Cellular Metabolism and Hypoxia Interfacing with Allergic Diseases.

Allergic diseases display significant heterogeneity in their pathogenesis. Understanding the influencing factors, pathogenesis and advancing new treatments for allergic diseases is becoming more and more vital as currently, prevalence continues to rise, and mechanisms of allergic diseases are not fully understood. The upregulation of the hypoxia response is linked to an elevated infiltration of activated inflammatory cells, accompanied by elevated metabolic requirements. An enhanced hypoxia response may potentially contribute to inflammation, remodelling, and the onset of allergic diseases. It has become increasingly clear that the process underlying immune and stromal cell activation during allergic sensitization require well-tuned and dynamic changes in cellular metabolism. The purpose of this review is to examine current perspectives regarding metabolic dysfunction in allergic diseases. In the last decade, new technological platforms such as 'omic' techniques have been applied, allowing for the identification of different biomarkers in multiple models ranging from altered lipid species content, increased nutrient transporters and altered serum amino acids in various allergic diseases. Better understanding, recognition and integration of these alterations would increase our knowledge of pathogenesis and potentially actuate a novel repertoire of targeted treatment approaches that regulate immune metabolic pathways.

α7 Nicotinic Receptor Activation Mitigates Herpes Simplex Virus Type 1 Infection in Microglia Cells.

Herpes simplex virus type 1 (HSV-1), a neurotropic DNA virus, establishes latency in neural tissues, with reactivation causing severe consequences like encephalitis. Emerging evidence links HSV-1 infection to chronic neuroinflammation and neurodegenerative diseases. Microglia, the central nervous system's (CNS) immune sentinels, express diverse receptors, including α7 nicotinic acetylcholine receptors (α7 nAChRs), critical for immune regulation. Recent studies suggest α7 nAChR activation protects against viral infections. Here, we show that α7 nAChR agonists, choline and PNU-282987, significantly inhibit HSV-1 replication in microglial BV2 cells. Notably, this inhibition is independent of the traditional ionotropic nAChR signaling pathway. mRNA profiling revealed that choline stimulates the expression of antiviral factors, IL-1ß and Nos2, and down-regulates the apoptosis genes and type A Lamins in BV2 cells. These findings suggest a novel mechanism by which microglial α7 nAChRs restrict viral infections by regulating innate immune responses.

Examining relationships between adverse childhood experiences and coping during the cost-of-living crisis using a national cross-sectional survey in Wales, UK.

OBJECTIVES: Adverse childhood experiences (ACEs) can affect individuals' resilience to stressors and their vulnerability to mental, physical and social harms. This study explored associations between ACEs, financial coping during the cost-of-living crisis and perceived impacts on health and well-being. DESIGN: National cross-sectional face-to-face survey. Recruitment used a random quota sample of households stratified by health region and deprivation quintile. SETTING: Households in Wales, UK. PARTICIPANTS: 1880 Welsh residents aged ≥18 years. MEASURES: Outcome variables were perceived inability to cope financially during the cost-of-living crisis; rising costs of living causing substantial distress and anxiety; and self-reported negative impact of rising costs of living on mental health, physical health, family relationships, local levels of antisocial behaviour and violence, and community support. Nine ACEs were measured retrospectively. Socioeconomic and demographic variables included low household income, economic inactivity, residential deprivation and activity limitation. RESULTS: The prevalence of all outcomes increased strongly with ACE count. Perceived inability to cope financially during the cost-of-living crisis increased from 14.0% with 0 ACEs to 51.5% with 4+ ACEs. Relationships with ACEs remained after controlling for socioeconomic and demographic factors. Those with 4+ ACEs (vs 0 ACEs) were over three times more likely to perceive they would be unable to cope financially and, correspondingly, almost three times more likely to report substantial distress and anxiety and over three times more likely to report negative impacts on mental health, physical health and family relationships. CONCLUSIONS: Socioeconomically deprived populations are recognised to be disproportionately impacted by rising costs of living. Our study identifies a history of ACEs as an additional vulnerability that can affect all socioeconomic groups. Definitions of vulnerability during crises and communications with services on who is most likely to be impacted should consider childhood adversity and history of trauma.

Diabetes and Hearing Impairment: Knowledge, Attitudes, and Practices Among Providers and Patients.

