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Background/objectives : The association between adverse childhood experiences (ACEs) and asthma severity among United States (US) adults with asthma has not been well documented. In addition, whether gender differences exist in this association has been underexplored. We aimed to examine the prevalence of asthma severity in the US adult population with asthma and investigate the association between ACEs and asthma severity by using data from non-institutionalized US adults with asthma. Methods : This cross-sectional study used data from the Adult 2019 and 2020 Behavioral Risk Factor Surveillance System (BRFSS) Asthma Call-Back Survey (ACBS), a survey of US adults aged 18 years or older in 31 US states and Puerto Rico. A total of 22934 adults with asthma participated in 2019 and 2020 ACBS. The 11 BRFSS ACE variables encompassing abuse and household dysfunction were used as ACE measures. ACE measures were summed up as cumulative ACE scores (continuous) and categorized (zero, one ACE, two ACEs, ≥ three ACEs). Asthma severity was categorized as intermittent or persistent. Weighted logistic regression models were used to assess associations of the cumulative ACE score, categorical ACE measures, and the 11 individual ACE responses with asthma severity controlling confounders. Gender differences were explored by stratifying by gender. Results: The prevalence of persistent asthma among US adults with asthma was 45.3%. The mean cumulative ACE score in adults with intermittent vs. persistent asthma was (2.43 vs. 2.70, p -value < 0.05). About 22% of adults with asthma had no ACEs, 19% had one ACE, 14% had two ACEs, and 45% had three or more ACEs. A one-unit increase in ACEs score was associated with a 5.4% increase in the odds of persistent asthma (adjusted odds ratio, aOR = 1.054 (95% confidence interval, CI = 1.01-1.10). Experiencing ≥ three ACEs compared to no ACEs was associated with 31% increased odds of persistent asthma (aOR = 1.31, 95% CI = 1.01-1.70). Individual ACE items significantly associated with persistent asthma include parent/adult ever touched you sexually (aOR = 1.33, 95% CI = 1.03-1.74), adult tried to make you touch them (aOR = 1.34, 95% CI = 1.01-1.79), any adult forced you to have sex (aOR = 1.44, 95% CI = 1.04-1.20), parental separation/divorce (aOR = 1.31, 95% CI = 1.05-1.63), and household alcohol abuse (aOR = 1.24, 95% CI = 1.01-1.53). In women, experiencing one ACE and ≥ three ACEs (compared to no ACEs) was associated with 51% and 60% increased odds of persistent asthma, respectively (aOR = 1.51, 95% CI = 1.02-2.23; aOR = 1.60, 95% CI = 1.12-2.27). No significant association was observed between ACEs and asthma severity in men; however, experiencing household physical violence (compared to no household physical violence) was associated with persistent asthma in men (aOR = 1.69, 95% CI = 1.18-2.42). Conclusions : In this cross-sectional study of US adults with asthma, exposure to ACEs was associated with higher odds of asthma overall and in women. These findings highlight the importance of preventive strategies and early interventions to reduce ACEs, potentially mitigating asthma's severity in adulthood.

We investigated the association between discrimination, neighborhood unsafety, and household food insecurity (FI) among Nigerian adults, as well as the gender-specific differences in these associations. Our analysis utilized data from the 2021 Multiple Indicator Cluster Survey (MICS), comprising 56,146 Nigerian adults aged 15-49 (17,346 males and 38,800 females). For bivariate analysis, we employed the Rao-Scott chi-square test to examine the relationship between predictors (discrimination, neighborhood unsafety, and a composite variable of both) and the outcome variable (FI). Food insecurity was assessed using both a dichotomous measure (food insecure vs. food secure) and a multinomial variable (food secure, mild FI, moderate FI, and severe FI). To model the association between predictors and FI while controlling for potential confounding factors, we utilized weighted binary and multinomial logistic regression. Among Nigerian adults, the prevalence of having ever experienced FI was 86.1%, with the prevalence of mild FI, moderate FI, and severe FI being 11.5%, 30.1%, and 44.5%, respectively. In the binary model, experiencing discrimination (OR = 1.36, 95% CI = 1.19-1.55), living in an unsafe neighborhood (OR = 1.33, 95% CI = 1.14-1.54), and facing both discrimination and unsafe neighborhood conditions (OR = 1.97, 95% CI = 1.57-2.48) were significantly associated with FI. In the multinomial model, discrimination, neighborhood unsafety, and experiencing both remained associated with moderate and severe FI. In the gender-specific models, discrimination and neighborhood unsafety were found to be significantly associated with FI in women but not in men. This study underscores the importance of implementing policies and programs that address the underlying causes of food insecurity, with specific attention to discrimination and neighborhood safety concerns, particularly for Nigerian women.

