Partnering With Community Health Workers to Address COVID-19 Health Inequities: Experiences of the California Alliance Against COVID-19.

With funding from the National Institutes of Health's Community Engagement Alliance, starting in fall 2020, 11 academic medical centers and 75 community partners came together as the California Alliance Against COVID-19 to address COVID-19 inequities in California. Using data from focus groups, statewide meetings, and a statewide partner survey, we describe how promotoras and community health workers (P/CHWs; n = 540) helped to promote access to COVID-19 information, testing, and vaccination. We highlight opportunities to promote health equity among other public health collaborators with a P/CHW model. (Am J Public Health. 2024;114(S1):S45-S49. https://doi.org/10.2105/AJPH.2023.307471).

Analysis and comparison of SARS-CoV-2 variant antibodies and neutralizing activity for 6 months after a booster mRNA vaccine in a healthcare worker population.

Introduction: In the context of recurrent surges of SARS-CoV-2 infections, a detailed characterization of antibody persistence over a 6-month period following vaccine booster dose is necessary to crafting effective public health policies on repeat vaccination. Methods: To characterize the SARS-CoV-2 antibody profile of a healthcare worker population over a 6-month period following mRNA vaccination and booster dose. 323 healthcare workers at an academic medical center in Orange County, California who had completed primary vaccination and booster dose against SARS-CoV-2 were recruited for the study. A total of 690 blood specimens over a 6-month period were collected via finger-stick blood and analyzed for the presence of antibodies against 9 SARS-CoV-2 antigens using a coronavirus antigen microarray. Results: The primary outcome of this study was the average SARS-CoV-2 antibody level as measured using a novel coronavirus antigen microarray. Additional outcomes measured include levels of antibodies specific to SARS-CoV-2 variants including Delta, Omicron BA.1, and BA.2. We also measured SARS-CoV-2 neutralization capacity for a subset of the population to confirm correlation with antibody levels. Although antibodies against SARS-CoV-2 wane throughout the 6-month period following a booster dose, antibody levels remain higher than pre-boost levels. However, a booster dose of vaccine based on the original Wuhan strain generates approximately 3-fold lower antibody reactivity against Omicron variants BA.1 and BA.2 as compared to the vaccine strain. Despite waning antibody levels, neutralization activity against the vaccine strain is maintained throughout the 6-month period. Discussion: In the context of recurrent surges of SARS-CoV-2 infections, our data indicate that breakthrough infections are likely driven by novel variants with different antibody specificity and not by time since last dose of vaccination, indicating that development of vaccinations specific to these novel variants is necessary to prevent future surges of SARS-CoV-2 infections.

Risk factors for SARS-CoV-2 seropositivity in a health care worker population during the early pandemic.

BACKGROUND: While others have reported severe acute respiratory syndrome-related coronavirus 2(SARS-CoV-2) seroprevalence studies in health care workers (HCWs), we leverage the use of a highly sensitive coronavirus antigen microarray to identify a group of seropositive health care workers who were missed by daily symptom screening that was instituted prior to any epidemiologically significant local outbreak. Given that most health care facilities rely on daily symptom screening as the primary method to identify SARS-CoV-2 among health care workers, here, we aim to determine how demographic, occupational, and clinical variables influence SARS-CoV-2 seropositivity among health care workers. METHODS: We designed a cross-sectional survey of HCWs for SARS-CoV-2 seropositivity conducted from May 15th to June 30th 2020 at a 418-bed academic hospital in Orange County, California. From an eligible population of 5,349 HCWs, study participants were recruited in two ways: an open cohort, and a targeted cohort. The open cohort was open to anyone, whereas the targeted cohort that recruited HCWs previously screened for COVID-19 or work in high-risk units. A total of 1,557 HCWs completed the survey and provided specimens, including 1,044 in the open cohort and 513 in the targeted cohort. Demographic, occupational, and clinical variables were surveyed electronically. SARS-CoV-2 seropositivity was assessed using a coronavirus antigen microarray (CoVAM), which measures antibodies against eleven viral antigens to identify prior infection with 98% specificity and 93% sensitivity. RESULTS: Among tested HCWs (n = 1,557), SARS-CoV-2 seropositivity was 10.8%, and risk factors included male gender (OR 1.48, 95% CI 1.05-2.06), exposure to COVID-19 outside of work (2.29, 1.14-4.29), working in food or environmental services (4.85, 1.51-14.85), and working in COVID-19 units (ICU: 2.28, 1.29-3.96; ward: 1.59, 1.01-2.48). Amongst 1,103 HCWs not previously screened, seropositivity was 8.0%, and additional risk factors included younger age (1.57, 1.00-2.45) and working in administration (2.69, 1.10-7.10). CONCLUSION: SARS-CoV-2 seropositivity is significantly higher than reported case counts even among HCWs who are meticulously screened. Seropositive HCWs missed by screening were more likely to be younger, work outside direct patient care, or have exposure outside of work.

