A Quantitative Approach to Unravel the Role of Host Genetics in IgG-FcγR Complex Formation After Vaccination.

Fc-mediated immune functions have been correlated with protection in the RV144 HIV vaccine trial and are important for immunity to a range of pathogens. IgG antibodies (Abs) that form complexes with Fc receptors (FcRs) on innate immune cells can activate Fc-mediated immune functions. Genetic variation in both IgGs and FcRs have the capacity to alter IgG-FcR complex formation via changes in binding affinity and concentration. A growing challenge lies in unraveling the importance of multiple variations, especially in the context of vaccine trials that are conducted in homogenous genetic populations. Here we use an ordinary differential equation model to quantitatively assess how IgG1 allotypes and FcγR polymorphisms influence IgG-FcγRIIIa complex formation in vaccine-relevant settings. Using data from the RV144 HIV vaccine trial, we map the landscape of IgG-FcγRIIIa complex formation predicted post-vaccination for three different IgG1 allotypes and two different FcγRIIIa polymorphisms. Overall, the model illustrates how specific vaccine interventions could be applied to maximize IgG-FcγRIIIa complex formation in different genetic backgrounds. Individuals with the G1m1,17 and G1m1,3 allotypes were predicted to be more responsive to vaccine adjuvant strategies that increase antibody FcγRIIIa affinity (e.g. glycosylation modifications), compared to the G1m-1,3 allotype which was predicted to be more responsive to vaccine boosting regimens that increase IgG1 antibody titers (concentration). Finally, simulations in mixed-allotype populations suggest that the benefit of boosting IgG1 concentration versus IgG1 affinity may be dependent upon the presence of the G1m-1,3 allotype. Overall this work provides a quantitative tool for rationally improving Fc-mediated functions after vaccination that may be important for assessing vaccine trial results in the context of under-represented genetic populations.

Ex Vivo Evaluation of Mucosal Responses to Vaccination with ALVAC and AIDSVAX of Non-Human Primates.

Non-human primates (NHPs) remain the most relevant challenge model for the evaluation of HIV vaccine candidates; however, discrepancies with clinical trial results have emphasized the need to further refine the NHP model. Furthermore, classical evaluation of vaccine candidates is based on endpoints measured systemically. We assessed the mucosal responses elicited upon vaccination with ALVAC and AIDSVAX using ex vivo Rhesus macaque mucosal tissue explant models. Following booster immunization with ALVAC/AIDSVAX, anti-gp120 HIV-1CM244-specific IgG and IgA were detected in culture supernatant cervicovaginal and colorectal tissue explants, as well as systemically. Despite protection from ex vivo viral challenge, no neutralization was observed with tissue explant culture supernatants. Priming with ALVAC induced distinct cytokine profiles in cervical and rectal tissue. However, ALVAC/AIDSVAX boosts resulted in similar modulations in both mucosal tissues with a statistically significant decrease in cytokines linked to inflammatory responses and lymphocyte differentiation. With ALVAC/AIDSVAX boosts, significant correlations were observed between cytokine levels and specific IgA in cervical explants and specific IgG and IgA in rectal tissue. The cytokine secretome revealed differences between vaccination with ALVAC and ALVAC/AIDSVAX not previously observed in mucosal tissues and distinct from the systemic response, which could represent a biosignature of the vaccine combination.

A systems approach to elucidate personalized mechanistic complexities of antibody-Fc receptor activation post-vaccination.

Immunoglobulin G (IgG) antibodies that activate Fc-mediated immune functions have been correlated with vaccine efficacy, but it is difficult to unravel the relative roles of multiple IgG and Fc receptor (FcR) features that have the capacity to influence IgG-FcR complex formation but vary on a personalized basis. Here, we develop an ordinary differential-equation model to determine how personalized variability in IgG subclass concentrations and binding affinities influence IgG-FcγRIIIa complex formation and validate it with samples from the HIV RV144 vaccine trial. The model identifies individuals who are sensitive, insensitive, or negatively affected by increases in HIV-specific IgG1, which is validated with the addition of HIV-specific IgG1 monoclonal antibodies to vaccine samples. IgG1 affinity to FcγRIIIa is also prioritized as the most influential parameter for dictating activation broadly across a population. Overall, this work presents a quantitative tool for evaluating personalized differences underlying FcR activation, which is relevant to ongoing efforts to improve vaccine efficacy.

Systems serology detects functionally distinct coronavirus antibody features in children and elderly.