This study examined the association between caregivers' self-rated general health, poor physical/mental health days, disease morbidity and asthma control in children from the United States with current asthma. The data analyzed for this study were obtained from 7522 children aged 0-17 years who participated in the 2012-2014, 2015-2017, 2018, and 2019 cycles of the Behavioral Risk Factor Surveillance System Asthma Call-back Survey (ACBS). We employed univariate analysis to describe the study population and weighted binary logistic regression to examine the association of predictors with asthma control. Approximately 50% of the children had uncontrolled asthma. The results show that caregivers who reported fair general health had a 61% higher likelihood of reporting uncontrolled asthma in their children compared to those who reported good/very good/excellent health (adjusted odds ratio [aOR] = 1.61; 95% confidence interval [CI], 1.14-2.26). Poor caregiver general health did not reach statistical significance in predicting uncontrolled asthma (aOR = 1.05, 95% CI, 0.62-1.75). Furthermore, having 1 to 14 poor physical/mental health days ([aOR] = 1.70; 95% CI, 1.28-2.227) and ≥15 poor physical/mental health days (aOR = 1.82, 95% CI, 1.31-2.53) was predictive of uncontrolled asthma in children. Additionally, endorsing one reported disease (aOR = 1.49, 95% CI, 1.15-1.93) and ≥2 diseases (aOR = 1.38, 95% CI, 1.08-1.78) was associated with uncontrolled child asthma. These findings underscore the association between caregivers' self-reported general health, poor mental/physical health days, disease morbidity and uncontrolled asthma among children from the U.S. with asthma. Pediatricians and child health practitioners should recall the importance of this relationship. To facilitate the identification of caregivers at risk and provide more comprehensive and effective care for children with asthma, healthcare practitioners should utilize every child asthma care encounter to inquire about the overall health of caregivers.

Complementary and Alternative Medicines/Therapies (CAM) are commonly used by US asthma adults, yet little is known about recent trends in their use. Our aim was to report trends in CAM use among US adults with current asthma. We conducted a serial cross-sectional study using nationally representative data from the BRFSS Asthma Call-Back Survey (ACBS) collected between 2008 and 2019 (sample size per cycle, 8222 to 14,227). The exposure was calendar time, as represented by ACBS cycle, while the main outcomes were use of at least one CAM and eleven alternative therapies. We analyzed CAM use overall and by population subgroups based on age, gender, race/ethnicity, income, and daytime and night-time asthma symptoms. Our findings show that there was an increase in the use of at least one CAM from 41.3% in 2008 to 47.9% in 2019 ( p -trend < 0.001) and an upward trend in the use of herbs, aromatherapy, yoga, breathing exercises, homeopathy, and naturopathy ( p -trend < 0.05). However, the use of vitamins, acupuncture, acupressure, reflexology, and other CAM therapies remained stable ( p -trend > 0.05). These trends varied according to population characteristics (age, sex, race, income) and asthma symptoms. In conclusion, our study suggests that CAM use among US adults with current asthma is either increasing or stable, and further studies are needed to explore the factors influencing these trends.

