Background Concerns about stigmatization and barriers to access to reproductive health among Asian American women have been raised. Methods To explore the characteristics of associated factors of non-natural sex ratio at birth (SRB), we analyzed the National Vital Statistics System Natality Data from 2016 to 2021 (N=1,668,875). We defined Asian Americans as people with ancestors from Asia, including Asian Indian, Chinese, Filipino, Vietnamese, Korean, and Japanese. Additionally, we stratified data according to the Asian-American subgroup. Per each group, we estimated changes in the male-to-female SRB over time. We performed logistic regression for male birth, adjusting for birth order and sociodemographic factors. Results Most Asian-American subgroups demonstrated SRBs within natural ranges for the first and second child, whereas, from the third child, SRBs skewed and differed by Asian-Americans. For respective Asian countries with skewed SRBs, Asian-American subgroups had lower SRBs than those. After adjustments, the third child had 8.0% greater odds (for male birth in the ratio scale) than the first in Asian Indians (95% CI 5.7, 10.4) and 6.9% greater odds in Chinese (95% CI 4.4, 9.5). Foreign-born mothers had 3.6% greater odds than U.S.-borns in Asian Indians (95% CI 2.0, 5.2) and 5.2% greater odds in Chinese (95% CI 3.5-6.9). Among the Filipinos, mothers with high school degrees had 2.2% lower odds than mothers with college degrees (95% CI 0.2, 4.1), while Japanese mothers with lower education categories had greater odds. Unmarried Asian Indians had 2.9% decreased odds than married (95% CI 0.0, 5.7), and unmarried Koreans showed 5.6% increased odds (95% CI 0.6, 10.9). Discussion We found differential associations of SRB with sociodemographic factors and birth order by subgroup. Conclusion Future demographic analyses of SRBs must disaggregate Asian populations into subgroups. Policy actions need to consider the specific backgrounds of different Asian-American subgroups while empowering women in all Asian-American communities.

Background

Spirometric Z-scores from the Global Lung Initiative (GLI) rigorously account for age-related changes in lung function and are thus age-appropriate when establishing spirometric impairments, including a restrictive pattern and air-flow obstruction. However, GLI-defined spirometric impairments have not yet been evaluated regarding associations with static lung volumes (total lung capacity [TLC], functional residual capacity [FRC], and residual volume [RV]) and gas exchange (diffusing capacity).

Methods

We performed a retrospective review of pulmonary function tests in subjects ≥40 y old (mean age 64.6 y), including pre-bronchodilator measures for: spirometry (n = 2,586), static lung volumes by helium dilution with inspiratory capacity maneuver (n = 2,586), and hemoglobin-adjusted single-breath diffusing capacity (n = 2,508). Using multivariable linear regression, adjusted least-squares means (adj_LSMeans) were calculated for TLC, FRC, RV, and hemoglobin-adjusted single-breath diffusing capacity. The adj_LSMeans were expressed with and without height-cubed standardization and stratified by GLI-defined spirometry, including normal (n = 1,251), restrictive pattern (n = 663), and air-flow obstruction (mild, [n = 128]; moderate, [n = 150]; and severe, [n = 394]).

Results

Relative to normal spirometry, restrictive-pattern had lower adj_LSMeans for TLC, FRC, RV, and hemoglobin-adjusted single-breath diffusing capacity (P ≤ .001). Conversely, relative to normal spirometry, mild, moderate, and severe air-flow obstruction had higher adj_LSMeans for FRC and RV (P < .001). However, only mild and moderate air-flow obstruction had higher adj_LSMeans for TLC (P < .001), while only moderate and severe air-flow obstruction had higher adj_LSMeans for RV/TLC (P < .001) and lower adj_LSMeans for hemoglobin-adjusted single-breath diffusing capacity (P < .001). Notably, TLC (calculated as FRC + inspiratory capacity) was not increased in severe air-flow obstruction (P ≥ .11) because inspiratory capacity decreased with increasing air-flow obstruction (P < .001), thus opposing the increased FRC (P < .001). Finally, P values were similar whether adj_LSMeans were height-cubed standardized.

Conclusions

A GLI-defined spirometric restrictive pattern is strongly associated with a restrictive ventilatory defect (decreased TLC, FRC, and RV), while GLI-defined spirometric air-flow obstruction is strongly associated with hyperinflation (increased FRC) and air trapping (increased RV and RV/TLC). Both spirometric impairments were strongly associated with impaired gas exchange (decreased hemoglobin-adjusted single-breath diffusing capacity).

