Participant attrition from statewide, population-based Survey of the Health of Wisconsin into the longitudinal SHOW COVID-19 cohort.

PURPOSE: Longitudinal studies are essential for examining how social and institutional determinants of health, historical and contemporary, affect disparities in COVID-19 related outcomes. The unequal impacts of COVID-19 likely exacerbated selected attrition in longitudinal research. This study examines attrition and survey mode effects in the SHOW COVID-19 study which recruited from a statewide, representative cohort. MATERIALS & METHODS: Participants were recruited from the Survey of the Health of Wisconsin (SHOW) cohort. Online surveys, or phone interviews, were administered at three timepoints during 2020-2021. The surveys captured social, behavioral, and structural determinants of health and the lived experience. Univariate and multivariate logistic regression was used to examine predictors of participation and survey mode effects. RESULTS: A total of 2304 adults completed at least one COVID-19 online survey. Participants were more educated, older, and more likely to be female, married, non-Hispanic, and White compared to non-participants. Phone participants were older, less educated, and more likely be non-White, food insecure, and have co-morbidities compared to online participants. Mode effects were seen with reporting COVID-19 beliefs, loneliness, and anxiety. CONCLUSION: The SHOW COVID-19 cohort offers unique longitudinal data but suffered from selected attrition. Phone interview is an important mode for retention and representation.

Psychological distress and well-being among sensory impaired individuals during COVID-19 lockdown measures.

PURPOSE: Hearing and vision impairment are prevalent chronic conditions associated with poorer mental health. Limitations of in-person contacts during COVID-19-related lockdown measures may affect those with sensory impairments more severely exacerbating mental health problems. We aimed to determine whether hearing and/or visual impairment were associated with more psychological distress during a time of lockdown measures in Spring/Summer 2020 in Wisconsin. METHODS: We included 1341(64% women, aged 20-92 years) Survey of the Health of Wisconsin COVID-19 survey participants (May 2020-July,2020). We assessed self-reported current mental health and well-being and vision and hearing impairment. Logistic regression models with sensory impairments as determinants and mental health outcomes were adjusted for age, gender, race, education, heart disease, hypertension, hyperlipidemia, and diabetes. RESULTS: Vision impairment was associated with increased odds of generalized anxiety disorder (odds ratio = 2.10; 95% confidence interval = 1.32-3.29) and depressive symptoms (2.57;1.58-4.11), greater likelihood to report loneliness (1.65;1.00-2.64) and hopelessness (1.45;1.01-2.08). Hearing impaired individuals reported more loneliness (1.80;1.05-2.98) and hopelessness (1.42;0.99-2.03). Exploratory analyses revealed that sensory impaired individuals less often chose walking as a coping strategy during the pandemic. CONCLUSIONS: Individuals with sensory impairment may represent a particularly vulnerable population during the COVID-19 pandemic. Future research should determine underlying reasons and interventions to mitigate this populations' disadvantages.

Self-reported hearing loss is associated with poorer perceived health care access, timeliness, satisfaction, and quality: Findings from the Survey of the Health of Wisconsin.

BACKGROUND: Hearing loss is a highly prevalent chronic condition impacting communication and may negatively influence patients' health care experiences. OBJECTIVE: Determine associations of hearing loss with perceived health care access, timeliness, satisfaction, and quality in a representative sample of the general population. METHODS: The Survey of the Health of Wisconsin (SHOW) is a household-based examination survey that collects data from a representative sample of Wisconsin residents. SHOW participants from years 2008-2013 with data on self-reported hearing loss and health care access, timeliness, satisfaction, and quality were included in this study. Age- and sex- and multivariable-adjusted (additionally adjusted for race/ethnicity, education, marital status, public health region, smoking, chronic disease, self-reported health, and insurance coverage) logistic regression models were used to evaluate associations of hearing loss with participants' health care experiences. Results are presented as odds ratios (OR) with corresponding 95% confidence intervals. RESULTS: There were 2438 individuals (42.1% men) included in this study with an average age of 48.3 (range 21-74; standard deviation [SD] 14.4) years. The number of participants who self-reported hearing loss was 642 (26.3%). After multivariable adjustment, hearing loss was associated with increased odds of perceived difficulties with health care access (OR 1.47 [1.05, 2.05]), timeliness (OR 1.69 [1.23, 2.32]), quality (OR 2.54 [1.50, 4.32]), and satisfaction (OR 2.50 [1.51, 4.13]). CONCLUSIONS: Given the high prevalence of hearing loss and the growing aging population, there is an urgent need to prioritize interventions to improve health care provision for individuals with hearing loss.