PURPOSE: The purpose of this study was to assess the knowledge, attitudes, and practices among providers and patients regarding hearing impairment and screening referrals in people with diabetes. METHODS: A cross-sectional survey design among health care providers and patients at an academic medical center in Oklahoma was used to gather knowledge, attitudes, and practices data. RESULTS: Only 25.6% of providers selected hearing impairment as a complication of diabetes, whereas 96.7% selected retinopathy, kidney dysfunction, and foot infection. Reported barriers to referring patients for hearing impairment screenings were being unfamiliar with recommended screening frequency (57.3%) and existence of higher priorities (35.4%). When asked to select parts of the body affected by diabetes, 21.0% of patients surveyed selected ears, 88.0% selected feet, and 85.0% selected eyes and kidneys. Fewer patients reported being told hearing impairment is a complication of diabetes compared to retinopathy (8.1% vs 85.9%). Additionally, 24.2% of patients reported having a hearing impairment screening, and 96.0% reported having a dilated eye exam. CONCLUSIONS: Most providers and patients at an academic medical center are unaware of the relationship between diabetes and hearing impairment. Providers reported there are several barriers that need to be overcome to refer patients to audiologists.

Trends and determinants of mental illness in humanitarian migrants resettled in Australia: Analysis of longitudinal data.

Given the frequent exposure of humanitarian migrants to traumatic or stressful circumstances, there exists a potential predisposition to mental illness. Our objective was to pinpoint the trends and determinants of mental illness among humanitarian migrants resettled in Australia. This study considered five waves of longitudinal data involving humanitarian migrants resettled in Australia. Post-traumatic stress disorder (PTSD) and psychological distress were assessed using PTSD-8 and Kessler-6 screening tools. Through a Generalised Linear Mixed model (GLMM), variables displaying a 95% CI that excluded the value of 1.0 for the odds ratio were identified as associated factors for both PTSD and elevated psychological distress. The selection of multivariable covariates was guided by causal loop diagrams and least absolute shrinkage and selection operators methods. At baseline, there were 2399 humanitarian migrants with 1881 retained and at the fifth yearly wave; the response rate was 78.4%. PTSD prevalence decreased from 33.3% (95% CI: 31.4-35.3) at baseline to 28.3% (95% CI: 26.2-30.5) at year 5. Elevated psychological distress persisted across all waves: 17.1% (95% CI: 15.5-18.6) at baseline and 17.1% (95% CI: 15.3-18.9) at year 5. Across the five waves, 34.0% of humanitarian migrants met screening criteria for mental illness, either PTSD or elevated psychological distress. In the multivariate model, factors associated with PTSD were loneliness (AOR 1.5, 95% CI: 1.3-1.8), discrimination (AOR 1.6: 1.2-2.1), temporary housing contract (AOR 3.7: 2.1-6.7), financial hardship (AOR 2.2:1.4-3.6) and chronic health conditions (AOR 1.3: 1.1-1.5), whereas the associated factors for elevated psychological distress were loneliness (AOR 1.8: 1.5-2.2), discrimination (AOR 1.7: 1.3-2.2) and short-term lease housing (AOR 1.6: 1.0-1.7). The prevalence, persistence and consequential burden of mental illness within this demographic underscore the urgent need for targeted social and healthcare policies. These policies should aim to mitigate modifiable risk factors, thereby alleviating the significant impact of mental health challenges on this population.

The carbon monoxide prodrug oCOm-21 increases Ca2+ sensitivity of the cardiac myofilament.