The hallmarks of COVID-19 are higher pathogenicity and mortality in the elderly compared to children. Examining baseline SARS-CoV-2 cross-reactive immunological responses, induced by circulating human coronaviruses (hCoVs), is needed to understand such divergent clinical outcomes. Here we show analysis of coronavirus antibody responses of pre-pandemic healthy children (n = 89), adults (n = 98), elderly (n = 57), and COVID-19 patients (n = 50) by systems serology. Moderate levels of cross-reactive, but non-neutralizing, SARS-CoV-2 antibodies are detected in pre-pandemic healthy individuals. SARS-CoV-2 antigen-specific Fcγ receptor binding accurately distinguishes COVID-19 patients from healthy individuals, suggesting that SARS-CoV-2 infection induces qualitative changes to antibody Fc, enhancing Fcγ receptor engagement. Higher cross-reactive SARS-CoV-2 IgA and IgG are observed in healthy elderly, while healthy children display elevated SARS-CoV-2 IgM, suggesting that children have fewer hCoV exposures, resulting in less-experienced but more polyreactive humoral immunity. Age-dependent analysis of COVID-19 patients, confirms elevated class-switched antibodies in elderly, while children have stronger Fc responses which we demonstrate are functionally different. These insights will inform COVID-19 vaccination strategies, improved serological diagnostics and therapeutics.

Traumatic Brain Injury Screening and the Unmet Health Needs of Shelter-Seeking Women with Head Injuries Related to Intimate Partner Violence.

Background: Unmet health needs of women with head injuries sustained by intimate partner violence (IPV) include risk of traumatic brain injury (TBI). The purpose of this evaluation was to explore the potential effectiveness of TBI screening as a health promotion strategy for shelter-seeking women with IPV head injuries. We wanted to learn if shelter-seeking women, willing to disclose IPV, would accept TBI screening if offered. Methods: An extended version of the HELPS TBI screening tool and survey of daily symptoms and health needs were used to screen new residents of an urban shelter for women. Results: The participants (N = 18) primarily were educated black women with one or more self-reported IPV-related head injury. Most participants (77.8%) had positive TBI screens for probable brain injury. The majority (88.8%) lived with one or more daily symptoms they did not have before sustaining a IPV head injury. The symptoms reported most frequently were depression (88.9%), anxiety (77.8%), and headache (66.7%). All participants had one or more unmet health need. Although most (77.8%) needed to see a primary care provider, mental health care was the most important health need identified. Conclusions: TBI screening could be considered an effective health promotion strategy for IPV survivors if screening facilitates treatment for positive screens and other unmet health needs. Further research is needed to properly assess this.

Quantitative modeling predicts mechanistic links between pre-treatment microbiome composition and metronidazole efficacy in bacterial vaginosis.

Bacterial vaginosis is a condition associated with adverse reproductive outcomes and characterized by a shift from a Lactobacillus-dominant vaginal microbiota to a polymicrobial microbiota, consistently colonized by strains of Gardnerella vaginalis. Metronidazole is the first-line treatment; however, treatment failure and recurrence rates remain high. To understand complex interactions between Gardnerella vaginalis and Lactobacillus involved in efficacy, here we develop an ordinary differential equation model that predicts bacterial growth as a function of metronidazole uptake, sensitivity, and metabolism. The model shows that a critical factor in efficacy is Lactobacillus sequestration of metronidazole, and efficacy decreases when the relative abundance of Lactobacillus is higher pre-treatment. We validate results in Gardnerella and Lactobacillus co-cultures, and in two clinical cohorts, finding women with recurrence have significantly higher pre-treatment levels of Lactobacillus relative to bacterial vaginosis-associated bacteria. Overall results provide mechanistic insight into how personalized differences in microbial communities influence vaginal antibiotic efficacy.

Immune responses to SARS-CoV-2 in three children of parents with symptomatic COVID-19.

Compared to adults, children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have predominantly mild or asymptomatic infections, but the underlying immunological differences remain unclear. Here, we describe clinical features, virology, longitudinal cellular, and cytokine immune profile, SARS-CoV-2-specific serology and salivary antibody responses in a family of two parents with PCR-confirmed symptomatic SARS-CoV-2 infection and their three children, who tested repeatedly SARS-CoV-2 PCR negative. Cellular immune profiles and cytokine responses of all children are similar to their parents at all timepoints. All family members have salivary anti-SARS-CoV-2 antibodies detected, predominantly IgA, that coincide with symptom resolution in 3 of 4 symptomatic members. Plasma from both parents and one child have IgG antibody against the S1 protein and virus-neutralizing activity detected. Using a systems serology approach, we demonstrate higher levels of SARS-CoV-2-specific antibody features of these family members compared to healthy controls. These data indicate that children can mount an immune response to SARS-CoV-2 without virological confirmation of infection, raising the possibility that immunity in children can prevent the establishment of SARS-CoV-2 infection. Relying on routine virological and serological testing may not identify exposed children, with implications for epidemiological and clinical studies across the life-span.

