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INTRODUCTION: Stigma has inhibited public health practitioners influence during the COVID-19 pandemic. We explore the experienced and anticipated stigma of people affiliated with a large university in the United States, using the Health Stigma and Discrimination Framework. METHODS: We conducted a qualitative secondary substudy of 20 people who tested SARS-CoV-2 positive and 10 who tested negative in the summer of 2020, selected from a study of 3,324 university students and employees. FINDINGS: No participants reported anticipated stigmatization prior to testing positive. However, eight of 20 participants recounted stigma marking (being marked by COVID-19 diagnosis or membership in a high-risk group) or manifestations of stigma after testing positive, including feelings of guilt or shame, and concerns about being judged as selfish or irresponsible. Three described being denied services or social interactions as a result of having had COVID-19, long after their infectiousness ended. Participants noted that clear public health messaging must be paired with detailed scientific information, rather than leaving people to resort to non-experts to understand the science. DISCUSSION: Public health messaging designed to mitigate spread of SARS-CoV-2 and protect the community may perpetuate stigma and exacerbate inequities. As a result, people may avoid testing or treatment, mistrust public health messaging, or even use risk-increasing behavior as coping mechanisms. IMPLICATIONS FOR PRACTICE: Intentional use of language that promotes equity and deters discrimination must be high priority for any COVID-19-related public health messaging. Partnership with community leaders to co-create programs and disseminate messaging is a critical strategy for reducing stigma, especially for historically mistreated groups.

We tested the hypothesis that dorsal cervical epidural electrical stimulation (CEES) increases respiratory activity in male and female anesthetized rats. Respiratory frequency and minute ventilation were significantly increased when CEES was applied dorsally to the C2-C6 region of the cervical spinal cord. By injecting pseudorabies virus into the diaphragm and using c-Fos activity to identify neurons activated during CEES, we found neurons in the dorsal horn of the cervical spinal cord in which c-Fos and pseudorabies were co-localized, and these neurons expressed somatostatin (SST). Using dual viral infection to express the inhibitory Designer Receptors Exclusively Activated by Designer Drugs (DREADD), hM4D(Gi), selectively in SST-positive cells, we inhibited SST-expressing neurons by administering Clozapine N-oxide (CNO). During CNO-mediated inhibition of SST-expressing cervical spinal neurons, the respiratory excitation elicited by CEES was diminished. Thus, dorsal cervical epidural stimulation activated SST-expressing neurons in the cervical spinal cord, likely interneurons, that communicated with the respiratory pattern generating network to effect changes in ventilation.SIGNIFICANCE STATEMENT A network of pontomedullary neurons within the brainstem generates respiratory behaviors that are susceptible to modulation by a variety of inputs; spinal sensory and motor circuits modulate and adapt this output to meet the demands placed on the respiratory system. We explored dorsal cervical epidural electrical stimulation (CEES) excitation of spinal circuits to increase ventilation in rats. We identified dorsal somatostatin (SST)-expressing neurons in the cervical spinal cord that were activated (c-Fos-positive) by CEES. CEES no longer stimulated ventilation during inhibition of SST-expressing spinal neuronal activity, thereby demonstrating that spinal SST neurons participate in the activation of respiratory circuits affected by CEES. This work establishes a mechanistic foundation to repurpose a clinically accessible neuromodulatory therapy to activate respiratory circuits and stimulate ventilation.

Epidemiological studies demonstrate an association between breast cancer (BC) and systemic dysregulation of glucose metabolism. However, how BC influences glucose homeostasis remains unknown. We show that BC-derived extracellular vesicles (EVs) suppress pancreatic insulin secretion to impair glucose homeostasis. EV-encapsulated miR-122 targets PKM in β-cells to suppress glycolysis and ATP-dependent insulin exocytosis. Mice receiving high-miR-122 EVs or bearing BC tumours exhibit suppressed insulin secretion, enhanced endogenous glucose production, impaired glucose tolerance and fasting hyperglycaemia. These effects contribute to tumour growth and are abolished by inhibiting EV secretion or miR-122, restoring PKM in β-cells or supplementing insulin. Compared with non-cancer controls, patients with BC have higher levels of circulating EV-encapsulated miR-122 and fasting glucose concentrations but lower fasting insulin; miR-122 levels are positively associated with glucose and negatively associated with insulin. Therefore, EV-mediated impairment of whole-body glycaemic control may contribute to tumour progression and incidence of type 2 diabetes in some patients with BC.