Prevalence of Self-Reported Hearing Loss and Associated Risk Factors: Findings From the Survey of the Health of Wisconsin.

PURPOSE: The purpose of this study was to determine the prevalence of self-reported hearing loss and associated risk factors in a representative population-based study of Wisconsin residents. METHOD: Survey of the Health of Wisconsin participants with data on self-reported hearing loss were included. We reported prevalence of self-reported hearing loss with corresponding 95% confidence intervals (CIs), overall, and stratified by age and sex. Age- and sex-adjusted and multivariable logistic regression models were used to evaluate determinants of self-reported hearing loss, and results are presented as odds ratios with corresponding 95% CIs. RESULTS: There were 2,767 participants (50.7% men) with a mean age of 46 years (range: 21-74) in this study. Prevalence of self-reported hearing loss was 26.8% (24.4, 28.4) and was higher in men (30.3% [27.1, 33.4]) than in women (22.5% [19.9, 25.0]). Prevalence increased with age. After multivariable adjustment, age (per +1 year increase; 1.05 [1.04, 1.06]), male sex (1.57 [1.18, 2.08]), having two chronic diseases (vs. 0; 1.93 [1.16, 3.23]), occupational (2.47 [1.91, 3.19]) and recreational (1.58 [1.22, 2.04]) noise exposure, and poor diet (1.88 [1.28, 2.78]) were associated with higher odds of self-reported hearing loss. CONCLUSIONS: Hearing loss is a highly prevalent public health concern and may be at least partially modifiable via interventions to reduce noise exposure and promote health. Statewide prevalence and risk factor data can be used to inform public health practice and promote hearing loss prevention. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.19661130.

NF-κB perturbation reveals unique immunomodulatory functions in Prx1+ fibroblasts that promote development of atopic dermatitis.

Skin is composed of diverse cell populations that cooperatively maintain homeostasis. Up-regulation of the nuclear factor κB (NF-κB) pathway may lead to the development of chronic inflammatory disorders of the skin, but its role during the early events remains unclear. Through analysis of single-cell RNA sequencing data via iterative random forest leave one out prediction, an explainable artificial intelligence method, we identified an immunoregulatory role for a unique paired related homeobox-1 (Prx1)+ fibroblast subpopulation. Disruption of Ikkb-NF-κB under homeostatic conditions in these fibroblasts paradoxically induced skin inflammation due to the overexpression of C-C motif chemokine ligand 11 (CCL11; or eotaxin-1) characterized by eosinophil infiltration and a subsequent TH2 immune response. Because the inflammatory phenotype resembled that seen in human atopic dermatitis (AD), we examined human AD skin samples and found that human AD fibroblasts also overexpressed CCL11 and that perturbation of Ikkb-NF-κB in primary human dermal fibroblasts up-regulated CCL11. Monoclonal antibody treatment against CCL11 was effective in reducing the eosinophilia and TH2 inflammation in a mouse model. Together, the murine model and human AD specimens point to dysregulated Prx1+ fibroblasts as a previously unrecognized etiologic factor that may contribute to the pathogenesis of AD and suggest that targeting CCL11 may be a way to treat AD-like skin lesions.

Regulation of T cell-associated tissues and T cell activation by RANKL-RANK-OPG.

The receptor activator of nuclear factor kappa-B ligand (RANKL)-RANK-osteoprotegerin (OPG) system is critical to bone homeostasis, but genetically deficient mouse models have revealed important roles in the immune system as well. RANKL-RANK-OPG is particularly important to T cell biology because of its organogenic control of thymic development and secondary lymphoid tissues influence central T cell tolerance and peripheral T cell function. RANKL-RANK-OPG cytokine-receptor interactions are often controlled by regulation of expression of RANKL on developing T cells, which interacts with RANK expressed on some lymphoid tissue cells to stimulate key downstream signaling pathways that affect critical tuning functions of the T cell compartment, like cell survival and antigen presentation. Activation of peripheral T cells is regulated by RANKL-enhanced dendritic cell survival, and dysregulation of the RANKL-RANK-OPG system in this context is associated with loss of T cell tolerance and autoimmune disease. Given its broader implications for immune homeostasis and osteoimmunology, it is critical to further understand how the RANKL-RANK-OPG system operates in T cell biology.