Adipose-derived stem cell-secreted factors promote early stage follicle development in a biomimetic matrix.

Development of primary follicles in vitro benefits from a three-dimensional matrix that is enriched with paracrine factors secreted from feeder cells and mimics the in vivo environment. In this study, we investigated the role of paracrine signaling from adipose-derived stem cells (ADSCs) in supporting primary follicle development in a biomimetic poly(ethylene glycol) (PEG)-based matrix. Follicles co-cultured with ADSCs and follicles cultured in conditioned medium from ADSCs encapsulated in gels (3D CM) exhibited significantly (p < 0.01 and p = 0.09, respectively) improved survival compared to follicles cultured in conditioned medium collected from ADSCs cultured in flasks (2D CM) and follicles cultured without paracrine support. The gene expression of ADSCs suggested that the stem cells maintained their multipotency in the 3D PEG environment over the culture period, regardless of the presence of the follicles, while under 2D conditions the multipotency markers were downregulated. The differences in cytokine signatures of follicles exposed to 3D and 2D ADSC paracrine factors suggest that early cytokine interactions are key for follicle survival. Taken together, the biomimetic PEG scaffold provides a three-dimensional, in vivo-like environment to induce ADSCs to secrete factors which promote early stage ovarian follicle development and survival.

Youth Chef Academy: Pilot Results From a Plant-Based Culinary and Nutrition Literacy Program for Sixth and Seventh Graders.

BACKGROUND: National data confirm that youth are not eating recommended amounts of fruits and vegetables (F/V), legumes, and whole grains (WGs). Establishing plant-based eating patterns early in life may positively impact long-term health through tracking of adolescent eating patterns into adulthood and through potential associations between adolescent dietary intake and adult disease risk. The study aim was to examine the effectiveness of Youth Chef Academy (YCA), a classroom-based experiential culinary and nutrition literacy intervention for sixth and seventh graders (11- to 13-year-olds) designed to impact healthy eating. METHODS: Study used a nonequivalent control group design with 8 schools selected for similarity in: free/reduced-price lunch, race/ethnicity, and student mobility rate (N = 248). Primary outcomes were times per day of F/V, vegetable, and WG consumption. Students completed a survey to assess primary outcomes and other measures at baseline and post-intervention. RESULTS: Significant increases in times per day of F/V (p = .022) and vegetable only (p = .015) consumption in the intervention group compared to the control group. Increases in WG consumption showed trended toward significance (p = .071). Student engagement and nutrition knowledge showed significant intervention effects. CONCLUSIONS: YCA positively impacts behavioral and knowledge variables related to healthy eating and increases students' engagement in their classrooms.

Synergy of Paracrine Signaling During Early-Stage Mouse Ovarian Follicle Development In Vitro.

Introduction: Paracrine signals, such as soluble cytokines and extracellular matrix cues, are essential for the survival and development of multicellular ovarian follicles. While it is well established that hydrogel-based culture systems successfully support the growth of late-stage follicles for fertility preservation, growing small, early-stage ovarian follicles still proves to be challenging. We hypothesized that paracrine factors secreted from neighboring follicles may be crucial for improving the survival of early-stage follicles in vitro. Methods: To test our hypothesis, we investigated the bi-directional crosstalk of the paracrine signals, such as cell-secreted cytokines, sex hormones and transcription factors (TFs), in follicles encapsulated and cultured for 12 days in alginate in groups of five (5×) and ten (10×). Results: The differential profiles of TF activity and secretome during folliculogenesis were analyzed using TRanscriptional Activity CEllular aRray (TRACER) and data-driven multivariate modeling approach. The mechano- and oxygen-responsive TFs, NF-κB and HIF1, exhibited a unique upregulation signature in 10× follicles. Consistently, levels of proangiogenic factors, such as VEGF-A and angiopoietin-2, were significantly higher in 10× follicles than those in 5× follicles, reaching 269.77 and 242.82 pg/mL on the last day of culture. The analysis of TRACER and secreted cytokines also revealed critical early interactions between cytokines and TFs, correlating with the observed phenotypical and functional differences between conditions. Conclusions: We identified unique signatures of synergism during successful early-stage ovarian follicle development. These findings bring us closer to understanding of mechanisms underlying the downstream effects of interactions between the extracellular microenvironment and early-stage folliculogenesis in vitro.