Analysis and comparison of SARS-CoV-2 variant antibodies and neutralizing activity for 6 months after a booster mRNA vaccine in a healthcare worker population.

In the context of recurrent surges of SARS-CoV-2 infections, a detailed characterization of antibody persistence over a 6-month period following vaccine booster dose is necessary to crafting effective public health policies on repeat vaccination. To characterize the SARS-CoV-2 antibody profile of a healthcare worker population over a 6-month period following mRNA vaccination and booster dose. 323 healthcare workers at an academic medical center in Orange County, California who had completed primary vaccination and booster dose against SARS-CoV-2 were recruited for the study. A total of 690 blood specimens over a 6-month period were collected via finger-stick blood and analyzed for the presence of antibodies against 9 SARS-CoV-2 antigens using a coronavirus antigen microarray. The primary outcome of this study was the average SARS-CoV-2 antibody level as measured using a novel coronavirus antigen microarray. Additional outcomes measured include levels of antibodies specific to SARS-CoV-2 variants including Delta, Omicron BA.1, and BA.2. We also measured SARS-CoV-2 neutralization capacity for a subset of the population to confirm correlation with antibody levels. Although antibodies against SARS-CoV-2 wane throughout the 6-month period following a booster dose, antibody levels remain higher than pre-boost levels. However, a booster dose of vaccine generates approximately 3-fold lower antibody reactivity against Omicron variants BA.1 and BA.2 as compared to the original Wuhan strain. Despite waning antibody levels, neutralization activity against the original Wuhan strain is maintained throughout the 6-month period. In the context of recurrent surges of SARS-CoV-2 infections despite vaccination with booster doses, our data indicate that breakthrough infections are likely driven by novel variants with different antibody specificity and not by time since last dose of vaccination, indicating that development of vaccinations specific to these novel variants is necessary to prevent future surges of SARS-CoV-2 infections.

Persistence of SARS-CoV-2 Antibodies in Vaccinated Health Care Workers Analyzed by Coronavirus Antigen Microarray.

Recent studies provide conflicting evidence on the persistence of SARS-CoV-2 immunity induced by mRNA vaccines. Here, we aim to quantify the persistence of humoral immunity following vaccination using a coronavirus antigen microarray that includes 10 SARS-CoV-2 antigens. In a prospective longitudinal cohort of 240 healthcare workers, composite SARS-CoV-2 IgG antibody levels did not wane significantly over a 6-month study period. In the subset of the study population previously exposed to SARS-CoV-2 based on seropositivity for nucleocapsid antibodies, higher composite anti-spike IgG levels were measured before the vaccine but no significant difference from unexposed individuals was observed at 6 months. Age, vaccine type, or worker role did not significantly impact composite IgG levels, although non-significant trends towards lower antibody levels in older participants and higher antibody levels with Moderna vaccine were observed at 6 months. A small subset of our cohort were classified as having waning antibody titers at 6 months, and these individuals were less likely to work in patient care roles and more likely to have prior exposure to SARS-CoV-2.