Patients undergoing cardiopulmonary bypass procedures require inotropic support to improve hemodynamic function and cardiac output. Current inotropes such as dobutamine, can promote arrhythmias, prompting a demand for improved inotropes with little effect on intracellular Ca2+ flux. Low-dose carbon monoxide (CO) induces inotropic effects in perfused hearts. Using the CO-releasing pro-drug, oCOm-21, we investigated if this inotropic effect results from an increase in myofilament Ca2+ sensitivity. Male Sprague Dawley rat left ventricular cardiomyocytes were permeabilized, and myofilament force was measured as a function of -log [Ca2+ ] (pCa) in the range of 9.0-4.5 under five conditions: vehicle, oCOm-21, the oCOm-21 control BP-21, and levosimendan, (9 cells/group). Ca2+ sensitivity was assessed by the Ca2+ concentration at which 50% of maximal force is produced (pCa50 ). oCOm-21, but not BP-21 significantly increased pCa50 compared to vehicle, respectively (pCa50 5.52 vs. 5.47 vs. 5.44; p < 0.05). No change in myofilament phosphorylation was seen after oCOm-21 treatment. Pretreatment of cardiomyocytes with the heme scavenger hemopexin, abolished the Ca2+ sensitizing effect of oCOm-21. These results support the hypothesis that oCOm-21-derived CO increases myofilament Ca2+ sensitivity through a heme-dependent mechanism but not by phosphorylation. Further analyses will confirm if this Ca2+ sensitizing effect occurs in an intact heart.

The genomics of adaptation to climate in European great tit (Parus major) populations.

The recognition that climate change is occurring at an unprecedented rate means that there is increased urgency in understanding how organisms can adapt to a changing environment. Wild great tit (Parus major) populations represent an attractive ecological model system to understand the genomics of climate adaptation. They are widely distributed across Eurasia and they have been documented to respond to climate change. We performed a Bayesian genome-environment analysis, by combining local climate data with single nucleotide polymorphisms genotype data from 20 European populations (broadly spanning the species' continental range). We found 36 genes putatively linked to adaptation to climate. Following an enrichment analysis of biological process Gene Ontology (GO) terms, we identified over-represented terms and pathways among the candidate genes. Because many different genes and GO terms are associated with climate variables, it seems likely that climate adaptation is polygenic and genetically complex. Our findings also suggest that geographical climate adaptation has been occurring since great tits left their Southern European refugia at the end of the last ice age. Finally, we show that substantial climate-associated genetic variation remains, which will be essential for adaptation to future changes.

Considerations from employed African-American and white prostate cancer survivors on prostate cancer treatment and survivorship: a qualitative analysis.

OBJECTIVE: To solicit information/suggestions from prostate cancer survivors to improve survivorship experiences specific to work/workability. DESIGN: The study employed a qualitative/phenomenological approach. Black/African-American and white prostate cancer survivors who: (1) had prostatectomy or radiation therapy 6-36 months prior, (2) were working for pay within 30 days before having treatment, and (3) expected to be working for pay 6 months later (n = 45) were eligible for this study. Survivors were engaged in 60-to-90-minute structured interviews. Content analysis was used to ascertain prominent themes. RESULTS: Participants had the following recommendations for survivors: ask about research on treatment options and side effects; speak with other survivors about cancer diagnosis; and inform family/friends and employers about needed accommodations. Considerations for family/friends emphasized the significance of instrumental (e.g. help finding information) and emotional support (e.g. encouragement). Employer/co-worker considerations most often related to work-related accommodations/support and avoiding stigmatization of the survivor. Considerations for healthcare providers commonly included the provision of unbiased, plain-language communication about treatment options and side effects. No major differences existed by race. CONCLUSIONS: Needs of employed PrCA survivors, regardless of their race or treatment type, are commonly related to their desire for informational, instrumental, and/or emotional support from family/friends, employers/co-workers, and healthcare providers. The requested supports are most often related to the side effects of prostate cancer treatment.

Consensus guideline for the diagnosis and management of pituitary adenomas in childhood and adolescence: Part 1, general recommendations.

Tumours of the anterior part of the pituitary gland represent just 1% of all childhood (aged <15 years) intracranial neoplasms, yet they can confer high morbidity and little evidence and guidance is in place for their management. Between 2014 and 2022, a multidisciplinary expert group systematically developed the first comprehensive clinical practice consensus guideline for children and young people under the age 19 years (hereafter referred to as CYP) presenting with a suspected pituitary adenoma to inform specialist care and improve health outcomes. Through robust literature searches and a Delphi consensus exercise with an international Delphi consensus panel of experts, the available scientific evidence and expert opinions were consolidated into 74 recommendations. Part 1 of this consensus guideline includes 17 pragmatic management recommendations related to clinical care, neuroimaging, visual assessment, histopathology, genetics, pituitary surgery and radiotherapy. While in many aspects the care for CYP is similar to that of adults, key differences exist, particularly in aetiology and presentation. CYP with suspected pituitary adenomas require careful clinical examination, appropriate hormonal work-up, dedicated pituitary imaging and visual assessment. Consideration should be given to the potential for syndromic disease and genetic assessment. Multidisciplinary discussion at both the local and national levels can be key for management. Surgery should be performed in specialist centres. The collection of outcome data on novel modalities of medical treatment, surgical intervention and radiotherapy is essential for optimal future treatment.