Protocadherin-7 contributes to maintenance of bone homeostasis through regulation of osteoclast multinucleation.

Osteoclasts are hematopoietic-derived cells that resorb bone. They are required to maintain proper bone homeostasis and skeletal strength. Although osteoclast differentiation depends on receptor activator of NF-κB ligand (RANKL) stimulation, additional molecules further contribute to osteoclast maturation. Here, we demonstrate that protocadherin-7 (Pcdh7) regulates formation of multinucleated osteoclasts and contributes to maintenance of bone homeostasis. We found that Pcdh7 expression is induced by RANKL stimulation, and that RNAi-mediated knockdown of Pcdh7 resulted in impaired formation of osteoclasts. We generated Pcdh7-deficient mice and found increased bone mass due to decreased bone resorption but without any defect in bone formation. Using an in vitro culture system, it was revealed that formation of multinucleated osteoclasts is impaired in Pcdh7-deficient cultures, while no apparent defects were observed in differentiation and function of Pcdh7-deficient osteoblasts. Taken together, these results reveal an osteoclast cell-intrinsic role for Pcdh7 in maintaining bone homeostasis. [BMB Reports 2020; 53(9): 472-477].

Mice Lacking the Purinergic Receptor P2X5 Exhibit Defective Inflammasome Activation and Early Susceptibility to Listeria monocytogenes.

P2X5 is a member of the P2X purinergic receptor family of ligand-gated cation channels and has recently been shown to regulate inflammatory bone loss. In this study, we report that P2X5 is a protective immune regulator during Listeria monocytogenes infection, as P2X5-deficient mice exhibit increased bacterial loads in the spleen and liver, increased tissue damage, and early (within 3-6 d) susceptibility to systemic L. monocytogenes infection. Whereas P2X5-deficient mice experience normal monocyte recruitment in response to L. monocytogenes, P2X5-deficient bone marrow-derived macrophages (BMMs) exhibit defective cytosolic killing of L. monocytogenes We further showed that P2X5 is required for L. monocytogenes-induced inflammasome activation and IL-1ß production and that defective L. monocytogenes killing in P2X5-deficient BMMs is substantially rescued by exogenous IL-1ß or IL-18. Finally, in vitro BMM killing and in vivo L. monocytogenes infection experiments employing either P2X7 deficiency or extracellular ATP depletion suggest that P2X5-dependent anti-L. monocytogenes immunity is independent of the ATP-P2X7 inflammasome activation pathway. Together, our findings elucidate a novel and specific role for P2X5 as a critical mediator of protective immunity.

CD44 Can Compensate for IgSF11 Deficiency by Associating with the Scaffold Protein PSD-95 during Osteoclast Differentiation.

Differentiation of osteoclasts, which are specialized multinucleated macrophages capable of bone resorption, is driven primarily by receptor activator of NF-κB ligand (RANKL). Additional signaling from cell surface receptors, such as cell adhesion molecules (CAMs), is also required for osteoclast maturation. Previously, we have demonstrated that immunoglobulin superfamily 11 (IgSF11), a member of the immunoglobulin-CAM (IgCAM) family, plays an important role in osteoclast differentiation through association with the scaffold protein postsynaptic density protein 95 (PSD-95). Here, we demonstrate that the osteoclast-expressed CAM CD44 can compensate for IgSF11 deficiency when cell-cell interaction conditions are suboptimal by associating with PSD-95. Impaired osteoclast differentiation in IgSF11-deficient (IgSF11-/-) cultures was rescued by antibody-mediated stimulation of CD44 or by treatment with low-molecular-weight hyaluronan (LMW-HA), a CD44 ligand. Biochemical analysis revealed that PSD-95, which is required for osteoclast differentiation, associates with CD44 in osteoclasts regardless of the presence or absence of IgSF11. RNAi-mediated knockdown of PSD-95 abrogated the effects of either CD44 stimulation or LMW-HA treatment on osteoclast differentiation, suggesting that CD44, similar to IgSF11, is functionally associated with PSD-95 during osteoclast differentiation. Taken together, these results reveal that CD44 can compensate for IgSF11 deficiency in osteoclasts through association with PSD-95.