STOP COVID-19 CA: Community engagement to address the disparate impacts of the COVID-19 pandemic in California.

Objective: To describe the early activities and lessons of the Share, Trust, Organize, Partner COVID-19 California Alliance (STOP COVID-19 CA), the California awardee of the NIH-funded multi-state Community Engagement Alliance (CEAL) against COVID-19. The Alliance was established to ensure equity in Coronavirus-19 disease (COVID-19) research, clinical practice, and public health for communities most impacted by the COVID-19 pandemic. Study setting: The STOP COVID-19 CA Alliance network of 11 universities and affiliated partner community-based organizations (CBOs) across California. Study design: Mixed methods evaluation consisting of an analysis of activity (August 2020 to December 2021) detailed in reports submitted by community-academic teams and a survey (August 2021) of academic investigators and affiliated community-based organization (CBO) partners. Data collection: We summarized activities from the 11 community-academic teams' progress reports and described results from an online survey of academic investigators and CBO partners in the California Alliance. Principal findings: A review of progress reports (n = 256) showed that teams fielded surveys to 11,000 Californians, conducted 133 focus groups, partnered with 29 vaccine/therapeutics clinical trials, and led more than 300 town halls and vaccine events that reached Californians from communities disproportionately impacted by COVID-19. Survey responses from academic investigators and CBO partners emphasized the importance of learning from the successes and challenges of the California Alliance teams' COVID-19 initiatives. Both academic and CBO respondents highlighted the need for streamlined federal and institutional administrative policies, and fiscal practices to promote more effective and timely operations of teams in their efforts to address the numerous underlying health and social disparities that predispose their communities to higher rates of, and poor outcomes from, COVID-19. Conclusions: STOP COVID-19 CA represents a new and potentially sustainable statewide community engagement model for addressing health disparities in multiethnic/multicultural and geographically dispersed communities.

SARS-CoV-2 vaccine testing and trials in the pediatric population: biologic, ethical, research, and implementation challenges.

As the nation implements SARS-CoV-2 vaccination in adults at an unprecedented scale, it is now essential to focus on the prospect of SARS-CoV-2 vaccinations in pediatric populations. To date, no children younger than 12 years have been enrolled in clinical trials. Key challenges and knowledge gaps that must be addressed include (1) rationale for vaccines in children, (2) possible effects of immune maturation during childhood, (3) ethical concerns, (4) unique needs of children with developmental disorders and chronic conditions, (5) health inequities, and (6) vaccine hesitancy. Because COVID-19 is minimally symptomatic in the vast majority of children, a higher acceptable risk threshold is required when evaluating pediatric clinical trials. Profound differences in innate and adaptive immunity during childhood and adolescence are known to affect vaccine responsiveness for a variety of childhood diseases. COVID-19 and the accompanying social disruption, such as the school shutdowns, has been disproportionately damaging to minority and low-income children. In this commentary, we briefly address each of these key issues, specify research gaps, and suggest a broader learning health system approach to accelerate testing and clinical trial development for an ethical and effective strategy to implement a pediatric SARS-CoV-2 vaccine as rapidly and safely as possible. IMPACT: As the US begins an unprecedented implementation of SARS-CoV-2 vaccination, substantial knowledge gaps have yet to be addressed regarding vaccinations in the pediatric population. Maturational changes in the immune system during childhood have influenced the effectiveness of pediatric vaccines for other diseases and conditions, and could affect SARS-CoV-2 vaccine responsiveness in children. Given that COVID-19 disease is far milder in the majority of children than in adults, the risk-benefit of a pediatric SARS-CoV-2 vaccine must be carefully weighed. The needs of children with developmental disabilities and with chronic disease must be addressed. Minority and low-income children have been disproportionately adversely affected by the COVID-19 pandemic; care must be taken to address issues of health equity regarding pediatric SARS-CoV-2 vaccine trials and allocation. Research and strategies to address general vaccine hesitancy in communities must be addressed in the context of pediatric SARS-CoV-2 vaccines.