Consensus guideline for the diagnosis and management of pituitary adenomas in childhood and adolescence: Part 2, specific diseases.

Pituitary adenomas are rare in children and young people under the age of 19 (hereafter referred to as CYP) but they pose some different diagnostic and management challenges in this age group than in adults. These rare neoplasms can disrupt maturational, visual, intellectual and developmental processes and, in CYP, they tend to have more occult presentation, aggressive behaviour and are more likely to have a genetic basis than in adults. Through standardized AGREE II methodology, literature review and Delphi consensus, a multidisciplinary expert group developed 74 pragmatic management recommendations aimed at optimizing care for CYP in the first-ever comprehensive consensus guideline to cover the care of CYP with pituitary adenoma. Part 2 of this consensus guideline details 57 recommendations for paediatric patients with prolactinomas, Cushing disease, growth hormone excess causing gigantism and acromegaly, clinically non-functioning adenomas, and the rare TSHomas. Compared with adult patients with pituitary adenomas, we highlight that, in the CYP group, there is a greater proportion of functioning tumours, including macroprolactinomas, greater likelihood of underlying genetic disease, more corticotrophinomas in boys aged under 10 years than in girls and difficulty of peri-pubertal diagnosis of growth hormone excess. Collaboration with pituitary specialists caring for adult patients, as part of commissioned and centralized multidisciplinary teams, is key for optimizing management, transition and lifelong care and facilitates the collection of health-related quality of survival outcomes of novel medical, surgical and radiotherapeutic treatments, which are currently largely missing.

Culture of Safety and Preparedness: Benefits of Applying a Daily Mitigation Mindset in the Hospital Setting.

AIM: Utilizing the subjective experience of nurse executives who have supervised nurses during a major disaster in a hospital setting, this study aims to describe the subjective experience of nurse executives (NE) who have supervised nurses' responses to major disasters. This paper will focus on strategies to support nursing response to disasters, specifically to strengthen resiliency and the ability to maintain function despite the shock of a disaster, including those caused by climate change. METHODS: Semi-structured interviews were conducted with 11 hospital-based nurse executives who supervised nurses during some of the worst natural and human-made disasters in different regions of the United States. A phenomenological approach was used to analyze and describe emerging themes from the qualitative data. RESULTS: Three nurse executives demonstrated theme saturation for mitigation steps to augment traditional disaster readiness activities: (1) Assessment of human infrastructure: daily skills needed during disaster response; (2) Identification and study of failure points and metrics; (3) Strengthening human infrastructure: rectifying deficiencies; and (4) Monitoring metrics and making corrections during conventional periods. CONCLUSION: Mitigation steps may improve outcomes in hospital function during conventional times; therefore, these steps may improve resiliency and the ability to maintain functions during major disasters, including climate change.

Cross-Platform Comparison of Highly Sensitive Immunoassays for Inflammatory Markers in a COVID-19 Cohort.

A variety of commercial platforms are available for the simultaneous detection of multiple cytokines and associated proteins, often employing Ab pairs to capture and detect target proteins. In this study, we comprehensively evaluated the performance of three distinct platforms: the fluorescent bead-based Luminex assay, the proximity extension-based Olink assay, and a novel proximity ligation assay platform known as Alamar NULISAseq. These assessments were conducted on human serum samples from the National Institutes of Health IMPACC study, with a focus on three essential performance metrics: detectability, correlation, and differential expression. Our results reveal several key findings. First, the Alamar platform demonstrated the highest overall detectability, followed by Olink and then Luminex. Second, the correlation of protein measurements between the Alamar and Olink platforms tended to be stronger than the correlation of either of these platforms with Luminex. Third, we observed that detectability differences across the platforms often translated to differences in differential expression findings, although high detectability did not guarantee the ability to identify meaningful biological differences. Our study provides valuable insights into the comparative performance of these assays, enhancing our understanding of their strengths and limitations when assessing complex biological samples, as exemplified by the sera from this COVID-19 cohort.

