include determining bedsharing frequency among parents who choose to use the cardboard box for their infant.

The Influence of Sex and Gender on Health: How Much Is Being Taught in Medical School Curricula?

Background: Sex is a biological variable linked to our chromosomal complement, while gender refers to one's personal identification as influenced by social, cultural, and personal experience. Both sex and gender and their interactions influence health outcomes. Although this is increasingly clear, we have not yet ensured that the next generation of physicians and physician-scientists is being taught the empirical findings necessary to understand these relationships. We assert that medical schools must incorporate these data into didactics throughout an integrated curriculum. Materials and Methods: This study evaluates a medical curriculum for sex- and gender-based content and provides recommendations for establishing and integrating pertinent sex and gender medicine didactics. Trained first-and second-year medical students audited 548 lectures and workshops to determine sex- and gender-based content. Results: Less than 25% of all sessions raised the topic of sex or gender influences on physiology and pathophysiology or the experience of the patient in the health care environment. Only 8.1% of all sessions included an in-depth discussion of sex or gender differences, and these discussions predominantly focused on basic physiology and prevalence and/or incidence of disease, and not on available data on sex- and gender-specific influences on diagnosis, treatment, prognosis, and drug effects. The didactics that included data on sex or gender influences were largely in lectures rather than small group sessions, which are important for the development of critical clinical reasoning skills. Conclusions: A survey-based audit of medical school curricula can inform recommendations for improving the inclusion of data on sex- and gender-based content.