Objectives To explore the association between depression, poor mental health status, and asthma control patterns among US adults using a latent class analysis (LCA) approach. Methods We used data from 10,337 adults aged 18 years and above from the 2016 Behavioral Risk Factor Surveillance System (BRFSS) Asthma Call-back Survey. Data-reductive LCA was used to derive asthma control patterns in the population using class variables indicative of asthma control. Besides univariate analysis, adjusted and unadjusted logistic regression models were used to examine the association of depression and poor mental health on the derived asthma control patterns.  Results About 27.8% of adults aged <55 reported depression, while 27.3% aged ≥55 years were depressed. The latent class prevalence of asthma control patterns was 42.8%, 31.1%, and 26.1%, corresponding to good, fair, and poor asthma control patterns, respectively. In adults aged <55 years, odds of depression (OR=1.52, 95% CI=1.27-1.82) and poor mental health (OR=1.58, 95% CI=1.27-1.96) were higher in the poor asthma control group compared to the good asthma control group. Odds for depression (OR=1.28, 95% CI=1.06-1.53) were also higher in the moderate asthma control group compared to the good asthma control group. Among those aged ≥55 years, depression odds (OR=1.57, 95% CI=1.31-1.87) were higher in only the poor asthma control group. Conclusions These findings may have public health implications. Detecting, screening, and treating depression and mental health disorders may help improve asthma control in people with asthma., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Ogbu et al.)

Breast cancer, as the most prevalent cancer in women, is responsible for more than 15% of new cancer cases and about 6.9% of all cancer-related death in the US. A major cause of therapeutic failure in breast cancer is the development of resistance to chemotherapy, especially for triple-negative breast cancer (TNBC). Therefore, how to overcome chemoresistance is the major challenge to improve the life expectancy of breast cancer patients. Our studies demonstrate that TNBC cells surviving the chronic treatment of chemotherapeutic drugs show significantly higher expression of the dual serine/threonine and tyrosine protein kinase (DSTYK) than non-treated parental cells. In our in vitro cellular models, DSTYK knockout via the CRISPR/Cas9-mediated technique results in apoptotic cell death of chemoresistant cells upon drug treatment. Moreover, DSTYK knockout promotes chemotherapeutic drug-induced tumor cell death in an orthotopic mouse model. These findings suggest that DSTYK exerts an important and previously unknown role in promoting chemoresistance. Our studies provide fundamental insight into the role of DSTYK in chemoresistance in TNBC cells and lay the foundation for the development of new strategies targeting DSTYK for improving TNBC therapy.

Objectives: We examined the association between exclusive breastfeeding, early introduction of feeding formula, early weaning, and asthma in children aged six months to five years in a sample of non-institutionalized US children using a propensity score approach., Methods: Our study used data from the National Survey of Children's Health (2012-2018) of 3,820 children with physician-diagnosed asthma aged 6 months to 5 years. Propensity score matching (PSM) was applied to control selection bias with age, sex, race, birth weight, Federal Poverty Level, parent's education, and parent smoking history used as covariates in PSM. The total number in the matched sample was 6,904 (3,452 non-asthmatics; 3,452 asthmatics). Matched and unmatched samples were analysed using the χ 2 test and multiple logistic regression., Results: Exclusive breastfeeding was protective against asthma in the pre-matching (AOR 0.72; 95% CI: 0.54-0.97; p = 0.03) and post-matching (AOR 0.66; 95% CI: 0.55-0.81; p < 0.001) samples. Formula feeding before 6 months was associated with asthma in unmatched (AOR 1.38; 95% CI: 1.15-1.66; p < 0.001) and matched (AOR 1.31; 95% CI: 1.16-1.47; p < 0.001) sample. Early weaning before 6 months was associated with asthma in unmatched (AOR 1.62; 95% CI: 1.35-1.54; p < 0.001) and matched sample (AOR 1.37; 95% CI: 1.23-1.54; p < 0.001)., Conclusion: Public health systems should continue to recommend the implementation of the World Health Organization exclusive breastfeeding guideline in developed countries. Asthma interventions in children under two years should continue to emphasize exclusive breastfeeding to reduce the incidence of infant asthma.