Salivary Cotinine Levels of Hired Latino Youth Tobacco Workers in North Carolina.

BACKGROUND: Limited research has examined the health implications for youth working in United States tobacco production. Agricultural labor is hazardous, yet youth are legally permitted to be hired as farmworkers. Many youth farmworkers are members of the vulnerable Latino farmworker community. In North Carolina, youth work in many agricultural crops including tobacco. METHODS: A sample of 152 Latino youth farmworkers ages 12-20 years (M = 16.7, SD = 2.0) across 19 North Carolina counties completed a cross-sectional survey and provided saliva samples in 2019. Surveys detailed personal and work characteristics. Saliva samples were analyzed for salivary cotinine and reported in geometric means (ng/ml). Bivariate associations were used to delineate the relationship between personal and work characteristics with salivary cotinine levels. RESULTS: Cotinine levels ranged from 0.05 to 313.5 ng/ml. Older age and working in tobacco were significantly associated with higher salivary cotinine levels. For every one year increase in age, there was a 31% increase in mean salivary cotinine levels (b = 1.31; 95% CI = [1.15-1.50]; p < .0001). Youth tobacco workers' (n = 15) salivary cotinine levels were 890% higher than those not working in tobacco (n = 137) (13.26, 95% CI = [5.95-29.56] ng/ml compared to 1.34, 95% CI = [1.03-1.75] ng/ml (p < .0001)). CONCLUSIONS: Latino youth tobacco workers are exposed to nicotine through their work. This exposure presents serious risk of Green Tobacco Sickness (acute nicotine poisoning) and other health concerns given the growing evidence for risk of epigenetic changes negatively affecting long-term cognitive function. Policy is urgently needed to protect this vulnerable population of adolescent workers.

Alternative Mental Health Interventions for Hispanic Women With Breast Cancer: A State of the Science Review.

Introduction: Current disadvantages in accessing healthcare services, particularly mental health resources, result in increased psychological dysfunction among Hispanic women with advanced breast cancer. Little is known about using alternative nonpharmacological therapies for Hispanic women experiencing psychological distress secondary to a breast cancer diagnosis. This state-of-the-science paper synthesizes current culturally appropriate alternative therapies that effectively address depressive symptoms, anxiety, and psychological distress among Hispanic women with breast cancer (HWBC). Methods: The search criteria included published articles that used alternative interventions to address psychological needs among HWBC. Ten studies met the inclusion criteria. Results: Four alternative interventions were identified in the literature that significantly met the cultural mental health needs of HWBC. Mindfulness and technology use were the two interventions most studied in this review. Conclusion: Evidence indicates that alternative therapies for mental health improve overall quality of life. Further research to attenuate psychological distress is needed to meet mental health needs among HWBC. Innovative methods such as the use of technology and mindfulness as well as integrating personalized care are crucial to address the cultural needs of HWBC.

Disparities in care of older adults of color with cancer: A narrative review.

This review describes the barriers and challenges faced by older adults of color with cancer and highlights methods to improve their overall care. In the next decade, cancer incidence rates are expected to increase in the United States for people aged ≥65 years. A large proportion will be older adults of color who often have worse outcomes than older White patients. Many issues contribute to racial disparities in older adults, including biological factors and social determinants of health (SDOH) related to healthcare access, socioeconomic concerns, systemic racism, mistrust, and the neighborhood where a person lives. These disparities are exacerbated by age-related challenges often experienced by older adults, such as decreased functional status, impaired cognition, high rates of comorbidities and polypharmacy, poor nutrition, and limited social support. Additionally, underrepresentation of both patients of color and older adults in cancer clinical research results in a lack of adequate data to guide the management of these patients. Use of geriatric assessments (GA) can aid providers in uncovering age-related concerns and personalizing interventions for older patients. Research demonstrates the ability of GA-directed care to result in fewer treatment-related toxicities and improved quality of life, thus supporting the routine incorporation of validated GA into these patients' care. GA can be enhanced by including evaluation of SDOH, which can help healthcare providers understand and address the needs of older adults of color with cancer who face disparities related to their age and race.

Trivalent nanobody-based ligands mediate powerful activation of GPVI, CLEC-2, and PEAR1 in human platelets whereas FcγRIIA requires a tetravalent ligand.