We previously reported that the canonical innate immune receptor toll-like receptor 4 (TLR4) is critical in maintaining lung integrity. However, the molecular mechanisms via which TLR4 mediates its effect remained unclear. In the present study, we identified distinct contributions of lung endothelial cells (Ec) and epithelial cells TLR4 to pulmonary homeostasis using genetic-specific, lung- and cell-targeted in vivo methods. Emphysema was significantly prevented via the reconstituting of human TLR4 expression in the lung Ec of TLR4-/- mice. Lung Ec-silencing of TLR4 in wild-type mice induced emphysema, highlighting the specific and distinct role of Ec-expressed TLR4 in maintaining lung integrity. We also identified a previously unrecognized role of TLR4 in preventing expression of p16^INK4a , a senescence-associated gene. Lung Ec-p16^INK4a -silencing prevented TLR4-/- induced emphysema, revealing a new functional role for p16^INK4a in lungs. TLR4 suppressed endogenous p16^INK4a expression via HDAC2-mediated deacetylation of histone H4. These findings suggest a novel role for TLR4 in maintaining of lung homeostasis via epigenetic regulation of senescence-related gene expression.

Background

The association between HIV and emphysema remains incompletely understood. We sought to determine whether HIV is an independent risk factor for emphysema severity and whether markers of HIV severity and systemic biomarkers of inflammation (IL-6), altered coagulation (D-dimer), and immune activation (soluble CD14) are associated with emphysema.

Methods

We performed a cross-sectional analysis of 114 participants with HIV infection and 89 participants without HIV infection in the Examinations of HIV-Associated Lung Emphysema (EXHALE) study. Participants underwent chest CT imaging with blinded semiquantitative interpretation of emphysema severity, distribution, and type. We generated multivariable logistic regression models to determine the risk of HIV for radiographic emphysema, defined as > 10% lung involvement. Similar analyses examined associations of plasma biomarkers, HIV RNA, and recent and nadir CD4 cell counts with emphysema among participants with HIV infection.

Results

Participants with HIV infection had greater radiographic emphysema severity with increased lower lung zone and diffuse involvement. HIV was associated with significantly increased risk for > 10% emphysema in analyses adjusted for cigarette smoking pack-years (OR, 2.24; 95% CI, 1.12-4.48). In multivariable analyses restricted to participants with HIV infection, nadir CD4 < 200 cells/μL (OR, 2.98; 95% CI, 1.14-7.81), and high soluble CD14 level (upper 25th percentile) (OR, 2.55; 95% CI, 1.04-6.22) were associated with increased risk of > 10% emphysema. IL-6 and D-dimer were not associated with emphysema in HIV.

Conclusions

HIV is an independent risk factor for radiographic emphysema. Emphysema severity was significantly greater among participants with HIV infection. Among those with HIV, nadir CD4 < 200 cells/μL and elevated soluble CD14 level were associated with emphysema, highlighting potential mechanisms linking HIV with emphysema.

GWAS have repeatedly mapped susceptibility loci for emphysema to genes that modify hedgehog signaling, but the functional relevance of hedgehog signaling to this morbid disease remains unclear. In the current study, we identified a broad population of mesenchymal cells in the adult murine lung receptive to hedgehog signaling, characterized by higher activation of hedgehog surrounding the proximal airway relative to the distal alveoli. Single-cell RNA-sequencing showed that the hedgehog-receptive mesenchyme is composed of mostly fibroblasts with distinct proximal and distal subsets with discrete identities. Ectopic hedgehog activation in the distal fibroblasts promoted expression of proximal fibroblast markers and loss of distal alveoli and airspace enlargement of over 20% compared with controls. We found that hedgehog suppressed mesenchymal-derived mitogens enriched in distal fibroblasts that regulate alveolar stem cell regeneration and airspace size. Finally, single-cell analysis of the human lung mesenchyme showed that segregated proximal-distal identity with preferential hedgehog activation in the proximal fibroblasts was conserved between mice and humans. In conclusion, we showed that differential hedgehog activation segregates mesenchymal identities of distinct fibroblast subsets and that disruption of fibroblast identity can alter the alveolar stem cell niche, leading to emphysematous changes in the murine lung.