Effects of cold water immersion on circulating inflammatory markers at the Kona Ironman World Championship.

Cold water immersion (CWI) purportedly reduces inflammation and improves muscle recovery after exercise, yet its effectiveness in specific contexts (ultraendurance) remains unclear. Thus, our aim was to study hematological profiles, systemic inflammation, and muscle damage responses to a specific post-race CWI (vs. control) during recovery after the Ironman World Championship, a culmination of ∼100 000 athletes competing in global qualifying Ironman events each year. Twenty-nine competitors were randomized into either a CWI or control (CON) group. Physiological parameters and blood samples were taken at pre-race, after intervention (POST), and 24 (+1DAY) and 48 hours (+2DAY) following the race. Muscle damage markers (plasma myoglobin, serum creatine kinase) were elevated at POST, +1DAY, and +2DAY, while inflammatory cytokines interleukin (IL)-6, IL-8, and IL-10 and total leukocyte counts were increased only at POST. CWI had no effect on these markers. Numbers of the most abundant circulating cell type, neutrophils, were elevated at POST more so in CWI (p < 0.05, vs. CON). Despite that neutrophil counts may be a sensitive marker to detect subtle effects, CWI does not affect recovery markers 24- and 48-hours post-race (vs. CON). Overall, we determined that our short CWI protocol was not sufficient to improve recovery. Novelty: Ironman World Championship event increased circulating muscle damage markers, inflammatory markers, and hematological parameters, including circulating immune cell sub-populations that recover 24-48 hours after the race. 12-min CWI post-ultraendurance event affects the absolute numbers of neutrophils acutely, post-race (vs. CON), but does not impact recovery 24- and 48-hours post-race.

Differential dynamics of peripheral immune responses to acute SARS-CoV-2 infection in older adults.

In this study, peripheral blood mononuclear cells from young and old patients with COVID-19 were examined phenotypically, transcriptionally and functionally to reveal age-, time- and severity-specific adaptations. Gene signatures within memory B cells and plasmablasts correlated with reduced frequency of antigen-specific B cells and neutralizing antibodies in older patients with severe COVID-19. Moreover, these patients exhibited exacerbated T cell lymphopenia, which correlated with lower plasma interleukin-2, and diminished antigen-specific T cell responses. Single-cell RNA sequencing revealed augmented signatures of activation, exhaustion, cytotoxicity and type I interferon signaling in memory T and natural killer cells with age. Although cytokine storm was evident in both age groups, older individuals exhibited elevated levels of myeloid cell recruiting factors. Furthermore, we observed redistribution of monocyte and dendritic cell subsets and emergence of a suppressive phenotype with severe disease, which was reversed only in young patients over time. This analysis provides new insights into the impact of aging on COVID-19.

Distinct whole-blood transcriptome profile of children with metabolic healthy overweight/obesity compared to metabolic unhealthy overweight/obesity.