IntroductionUntil vaccines became available in late 2020, our ability to prevent the spread of COVID-19 within countries depended largely on voluntary adherence to mitigation measures. However, individual decision-making regarding acceptable COVID-19 risk is complex. To better understand decision-making regarding COVID-19 risk, we conducted a qualitative substudy within a larger Berkeley COVID-19 Safe Campus Initiative (BCSCI) during the summer of 2020, and completed a mixed-methods analysis of factors influencing decision-making.Materials and methodsWe interviewed 20 participants who tested positive for SARS-CoV-2 and 10 who remained negative, and analyzed quantitative survey data from 3,324 BCSCI participants. The BCSCI study enrolled university-affiliated people living in the local area during summer of 2020, collected data on behaviors and attitudes toward COVID-19, and conducted SARS-CoV-2 testing at baseline and endline.ResultsAt baseline, 1362 students (57.5%) and 285 non-students (35.1%) said it had been somewhat or very difficult to comply with COVID-19-related mandates. Most-cited reasons were the need to go out for food/essentials, difficulty of being away from family/friends, and loneliness. Eight interviewees explicitly noted they made decisions partially because of others who may be at high risk. We did not find significant differences between the behaviors of students and non-students.DiscussionDespite prevailing attitudes about irresponsibility of college students during the COVID-19 pandemic, students in our study demonstrated a commitment to making rational choices about risk behavior, not unlike non-students around them. Decision-making was driven by perceived susceptibility to severe disease, need for social interaction, and concern about risk to others. A harm reduction public health approach may be beneficial.

Plant diversity varies immensely over large-scale gradients in temperature, precipitation, and seasonality at global and regional scales. This relationship may be driven in part by climatic variation in the relative importance of abiotic and biotic interactions to the diversity and composition of plant communities. In particular, biotic interactions may become stronger and more host specific with increasing precipitation and temperature, resulting in greater plant species richness in wetter and warmer environments. This hypothesis predicts that the many defensive compounds found in plants’ metabolomes should increase in richness and decrease in interspecific similarity with precipitation, temperature, and plant diversity. To test this prediction, we compared patterns of chemical and morphological trait diversity of 140 woody plant species among seven temperate forests in North America representing 16.2°C variation in mean annual temperature (MAT), 2,115 mm variation in mean annual precipitation (MAP), and from 10 to 68 co-occurring species. We used untargeted metabolomics methods based on data generated with liquid chromatography-tandem mass spectrometry to identify, classify, and compare 13,480 unique foliar metabolites and to quantify the metabolomic similarity of species in each community with respect to the whole metabolome and each of five broad classes of metabolites. In addition, we compiled morphological trait data from existing databases and field surveys for three commonly measured traits (specific leaf area [SLA], wood density, and seed mass) for comparison with foliar metabolomes. We found that chemical defense strategies and growth and allocation strategies reflected by these traits largely represented orthogonal axes of variation. In addition, functional dispersion of SLA increased with MAP, whereas functional richness of wood density and seed mass increased with MAT. In contrast, chemical similarity of co-occurring species decreased with both MAT and MAP, and metabolite richness increased with MAT. Variation in metabolite richness among communities was positively correlated with species richness, but variation in mean chemical similarity was not. Our results are consistent with the hypothesis that plant metabolomes play a more important role in community assembly in wetter and warmer climates, even at temperate latitudes, and suggest that metabolomic traits can provide unique insight to studies of trait-based community assembly.