IgSF11 regulates osteoclast differentiation through association with the scaffold protein PSD-95.

Osteoclasts are multinucleated, giant cells derived from myeloid progenitors. While receptor activator of NF-κB ligand (RANKL) stimulation is the primary driver of osteoclast differentiation, additional signaling further contributes to osteoclast maturation. Here, we demonstrate that immunoglobulin superfamily member 11 (IgSF11), whose expression increases during osteoclast differentiation, regulates osteoclast differentiation through interaction with postsynaptic density protein 95 (PSD-95), a scaffold protein with multiple protein interaction domains. IgSF11 deficiency in vivo results in impaired osteoclast differentiation and bone resorption but no observed defect in bone formation. Consequently, IgSF11-deficient mice exhibit increased bone mass. Using in vitro osteoclast culture systems, we show that IgSF11 functions through homophilic interactions. Additionally, we demonstrate that impaired osteoclast differentiation in IgSF11-deficient cells is rescued by full-length IgSF11 and that the IgSF11-PSD-95 interaction requires the 75 C-terminal amino acids of IgSF11. Our findings reveal a critical role for IgSF11 during osteoclast differentiation and suggest a role for IgSF11 in a receptor- and signal transduction molecule-containing protein complex.

Methylosome protein 50 associates with the purinergic receptor P2X5 and is involved in osteoclast maturation.

Purinergic signaling plays important roles in bone. P2X5, a member of ligand-gated ion channel receptors, has been demonstrated to regulate osteoclast maturation. However, the molecular mechanism of P2X5-mediated osteoclast regulation remains unclear. Here, we identified methylosome protein 50 (MEP50), a critical cofactor of the protein arginine methyltransferase 5 (PRMT5), as a P2X5-associating molecule. RNAi-mediated knockdown of MEP50 results in decreased formation of mature osteoclasts. MEP50 associates with P2X5, and this association requires the C-terminal intracellular region of P2X5. Additionally, impaired maturation of P2X5-deficient osteoclasts could be restored by transduction of full-length P2X5, but not a C-terminal deletion mutant of P2X5. These results indicate that P2X5 associates with MEP50 and suggest a link between the PRMT5 complex and P2X5 signaling in osteoclast maturation.

The purinergic receptor P2X5 contributes to bone loss in experimental periodontitis.

Purinergic receptor signaling is increasingly recognized as an important regulator of inflammation. The P2X family purinergic receptors P2X5 and P2X7 have both been implicated in bone biology, and it has been suggested recently that P2X5 may be a significant regulator of inflammatory bone loss. However, a role for P2X5 in periodontitis is unknown. The present study aimed to evaluate the functional role of P2X5 in ligatureinduced periodontitis in mice. Five days after placement of ligature, analysis of alveolar bone revealed decreased bone loss in P2rx5-/- mice compared to P2rx7-/- and WT control mice. Gene expression analysis of the gingival tissue of ligated mice showed that IL1b, IL6, IL17a and Tnfsf11 expression levels were significantly reduced in P2rx5-/- compared to WT mice. These results suggest the P2X5 receptor may regulate bone loss related to periodontitis and it may thus be a novel therapeutic target in this oral disease. [BMB Reports 2018; 51(9): 468-473].

Updating osteoimmunology: regulation of bone cells by innate and adaptive immunity.

Osteoimmunology encompasses all aspects of the cross-regulation of bone and the immune system, including various cell types, signalling pathways, cytokines and chemokines, under both homeostatic and pathogenic conditions. A number of key areas are of increasing interest and relevance to osteoimmunology researchers. Although rheumatoid arthritis has long been recognized as one of the most common autoimmune diseases to affect bone integrity, researchers have focused increased attention on understanding how molecular triggers and innate signalling pathways (such as Toll-like receptors and purinergic signalling pathways) related to pathogenic and/or commensal microbiota are relevant to bone biology and rheumatic diseases. Additionally, although most discussions relating to osteoimmune regulation of homeostasis and disease have focused on the effects of adaptive immune responses on bone, evidence exists of the regulation of immune cells by bone cells, a concept that is consistent with the established role of the bone marrow in the development and homeostasis of the immune system. The active regulation of immune cells by bone cells is an interesting emerging component of investigations that seek to understand how to control immune-associated diseases of the bone and joints.