BACKGROUND: Youth populations with overweight/obesity (OW/OB) exhibit heterogeneity in cardiometabolic health phenotypes. The underlying mechanisms for those differences are still unclear. This study aimed to analyze the whole-blood transcriptome profile (RNA-seq) of children with metabolic healthy overweight/obesity (MHO) and metabolic unhealthy overweight/obesity (MUO) phenotypes. METHODS: Twenty-seven children with OW/OB (10.1 ± 1.3 years, 59% boys) from the ActiveBrains project were included. MHO was defined as having none of the following criteria for metabolic syndrome: elevated fasting glucose, high serum triglycerides, low high-density lipoprotein-cholesterol, and high systolic or diastolic blood pressure, while MUO was defined as presenting one or more of these criteria. Inflammatory markers were additionally determined. Total blood RNA was analyzed by 5'-end RNA-sequencing. RESULTS: Whole-blood transcriptome analysis revealed a distinct pattern of gene expression in children with MHO compared to MUO children. Thirty-two genes differentially expressed were linked to metabolism, mitochondrial, and immune functions. CONCLUSIONS: The identified gene expression patterns related to metabolism, mitochondrial, and immune functions contribute to a better understanding of why a subset of the population remains metabolically healthy despite having overweight/obesity. IMPACT: A distinct pattern of whole-blood transcriptome profile (RNA-seq) was identified in children with metabolic healthy overweight/obesity (MHO) compared to metabolic unhealthy overweight/obesity (MUO) phenotype. The most relevant genes in understanding the molecular basis underlying the MHO/MUO phenotypes in children could be: RREB1, FAM83E, SLC44A1, NRG1, TMC5, CYP3A5, TRIM11, and ADAMTSL2. The identified whole-blood transcriptome profile related to metabolism, mitochondrial, and immune functions contribute to a better understanding of why a subset of the population remains metabolically healthy despite having overweight/obesity.

An islet maturation media to improve the development of young porcine islets during in vitro culture.

BACKGROUND: The use of pancreata from pre-weaned piglets has the potential to serve as an unlimited alternative source of islets for clinical xenotransplantation. As pre-weaned porcine islets (PPIs) are immature and require prolonged culture, we developed an islet maturation media (IMM) and evaluated its effect on improving the quantity and quality of PPIs over 14 days of culture. METHODS: PPIs were isolated from the pancreata of pre-weaned Yorkshire piglets (8-15 days old). Each independent islet isolation was divided for culture in either control Ham's F-10 media (n = 5) or IMM (n = 5) for 14 days. On day 3, 7 and 14 of culture, islets were assessed for islet yield, isolation index, viability, insulin content, endocrine cellular composition, differentiation of beta cells, and insulin secretion during glucose stimulation. RESULTS: In comparison to control islets, culturing PPIs in IMM significantly increased islet yield. PPIs cultured in IMM also maintained a stable isolation index and viability throughout 14 days of culture. The insulin content, endocrine cellular composition, and differentiation of beta cells were significantly improved in PPIs cultured in IMM, which subsequently augmented their insulin secretory capacity in response to glucose challenge compared to control islets. CONCLUSIONS: Culturing PPIs in IMM increases islet yield, isolation index, viability, insulin content, endocrine cellular composition, differentiation of endocrine progenitor cells toward beta cells, and insulin secretion. Due to the improved islet quantity and quality after in vitro culture, the use of IMM in the culture of PPIs will assist to advance the outcomes of clinical islet xenotransplantation.

Potential Role of Monocyte Chemoattractant Protein-1 in Monitoring Disease Progression and Response to Treatment in Overactive Bladder Patients.

PURPOSE: To compare urinary levels of monocyte chemoattractant protein-1 (MCP-1), an inflammatory cytokine, in healthy controls and overactive bladder (OAB) patients, to correlate changes in urinary MCP-1 with OAB treatment response and symptom severity, and to study the diagnostic potential of MCP-1 for OAB, as well as the efficacy of MCP-1 as a potential biomarker for different phenotypes of OAB. METHODS: We used enzyme-linked immunosorbent assay to measure normalized urinary MCP-1 levels in 56 individuals (43 OAB patients and 13 controls). We assessed the OAB patients at 3 visits with 2 validated symptom severity questionnaires (OAB-V8 and Patient Perception of Bladder Condition). RESULTS: The mean pretreatment urinary MCP-1 level at visit 1 (229.2-pg/mg creatinine) was significantly greater than the MCP-1 levels at visit 3 in both the treatment (107.0-pg/mg creatinine) (P<0.001) and control (52.35-pg/mg creatinine) groups (P<0.001). Average OAB symptom severity decreased significantly from visit 1 (baseline) to visits 2 (4 weeks) and 3 (12-14 weeks) and was significantly correlated with urinary MCP-1 levels. Urinary MCP-1 levels dropped significantly (P=0.002) posttreatment in patients whose symptom severity improved by >30%, whereas nonresponders displayed no significant MCP-1 decrease (P=0.164). The receiver operating characteristic analysis of the OAB visit 1 and control groups produced an area under the curve of 0.891. We found no significant differences in sex, race, or age between the OAB and control groups. CONCLUSION: MCP-1 levels differed significantly between the control and OAB groups and were closely correlated with symptom severity and treatment response. The good diagnostic accuracy of MCP-1 for OAB suggests the potential usage of MCP-1 for OAB diagnosis. The varying response of urinary MCP-1 levels to treatment may indicate at least 2 potential phenotypes of OAB. MCP-1, in combination with other biomarkers and symptom severity questionnaires, could potentially aid in developing a patient-centered OAB treatment approach.