Policy Points Accountable care organizations (ACOs) have incentives to promote the adoption of patient engagement strategies such as shared decision making and self-management support programs to improve patient outcomes and contain health care costs. High adoption of patient engagement strategies among ACO-affiliated practices did not improve patient-reported outcomes (PROs) of physical, emotional, and social function among adult patients with diabetes and/or cardiovascular disease over a one-year time frame, likely because implementing these strategies requires extensive clinician and staff training, workflow redesign, and patient participation over time. A dominant focus on improving clinical measures to meet external requirements may crowd out time needed for care team members to address other outcomes that matter to patients, including PROs. Payers and policy-makers should explicitly incentivize the collection and use of PROs when contracting with ACOs.ContextAdult primary care practices of accountable care organizations (ACOs) are adopting a range of patient engagement strategies, but little is known about how these strategies are related to patient-reported outcomes (PROs) and how relational coordination among team members aids implementation.MethodsWe used a mixed-methods cohort study design integrating administrative and clinical data with two data collection waves (2014-2015 and 2016-2017) of clinician and staff surveys (n = 764), surveys of adult patients with diabetes and/or cardiovascular disease (CVD) (n = 1,276), and key informant interviews of clinicians, staff, and administrators (n = 103). Multivariable linear regression estimated the relationship of practice adoption of patient engagement strategies, relational coordination, and PROs of physical, social, and emotional function. The mediating role of patient activation was examined using cross-lagged panel models. Key informant interviews assessed how relational coordination influences the implementation of patient engagement strategies.FindingsThere were no differential improvements in PROs among patients of practices with high vs. low adoption of patient engagement strategies or among patients of practices with high vs. low relational coordination. The Patient Activation Measure (PAM) is strongly related to better physical, emotional, and social PROs over time. Relational coordination facilitated the implementation of patient engagement strategies, but key informants indicated that resources and systems to systematically track treatment preferences and goals beyond clinical indicators were needed to support effective implementation.ConclusionsAdult patients with diabetes and/or CVD of ACO-affiliated practices with high adoption of patient engagement strategies do not have improved PROs of physical, emotional, and social function over a one-year time frame. Implementing patient engagement strategies increases task interdependence among primary care team members, which needs to be carefully managed. ACOs may need to make greater investment in collecting, monitoring, and analyzing PRO data to ensure that practice adoption and implementation of patient engagement strategies leads to improved physical, emotional, and social function among patients.

Metabolic acidosis can lead to inflammation, tissue damage, and cancer metastasis. Dietary acid load contributes to metabolic acidosis if endogenous acid-base balance is not properly regulated. Breast cancer survivors have reduced capacities to adjust their acid-base balance; yet, the associations between dietary acid load and inflammation and hyperglycemia have not been examined among them. We analyzed data collected from 3042 breast cancer survivors enrolled in the Women's Healthy Eating and Living (WHEL) Study who had provided detailed dietary intakes and measurements of plasma C-reactive protein (CRP) and hemoglobin A1c (HbA1c). Using a cross-sectional design, we found positive associations between dietary acid load and plasma CRP and HbA1c. In the multivariable-adjusted models, compared to women with the lowest quartile, the intakes of dietary acid load among women with the highest quartile showed 30-33% increases of CRP and 6-9% increases of HbA1c. Our study is the first to demonstrate positive associations between dietary acid load and CRP and HbA1c in breast cancer survivors. Our study identifies a novel dietary factor that may lead to inflammation and hyperglycemia, both of which are strong risk factors for breast cancer recurrence and comorbidities.

What percentage of Americans have ever had a family member incarcerated? To answer this question, we designed the Family History of Incarceration Survey (FamHIS). The survey was administered in the summer of 2018 by NORC at the University of Chicago using their AmeriSpeak Panel. It was funded by FWD.us, which released a separate report using the data. The data show that 45 percent of Americans have ever had an immediate family member incarcerated. The incarceration of an immediate family member was most prevalent for blacks (63 percent) but common for whites (42 percent) and Hispanics (48 percent) as well. College graduates had a lower risk of having a family member incarcerated, but the risk for black college graduates was comparatively high. The most common form of family member incarceration was the incarceration of a sibling.

Drug resistance represents a major challenge to achieving durable responses to cancer therapeutics. Resistance mechanisms to epigenetically targeted drugs remain largely unexplored. We used bromodomain and extra-terminal domain (BET) inhibition in neuroblastoma as a prototype to model resistance to chromatin modulatory therapeutics. Genome-scale, pooled lentiviral open reading frame (ORF) and CRISPR knockout rescue screens nominated the phosphatidylinositol 3-kinase (PI3K) pathway as promoting resistance to BET inhibition. Transcriptomic and chromatin profiling of resistant cells revealed that global enhancer remodeling is associated with upregulation of receptor tyrosine kinases (RTKs), activation of PI3K signaling, and vulnerability to RTK/PI3K inhibition. Large-scale combinatorial screening with BET inhibitors identified PI3K inhibitors among the most synergistic upfront combinations. These studies provide a roadmap to elucidate resistance to epigenetic-targeted therapeutics and inform efficacious combination therapies.