Frequency of Eating Out at Both Fast-Food and Sit-Down Restaurants Was Associated With High Body Mass Index in Non-Large Metropolitan Communities in Midwest.

PURPOSE: We investigated the associations between frequency of eating at fast-food, fast-casual, all-you-can-eat, and sit-down restaurants and the body mass index (BMI) in non-large metro Wisconsin communities. To inform prevention efforts, we also analyzed the socioeconomic/environmental and nutrition attitudes/behavior variables that may drive the frequent eating away from home. DESIGN: Cross-sectional analysis of an ancillary data set from the Survey of Health of Wisconsin collected between October 2012 and February 2013. SETTING: Six Wisconsin counties: 1 classified as rural, 1 as large fringe metro, and 4 as small metro. SUBJECTS: Adults ≥18 years (N = 1418). MEASURES: Field staff measured height and weight and administered a survey on the frequency of eating away from home, and socioeconomic and nutritional behavior variables. ANALYSIS: Multivariable regression. RESULTS: The BMI of respondents averaged 29.4 kg/m2 (39% obese). Every 1-meal/week increase in fast-food and sit-down restaurant consumption was associated with an increase in BMI by 0.8 and 0.6 kg/m2, respectively. Unavailability of healthy foods at shopping and eating venues and lack of cooking skills were both positively associated with consumption of fast-food and sit-down meals. Individuals who described their diet as healthy, who avoided high-fat foods, and who believed their diet was keeping their weight controlled did not visit these restaurants frequently. CONCLUSION: Obesity prevention efforts in non-large metro Wisconsin communities should consider socioeconomic/environmental and nutritional attitudes/behavior of residents when designing restaurant-based or community education interventions.

The purinergic receptor P2X5 regulates inflammasome activity and hyper-multinucleation of murine osteoclasts.

Excessive bone resorption by osteoclasts (OCs) can result in serious clinical outcomes, including bone loss that may weaken skeletal or periodontal strength. Proper bone homeostasis and skeletal strength are maintained by balancing OC function with the bone-forming function of osteoblasts. Unfortunately, current treatments that broadly inhibit OC differentiation or function may also interfere with coupled bone formation. We therefore identified a factor, the purinergic receptor P2X5 that is highly expressed during the OC maturation phase, and which we show here plays no apparent role in early bone development and homeostasis, but which is required for osteoclast-mediated inflammatory bone loss and hyper-multinucleation of OCs. We further demonstrate that P2X5 is required for ATP-mediated inflammasome activation and IL-1ß production by OCs, and that P2X5-deficient OC maturation is rescued in vitro by addition of exogenous IL-1ß. These findings identify a mechanism by which OCs react to inflammatory stimuli, and may identify purinergic signaling as a therapeutic target for bone loss-related inflammatory conditions.

Dendritic cell expression of the signaling molecule TRAF6 is required for immune tolerance in the lung.

Immune tolerance in the lung is important for preventing hypersensitivity, such as allergic asthma. Maintenance of tolerance in the lung is established by coordinated activities of poorly understood cellular and molecular mechanisms, including participation of dendritic cells (DCs). We have previously identified DC expression of the signaling molecule TRAF6 as a non-redundant requirement for the maintenance of immune tolerance in the small intestine of mice. Because mucosal tissues share similarities in how they interact with exogenous antigens, we examined the role of DC-expressed TRAF6 in the lung. As with the intestine, we found that the absence TRAF6 expression by DCs led to spontaneous generation of Th2-associated immune responses and increased susceptibility to model antigen-induced asthma. To examine the role of commensal microbiota, mice deficient in TRAF6 in DCs were treated with broad-spectrum antibiotics and/or re-derived on a germ-free (GF) background. Interestingly, we found that antibiotics-treated specific pathogen-free, but not GF, mice showed restored immune tolerance in the absence of DC-expressed TRAF6. We further found that antibiotics mediate microbiota-independent effects on lung T cells to promote immune tolerance in the lung. This work provides both a novel tool for studying immune tolerance in the lung and an advance in our conceptual understanding of potentially common molecular mechanisms of immune tolerance in both the intestine and the lung.