Age, Sex and Weight Effects on Lactate and Leukocyte Response to Exercise in Children and Adolescents.

Post-exercise leucocytosis has been found in children and adults in response to exercise. When normalized to the work performed, children demonstrate a lower lactate response to exercise than in adults. This study examines the association between leukocyte and lactate response in children following exercise. 148 healthy children participated in this study. Each subject performed a ramp exercise on a cycle ergometer followed by ten 2-minute bouts of constant work rate separated by 1-minute rest intervals. Lactate, leukocyte and leukocyte subtype levels were taken pre- and post-exercise. Older children showed a significantly higher pre-to post-exercise leukocyte compared to younger children (3599 ± 165 cells/mL, 2544 ± 163, p<0.0001). Compared to older children, younger children demonstrated a smaller median fold change in lactate (2.7 (1.4-8.1), 4.1 (1.7-29.6)) and leukocyte levels (1.4 (1.0-2.1), 1.6 (1.2-2.8)) after exercise, with a larger leukocyte to lactate fold change ratio. CONCLUSION: Younger children have a greater leukocyte to lactate fold change ratio compared to older children. This finding may be due to the lower anaerobic dependence that is found in younger children.

A Translational Model of Incomplete Catch-Up Growth: Early-Life Hypoxia and the Effect of Physical Activity.

Advances in therapies have led to prolonged survival from many previously lethal health threats in children, notably among prematurely born babies and those with congenital heart disease. Evidence for catch-up growth is common in these children, but in many cases the adult phenotype is never achieved. A translational animal model is required in which specific tissues can be studied over a reasonable time interval. We investigated the impact of postnatal hypoxia (HY) (12%O2 (HY12) or 10% O2 (HY10)) on growth in rats relative to animals raised in room air. Subgroups had access to running wheels following the HY period. Growth was fully compensated in adult HY12 rats but not HY10 rats. The results of this study indicate that neonatal hypoxia can be a useful model for the elucidation of mechanisms that mediate successful catch-up growth following neonatal insults and identify the critical factors that prevent successful catch-up growth.

Cultural understanding, experiences, barriers, and facilitators of healthcare providers when providing preconception counseling to adolescent Latinas with diabetes.

BACKGROUND: Latinas are at a higher risk than Caucasians for both type 1 and type 2 diabetes (DM), as well as DM-associated reproductive health (RH) complications. Healthcare providers (HCPs) should deliver culturally-sensitive care to enhance the care relationship between Latinos and HCPs and to improve patient outcomes. This study explored an expert panel's cultural understanding, experiences, barriers, and facilitators regarding RH and preconception counseling (PC) for adolescent Latinas with DM and their families. METHODS: This study used open-ended questions with a focus group of 8 HCPs from the mid-Atlantic, Southwest, and Northwest regions of the United States in a teleconference format. Two researchers transcribed and reviewed the transcript for accuracy. Using content analysis, four members of the team identified themes. All researchers discussed themes and a 100% consensus was reached. For confirmation, a coding protocol was created based on the emerging themes. RESULTS: Five themes related to cultural understanding and experiences were identified: 1) issues of identity; 2) acculturation; 3) stigma; 4) ambivalence toward birth control, RH education, and PC; and 5) cultural sensitivity vs. best practice. Four barriers were identified: 1) language; 2) religion; 3) access to healthcare, and 4) discomfort with discussion. Ten facilitators were identified: 1) the importance of support and support networks; 2) promoting trust among HCPs, daughters, and families; 3) assessing emotional development; 4) empowerment; 5) emphasizing safety; 6) communicating in patients' preferred language; 7) discussing RH-related topics and PC using cultural sensitivity; 8) importance of being ready/temporality/planning for the future; 9) the importance of family-centered care; and 10) variation in educational tailoring and dissemination/ care delivery. CONCLUSIONS: Findings support the need for culturally sensitive and developmentally appropriate PC programs to empower adolescent Latinas with DM.