Correction to: Synergy of Paracrine Signaling During Early-Stage Mouse Ovarian Follicle Development In Vitro.

[This corrects the article DOI: 10.1007/s12195-018-0545-8.].

¡Venga Y Relájese! Pilot Stress Reduction Program for Migrant Latina Women Living in Low-Resource Settings From Milwaukee to Lima.

Latina women living in low-income communities frequently report a high prevalence of feeling physically and/or emotionally "unwell." Formative focus groups were used to design a 3-session stress reduction curriculum called ¡Venga y Relájese! (Come and relax yourself!). Survey data from 5 Milwaukee cohorts and 1 Peruvian cohort revealed statistically significant improvements in general health status, perceived stress status, and confidence to manage future stress among women who completed all sessions (n=54). The pilot ¡Venga y Relájese! stress reduction curriculum yielded benefits for Latina women living in low-income neighborhoods in Milwaukee, Wisconsin and Lima, Peru.

Training in Urban Medicine and Public Health: Preparing Physicians to Address Urban Health Care Needs.

BACKGROUND: Wisconsin is facing significant physician shortages. The University of Wisconsin School of Medicine and Public Health (UWSMPH) launched Training in Urban Medicine and Public Health (TRIUMPH) to recruit and prepare medical students to serve people living within urban Health Professional Shortage Areas. METHODS: Students are selected based on their commitment to improve health equity for urban populations. They complete clinical rotations, core curriculum, and community projects in Milwaukee, Wisconsin. RESULTS: Full program graduates are more likely to match into residencies serving the urban poor (50/50, 100%) and pursue primary care specialties (40/50, 80.0%) compared to nonprogram graduates. DISCUSSION: The TRIUMPH program has been successful in its mission to encourage graduates to serve urban communities. The authors discuss urban health disparities, TRIUMPH outcomes, and the need for similar programs.

Factors Associated With Truck Crashes in a Large Cross Section of Commercial Motor Vehicle Drivers.

OBJECTIVE: This large, cross-sectional study calculated prevalence of disorders and assessed factors associated with self-reported lifetime crashes. METHODS: Truck drivers (n = 797) completed computerized questionnaires reporting crashes, demographics, psychosocial factors, and other elements, as well as had taken measurements (eg, height, weight, serum, and blood pressure). RESULTS: Most drivers were male (n = 685, 85.9%), and the mean body mass index was 32.9 ±â€Š7.5  kg/m2 with 493 (61.9%) being obese. Many drivers (n = 326, 39.9%) experienced at least one, with 132 (16.6%) having multiple, lifetime, reportable crashes. Many factors were associated with crashes, including increasing age, increasing truck driving experience, male sex, alcohol, low back pain, heart disease, and feeling tense. The most consistent associations with crashes were pulse pressure, cell phone use, and feeling physically exhausted after work. CONCLUSIONS: Modifiable factors associated with self-reported crashes were identified. These suggest targeted interventions may reduce risks of crashes.

Development of a method for evaluating accessibility of medical equipment for patients with disabilities.

OBJECTIVE: The purpose of this study was to develop a method for evaluating accessibility of medical equipment for patients with disabilities. METHODS: The researchers reviewed videotapes of patient-participants with various physical and sensory disabilities using different types of medical equipment. For each of 11 videotapes, four observers independently identified and documented access and safety barriers, such as physical, sensory, cognitive, and environmental barriers. Inter-observer variability for identifying barrier presence was assessed with kappa statistics for pairs of observers. RESULTS: A list of 10 access and safety barriers was developed through an iterative consensus process, which identified design features of medical equipment that presented difficulties for participants with disabilities. The list is useful for identifying and categorizing accessibility problems found in equipment. While reliability of barrier identification was substantial or moderate for some barriers, reconciliation of barrier events identified by multiple video observers is recommended for optimal results.

Geographic analysis of diagnosis of Attention-Deficit/Hyperactivity Disorder in children: Eastern Wisconsin, USA.