Interaction of Tumor Necrosis Factor Receptor-associated Factor 6 (TRAF6) and Vav3 in the Receptor Activator of Nuclear Factor κB (RANK) Signaling Complex Enhances Osteoclastogenesis.

The signaling pathway downstream of stimulation of receptor activator of nuclear factor κB (RANK) by RANK ligand is crucial for osteoclastogenesis. RANK recruits TNF receptor-associated factor 6 (TRAF6) to TRAF6-binding sites (T6BSs) in the RANK cytoplasmic tail (RANKcyto) to trigger downstream osteoclastogenic signaling cascades. RANKcyto harbors an additional highly conserved domain (HCR) that also activates crucial signaling during RANK-mediated osteoclastogenesis. However, the functional cross-talk between T6BSs and the HCR in the RANK signaling complex remains unclear. To characterize the cross-talk between T6BSs and the HCR, we screened TRAF6-interacting proteins using a proteomics approach. We identified Vav3 as a novel TRAF6 binding partner and evaluated the functional importance of the TRAF6-Vav3 interaction in the RANK signaling complex. We demonstrated that the coiled-coil domain of TRAF6 interacts directly with the Dbl homology domain of Vav3 to form the RANK signaling complex independent of the TRAF6 ubiquitination pathway. TRAF6 is recruited to the RANKcyto mutant, which lacks T6BSs, via the Vav3 interaction; conversely, Vav3 is recruited to the RANKcyto mutant, which lacks the IVVY motif, via the TRAF6 interaction. Finally, we determined that the TRAF6-Vav3 interaction resulting from cross-talk between T6BSs and the IVVY motif in RANKcyto enhances downstream NF-κB, MAPK, and NFATc1 activation by further strengthening TRAF6 signaling, thereby inducing RANK-mediated osteoclastogenesis. Thus, Vav3 is a novel TRAF6 interaction partner that functions in the activation of cooperative signaling between T6BSs and the IVVY motif in the RANK signaling complex.

Acetyl CoA Carboxylase 2 Is Dispensable for CD8+ T Cell Responses.

Differentiation of T cells is closely associated with dynamic changes in nutrient and energy metabolism. However, the extent to which specific metabolic pathways and molecular components are determinative of CD8+ T cell fate remains unclear. It has been previously established in various tissues that acetyl CoA carboxylase 2 (ACC2) regulates fatty acid oxidation (FAO) by inhibiting carnitine palmitoyltransferase 1 (CPT1), a rate-limiting enzyme of FAO in mitochondria. Here, we explore the cell-intrinsic role of ACC2 in T cell immunity in response to infections. We report here that ACC2 deficiency results in a marginal increase of cellular FAO in CD8+ T cells, but does not appear to influence antigen-specific effector and memory CD8+ T cell responses during infection with listeria or lymphocytic choriomeningitis virus. These results suggest that ACC2 is dispensable for CD8+ T cell responses.

Health Literacy and Health-Related Quality of Life Among a Population-Based Sample of Cancer Patients.

Health-related quality of life is an important outcome in cancer care. A few studies indicate that health literacy influences cancer patients' health-related quality of life, but additional investigation is needed. The authors examined the relation between health literacy and health-related quality of life among cancer patients. A cross-sectional survey was conducted with cancer patients in Wisconsin during 2006-2007. Data on sociodemographics, clinical characteristics, health-related quality of life, and health literacy were obtained from the state's cancer registry and a mailed questionnaire. Regression analyses were used to characterize the association between health-related quality of life and health literacy. The study sample included 1,841 adults, newly diagnosed with lung, breast, colorectal, or prostate cancer in 2004 (response rate = 68%). Health-related quality of life was measured with the Functional Assessment of Cancer Therapy-General. Adjusting for confounders, higher health literacy was associated with greater health-related quality of life (p < .0001). Controlling for covariates, we found significant differences between those in the highest and lowest health literacy categories (p < .0001) and in the physical (p < .0001), functional (p < .0001), emotional (p < .0001), and social (p = .0007) well-being subscales. These associations exceeded the minimally important difference threshold for overall health-related quality of life and functional well-being. Health literacy is positively and independently associated with health-related quality of life among cancer patients. These findings support adoption of health literacy best practices by cancer care systems.