Inter- and intra-subject variability of nitric oxide levels in leukocyte subpopulations.

Assessment of nitric oxide (NO) dynamics in immune cells, commonly measured using NO surrogates such as inducible nitric oxide synthase (iNOS) rather than NO itself, has been effective in understanding pathophysiology across a wide range of diseases. Although the intracellular measurement of NO is now feasible, many technical issues remain unresolved. The principle aim of our study was to determine the effect of storage time of whole blood on nitric oxide (NO) level expression in leukocytes. This is important because immune cells remain chemically dynamic even after they are removed from the circulation, and the impact of storage time must be known to optimally quantify the effect of a disease or condition on NO dynamics in circulating leukocytes. We measured NO levels using the fluorescent probe, diaminofluorescein (DAF-2DA), and flow cytometry in monocytes, neutrophils, and natural killer cells from healthy subjects immediately after blood draw (Time 0) and 30, 60, and 120 min following the blood draw. There was no significant difference among the 4 study time points in NO (DAF-2) levels, though there was wide intra-subject variability at all time points. Using LPS stimulation, we compared iNOS (the more traditional surrogate marker of NO dynamics) with NO (by DAF-2) in natural killer cells and monocytes and, we found no difference in the response patterns. In summary, we did find that within a 2-hour interval from blood draw to sample processing, there was a remarkably wide intra-subject variability in expression of intracellular NO (DAF-2) in leukocytes of healthy individuals at baseline and over time. The mechanism(s) for these differences are not known but could clearly confound efforts to detect changes in NO metabolism in white blood cells. We speculate that rapid pulsatility of NO could explain the wide variability seen.

A porcine model to study the effect of brain death on kidney genomic responses.

INTRODUCTION: A majority of transplanted organs come from donors after brain death (BD). Renal grafts from these donors have higher delayed graft function and lower long-term survival rates compared to living donors. We designed a novel porcine BD model to better delineate the incompletely understood inflammatory response to BD, hypothesizing that adhesion molecule pathways would be upregulated in BD. METHODS: Animals were anesthetized and instrumented with monitors and a balloon catheter, then randomized to control and BD groups. BD was induced by inflating the balloon catheter and animals were maintained for 6 hours. RNA was extracted from kidneys, and gene expression pattern was determined. RESULTS: In total, 902 gene pairs were differently expressed between groups. Eleven selected pathways were upregulated after BD, including cell adhesion molecules. CONCLUSIONS: These results should be confirmed in human organ donors. Treatment strategies should target involved pathways and lessen the negative effects of BD on transplantable organs.

Glucocorticoid receptor expression on circulating leukocytes in healthy and asthmatic adolescents in response to exercise.