The hallmark of HIV/AIDS is a gradual depletion of CD4 T cells. Despite effective control by antiretroviral therapy (ART), a significant subgroup of people living with HIV (PLHIV) fails to achieve complete immune reconstitution, deemed as immune non-responders (INRs). The mechanisms underlying incomplete CD4 T cell recovery in PLHIV remain unclear. In this study, CD4 T cells from PLHIV were phenotyped and functionally characterized, focusing on their mitochondrial functions. The results show that while total CD4 T cells are diminished, cycling cells are expanded in PLHIV, especially in INRs. HIV-INR CD4 T cells are more activated, displaying exhausted and senescent phenotypes with compromised mitochondrial functions. Transcriptional profiling and flow cytometry analysis showed remarkable repression of mitochondrial transcription factor A (mtTFA) in CD4 T cells from PLHIV, leading to abnormal mitochondrial and T cell homeostasis. These results demonstrate a sequential cellular paradigm of T cell over-activation, proliferation, exhaustion, senescence, apoptosis, and depletion, which correlates with compromised mitochondrial functions. Therefore, reconstituting the mtTFA pathway may provide an adjunctive immunological approach to revitalizing CD4 T cells in ART-treated PLHIV, especially in INRs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhao, Schank, Wang, Li, Nguyen, Dang, Cao, Khanal, Nguyen, Thakuri, Ogbu, Lu, Wu, Morrison, Gazzar, Liu, Zhang, Ning, Moorman and Yao.)

Introduction Although studies have examined the association between childhood asthma and parental smoking and secondhand smoke, little research has explored the moderating role of birth weight and prematurity (BWP) status on this association. We examined the association between secondhand smoke exposure, asthma, and asthma severity in children aged six to 17 as well as the modifying effect of BWP on parental smoking and asthma. Methods We used data from 36,954 children from the National Survey of Children's Health 2017-2018. In addition to univariate analysis, adjusted and unadjusted logistic regression models were used to estimate the effect of secondhand smoke on asthma. The interaction term between parental smoking and BWP was tested. Multinomial regression was used to evaluate the association between secondhand smoke on asthma severity. Results About 15.1 % of children had asthma and 15.4% of parents reported smoking. Odds of asthma were higher in children living with an outdoor (AOR, 1.27; 95% CI, 1.06-1.52) and indoor (AOR, 1.46; 95% CI, 1.01-2.11) smoker in the adjusted model. The association of parental smoking with asthma differed by birth weight and premature status. Normal weight children who are premature had the highest odds ratio (AOR, 2.15; 95% CI, 1.2-3.86). In the multinomial model, low birth weight and premature children had higher odds of mild (AOR, 1.90; 95% CI, 1.40-2.56) and moderate/severe (AOR, 1.81; 95% CI, 1.16-2.84) asthma compared to the no asthma group. Conclusion The Association of parental smoking on asthma was modified by BWP. Focused asthma interventions in children should inquire about BWP status as well as parental smoking and household smoke exposure to reduce asthma morbidity and mortality., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Ogbu et al.)

Disabled-2 (Dab2/DOC-2) is a mitogen-responsive adaptor protein required for multiple cellular functions. It is involved in many signaling pathways and plays an integral role in vesicular uptake and trafficking, modulating immune function, protein-protein interactions, cellular homeostasis and differentiation, oncogenesis, and inflammatory processes in organ systems. It contains domains for binding to NPXY motif-containing and SH3 domain-containing adapter proteins, phosphoinositides, glycoprotein 100 (gp100, or megalin), integrins, clathrin, and myosin VI. However, the molecular mechanism(s) of Dab2's biological function still remain to be elucidated. In this review, we provide an extensive up-to-date understanding of the function of Dab2 and its regulation in cardiovascular diseases, immune disorders, tumorigenesis, and central nervous system disorders., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Telomere erosion and mitochondrial dysfunction are prominent features of aging cells with progressive declines of cellular functions. Whether telomere injury induces mitochondrial dysfunction in human T lymphocytes, the major component of adaptive host immunity against infection and malignancy, remains unclear. We have recently shown that disruption of telomere integrity by KML001, a telomere-targeting drug, induces T cell senescence and apoptosis via the telomeric DNA damage response (DDR). In this study, we used KML001 to further investigate the role and mechanism of telomere injury in mitochondrial dysregulation in aging T cells. We demonstrate that targeting telomeres by KML001 induces mitochondrial dysfunction, as evidenced by increased mitochondrial swelling and decreased mitochondrial membrane potential, oxidative phosphorylation, mitochondrial DNA content, mitochondrial respiration, oxygen consumption, glycolysis, and ATP energy production. Mechanistically, we found that the KML001-induced telomeric DDR activated p53 signaling, which in turn repressed the expression of peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) and nuclear respiratory factor 1 (NRF-1), leading to T cell mitochondrial dysfunction. These results, forging a direct link between telomeric and mitochondrial biology, shed new light on the human T cell aging network, and demonstrate that the p53-PGC-1α-NRF-1 axis contributes to mitochondrial dysfunction in the setting of telomeric DDR. This study suggests that targeting this axis may offer an alternative, novel approach to prevent telomere damage-mediated mitochondrial and T cell dysfunctions to combat a wide range of immune aging-associated human diseases.