OBJECTIVE: To perform a novel geographic analysis of Attention-Deficit/ Hyperactivity Disorder (ADHD) diagnosis in Midwest United States. METHOD: Primary care children age 5-17 with ADHD diagnosis (N = 6833; 13.5%) were compared to those receiving well child care without ADHD diagnosis (N = 43,630) in a Wisconsin integrated medical system. Street addresses, demographic, and block group level U.S. Census 2000 data were mapped and analyzed using ArcGIS, CrimeStat III, and SaTScan. Lead levels from a State database were linked to 2,837 subjects. Univariate analysis was done by chi-square test or Mann-Whitney U test, multivariate analysis by logistic regression. RESULTS: ADHD cases were 74% male (p = 0.0001), and more frequently diagnosed in White children (17.3%) than Blacks (10.6%), Hispanics (9.4%), or Asians (3.7%; all p values < 0.001). Overall, male gender, white race, lower block group median household income and population density, and greater distance to nearest park and airport were more predictive of ADHD (p values < 0.001). In urban Milwaukee County (865 cases/10,493 controls) male gender, white race, suburban residence, and younger age were more predictive of ADHD (p values < 0.01). Among children with ADHD diagnosis and linked lifetime lead values, those with a maximum level of 10 microg/dl or more differed significantly from controls (9.3% vs. 5.6%; p = 0.003); elevated lead remained a significant predictor of ADHD diagnosis in multivariate analysis. CONCLUSIONS: Further studies are needed to determine if geographic distribution of ADHD diagnosis can be partially explained by differential efficiency of referral for diagnosis by school districts, by race/ethnicity, and/or built environment.

Blastomycosis in urban southeastern Wisconsin.

PURPOSE: A previous study revealed a non-random distribution of blastomycosis cases by home site in urban Milwaukee County. This study was conducted to determine the proportion of cases with likely exposures solely in urban areas. METHODS: Records of 68 urban southeastern Wisconsin individuals, including 45 residents of Milwaukee, 19 from suburban Milwaukee County, and 4 from outside Milwaukee County, diagnosed with blastomycosis between January 2002 and July 2007 were studied using medical record reviews, case reports, and telephone interviews. Geographic Information Systems (GIS) proximity analysis was then used to compare the distance between case and control home sites to environmental risk factors. RESULTS: Of patients reporting their exposure history, 41 of 49 (84%) participated in outdoor work or leisure activities, and 12 of 47 (26%) engaged in fishing, hunting, camping, or hiking. Of the urban cases, 64 occurred among Milwaukee County residents; of those, 25 of 49 (51%) denied traveling, which suggests local urban exposure, and 8 of 11 (73%) specifically recalled urban waterway exposure prior to diagnosis. The 45 Milwaukee cases were concentrated on the north side of town and were closer to inland waterways than a random sample of 6528 controls (median 690 versus 1170 meters; P=0.003), but not closer to parks. CONCLUSION: Southeastern Wisconsin residents may acquire blastomycosis solely in their local urban area, sometimes without specific outdoor exposures. Proximity to inland waterways is associated with blastomycosis cases in urban areas, similar to rural areas of Wisconsin. Clinicians should include blastomycosis in appropriate differential diagnoses of symptomatic individuals, even in urban residents without travel history or history of significant outdoor exposures.

Accessibility of radiology equipment for patients with mobility disabilities.

OBJECTIVE: The purpose was to evaluate accessibility of typical radiology platforms by participants with mobility disabilities. BACKGROUND: These patients have difficulty using radiology equipment and have an increased risk of falling. METHODS: This field study evaluated three common types of radiology platforms - X ray, computed tomography (CT) scan, and fluoroscopy - by 20 patients/participants with mobility impairments who used walking aids. The participants were required to get onto the equipment, simulate a typical radiological procedure, and get off. Each participant then watched a video of his or her own session and answered questions. Four researchers independently reviewed the videotapes and identified accessibility and safety barriers. RESULTS: Overall, the CT scan platform was the easiest to use and the fluoroscopy platform the most difficult, primarily because of platform height differences. Sitting up on the Xray table was rated as difficult by most participants, primarily because of a lack of hand-holds and the surface pad not being fixed in place. Maintaining a position on the fluoroscopy platform while it rotated from horizontal to vertical was difficult and frightening for most participants. CONCLUSION: Some radiology platforms are difficult to use and are perceived to be less safe for patients with mobility disabilities. The interaction of patient disability and equipment design can impose substantial physical demands on medical personnel. Recommendations for improved design are provided to enhance radiology platform accessibility and safety. APPLICATION: The findings may be applicable to the design of a wide range of medical patient platforms.

A mobile tool for accessibility and usability testing of medical instrumentation.

The Mobile Usability Lab (MU-Lab) is a tool developed by the Rehabilitation Engineering Research Center on Accessible Medical Instrumentation (RERC-AMI) to study the accessibility and usability of medical devices by people with diverse abilities. The system includes a suite of data collection hardware components and a custom software interface to help coordinate problem identification and planning as well as data collection and analysis for usability and accessibility research of medical devices. Hardware components include a laptop computer, data acquisition card, video cameras, quad video processor and wireless microphones. Software components include a customized Web-based usability suite, real-time data collection package and several video editing and data analysis tools.