BackgroundPoor aerobic fitness is associated with worsening of asthma symptoms, and fitness training may improve asthma control. The mechanism linking fitness with asthma is not known. We hypothesized that repeated bouts of exercise would lead to a downregulation of glucocorticoid receptor (GR) expression on circulating leukocytes, reflecting a reduced responsiveness to stress.MethodsIn a prospective exercise training intervention of healthy and asthmatic adolescents, GR expression in leukocytes was measured using flow cytometry in response to an acute exercise challenge before and after the exercise training intervention. Peripheral blood mononuclear cell (PBMC) gene expression of GR, GRß, HSP70, TGFß1, and TGFß2 was determined using reverse-transcriptase PCR (RT-PCR).ResultsPeak VO2 increased by 14.6±2.3%, indicating an effective training (P<0.01). There was a significant difference in GR expression among leukocyte subtypes, with highest expression in eosinophils. Following the exercise training intervention, there was a significant decrease in baseline GR expression (P<0.05) in leukocyte and monocyte subtypes in both healthy and asthmatic adolescents.ConclusionsThis is the first study in adolescents to show that exercise training reduces GR expression in circulating leukocytes. We speculate that exercise training downregulates the stress response in general, manifested by decreased GR expression, and may explain why improving fitness improves asthma health.

Association of Growth Differentiation Factor 15 with Mortality in a Prospective Hemodialysis Cohort.

BACKGROUND/AIMS: Cardiovascular disease and protein-energy wasting are among the strongest predictors of the high mortality of dialysis patients. In the general population, the novel cardiovascular and wasting biomarker, growth differentiation factor 15 (GDF15), is associated with decreased survival. However, little is known about GDF15 in dialysis patients. METHODS: Among prevalent hemodialysis patients participating in a prospective study (October 2011 to August 2015), we examined the association of baseline GDF15 levels with all-cause mortality using unadjusted and case mix-adjusted death hazard ratios (HRs) that controlled for age, sex, race, ethnicity, diabetes, and dialysis vintage. RESULTS: The mean age ± SD of the 203 patients included in the study was 53.2 ± 14.5 years, and the cohort included 41% females, 34% African-Americans, and 48% Hispanics. GDF15 levels (mean ± SD 5.94 ± 3.90 ng/mL; range 1.58-39.8 ng/mL) were higher among older patients and were inversely associated with serum creatinine concentrations as a surrogate for muscle mass. Each 1.0 ng/mL increase in GDF15 was associated with an approximately 17-18% higher mortality risk in the unadjusted and case mix models (p < 0.05). Increments of about 1 SD (a 4.0 ng/mL increase in GDF15) were associated with a nearly 2-fold higher death risk. The highest GDF15 tertile was associated with higher mortality risk (reference: lowest tertile): the HRs (95% CI) were 3.19 (1.35-7.55) and 2.45 (1.00-6.00) in the unadjusted and the case mix-adjusted model, respectively. These incremental death trends were confirmed in cubic spline models. CONCLUSION: Higher circulating GDF15 levels are associated with higher mortality risk in hemodialysis patients. Future studies are needed to determine whether GDF15 may represent a novel therapeutic target for cardiovascular disease, wasting, and death in this population.

Glucocorticoid receptor expression on circulating leukocytes differs between healthy male and female adults.

INTRODUCTION: The glucocorticoid receptor (GR) is a key receptor involved in inflammatory responses and is influenced by sex steroids. This study measured GR expression on circulating leukocyte subtypes in males and females. METHODS: A total of 23 healthy adults (12 female) participated in this study. GR expression was measured in leukocyte subtypes using flow cytometry. Peripheral blood mononuclear cell (PBMC) gene expression of GR (NR3C1), GR ß, TGF-ß1 and 2, and glucocorticoid-induced leucine zipper (GILZ) were determined by real-time polymerase chain reaction. RESULTS: Leukocyte GR was lower in females, particularly in granulocytes, natural killer cells, and peripheral blood mononuclear cells (p≤0.01). GR protein expression was different across leukocyte subtypes, with higher expression in eosinophils compared with granulocytes, T lymphocytes, and natural killer cells (p<0.05). There was higher gene expression of GR ß in males (p=0.03). CONCLUSIONS: This is the first study to identify sexual dimorphism in GR expression in healthy adults using flow cytometry. These results may begin to explain the sexual dimorphism seen in many diseases and sex differences in glucocorticoid responsiveness.