T cells play a critical role in controlling viral infection; however, the mechanisms regulating their responses remain incompletely understood. Here, we investigated the role of topoisomerase IIA (Top2α, an enzyme that is essential in resolving entangled DNA strands during replication) in telomeric DNA damage and T cell dysfunction during viral infection. We demonstrated that T cells derived from patients with chronic viral (HBV, HCV, and HIV) infection had lower Top2α protein levels and enzymatic activity, along with an accumulation of the Top2α cleavage complex (Top2cc) in genomic DNA. In addition, T cells from virally infected subjects with lower Top2α levels were vulnerable to Top2α inhibitor-induced cell apoptosis, indicating an important role for Top2α in preventing DNA topological disruption and cell death. Using Top2α inhibitor (ICRF193 or Etoposide)-treated primary T cells as a model, we demonstrated that disrupting the DNA topology promoted DNA damage and T cell apoptosis via Top2cc accumulation that is associated with protein-DNA breaks (PDB) at genomic DNA. Disruption of the DNA topology was likely due to diminished expression of tyrosyl-DNA phosphodiesterase 2 (TDP2), which was inhibited in T cells in vitro by Top2α inhibitor and in vivo by chronic viral infection. These results suggest that immune-evasive viruses (HBV, HCV, and HIV) can disrupt T cell DNA topology as a mechanism of dysregulating host immunity and establishing chronic infection. Thus, restoring the DNA topologic machinery may serve as a novel strategy to protect T cells from unwanted DNA damage and to maintain immune competence.

HIV infection leads to a phenomenon of inflammaging, in which chronic inflammation induces an immune aged phenotype, even in individuals on combined antiretroviral therapy (cART) with undetectable viremia. In this study, we investigated T cell homeostasis and telomeric DNA damage and repair machineries in cART-controlled HIV patients at risk for inflammaging. We found a significant depletion of CD4 T cells, which was inversely correlated with the cell apoptosis in virus-suppressed HIV subjects compared to age-matched healthy subjects (HS). In addition, HIV CD4 T cells were prone to DNA damage that extended to chromosome ends-telomeres, leading to accelerated telomere erosion-a hallmark of cell senescence. Mechanistically, the DNA double-strand break (DSB) sensors MRE11, RAD50, and NBS1 (MRN complex) remained intact, but both expression and activity of the DNA damage checkpoint kinase ataxia-telangiectasia mutated (ATM) and its downstream checkpoint kinase 2 (CHK2) were significantly suppressed in HIV CD4 T cells. Consistently, ATM/CHK2 activation, DNA repair, and cellular functions were also impaired in healthy CD4 T cells following ATM knockdown or exposure to the ATM inhibitor KU60019 in vitro , recapitulating the biological effects observed in HIV-derived CD4 T cells in vivo . Importantly, ectopic expression of ATM was essential and sufficient to reduce the DNA damage, apoptosis, and cellular dysfunction in HIV-derived CD4 T cells. These results demonstrate that failure of DSB repair due to ATM deficiency leads to increased DNA damage and renders CD4 T cells prone to senescence and apoptotic death, contributing to CD4 T cell depletion or dysfunction in cART-controlled, latent HIV infection., (Copyright © 2019 Zhao, Nguyen, Nguyen, Dang, Cao, Khanal, Schank, Thakuri, Ogbu, Morrison, Wu, Li, Zou, El Gazzar, Ning, Wang, Moorman and Yao.)