BACKGROUND: Clustering of the receptors glycoprotein receptor VI (GPVI), C-type lectin-like receptor 2 (CLEC-2), low-affinity immunoglobulin γ Fc region receptor II-a (FcγRIIA), and platelet endothelial aggregation receptor 1 (PEAR1) leads to powerful activation of platelets through phosphorylation of tyrosine in their cytosolic tails and initiation of downstream signaling cascades. GPVI, CLEC-2, and FcγRIIA signal through YxxL motifs that activate Syk. PEAR1 signals through a YxxM motif that activates phosphoinositide 3-kinase. Current ligands for these receptors have an undefined valency and show significant batch variation and, for some, uncertain specificity. OBJECTIVES: We have raised nanobodies against each of these receptors and multimerized them to identify the minimum number of epitopes to achieve robust activation of human platelets. METHODS: Divalent and trivalent nanobodies were generated using a flexible glycine-serine linker. Tetravalent nanobodies utilize a mouse Fc domain (IgG2a, which does not bind to FcγRIIA) to dimerize the divalent nanobody. Ligand affinity measurements were determined by surface plasmon resonance. Platelet aggregation, adenosine triphosphate secretion, and protein phosphorylation were analyzed using standardized methods. RESULTS: Multimerization of the nanobodies led to a stepwise increase in affinity with divalent and higher-order nanobody oligomers having sub-nanomolar affinity. The trivalent nanobodies to GPVI, CLEC-2, and PEAR1 stimulated powerful and robust platelet aggregation, secretion, and protein phosphorylation at low nanomolar concentrations. A tetravalent nanobody was required to activate FcγRIIA with the concentration-response relationship showing a greater variability and reduced sensitivity compared with the other nanobody-based ligands, despite a sub-nanomolar binding affinity. CONCLUSION: The multivalent nanobodies represent a series of standardized, potent agonists for platelet glycoprotein receptors. They have applications as research tools and in clinical assays.

Detection of Neuroinflammation Induced by Typhoid Vaccine Using Quantitative Magnetization Transfer MR: A Randomized Crossover Study.

BACKGROUND: The role of neuroinflammation in psychiatric disorders is not well-elucidated. A noninvasive technique sensitive to low-level neuroinflammation may improve understanding of the pathophysiology of these conditions. PURPOSE: To test the ability of quantitative magnetization transfer (QMT) MR at 3 T for detection of low-level neuroinflammation induced by typhoid vaccine within a clinically reasonable scan time. STUDY TYPE: Randomized, crossover, placebo-controlled. SUBJECTS: Twenty healthy volunteers (10 males; median age 34 years). FIELD STRENGTH/SEQUENCE: Magnetization prepared rapid gradient-echo and MT-weighted 3D fast low-angle shot sequences at 3 T. ASSESSMENT: Participants were randomized to either vaccine or placebo first with imaging, then after a washout period received the converse with a second set of imaging. MT imaging, scan time, and blood-based inflammatory marker concentrations were assessed pre- and post-vaccine and placebo. Mood was assessed hourly using the Profile of Mood States questionnaire. QMT parameter maps, including the exchange rate from bound to free pool (kba) were generated using a two-pool model and then segmented into tissue type. STATISTICAL TESTS: Voxel-wise permutation-based analysis examined inflammatory-related alterations of QMT parameters. The threshold-free cluster enhancement method with family-wise error was used to correct voxel-wise results for multiple comparisons. Region of interest averages were fed into mixed models and Bonferroni corrected. Spearman correlations assessed the relationship between mood scores and QMT parameters. Results were considered significant if corrected P < 0.05. RESULTS: Scan time for the MT-weighted acquisition was approximately 11 minutes. Blood-based analysis showed higher IL-6 concentrations post-vaccine compared to post-placebo. Voxel-wise analysis found three clusters indicating an inflammatory-mediated increase in kba in cerebellar white matter. Cerebellar kba for white matter was negatively associated with vigor post-vaccine but not post-placebo. DATA CONCLUSION: This study suggested that QMT at 3 T may show some sensitivity to low-level neuroinflammation. Further studies are needed to assess the viability of QMT for use in inflammatory-based disorders. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 2.