Omega-3 Fatty Acids and Chronic Lung Diseases: A Narrative Review of Impacts from Womb to Tomb.

The lungs are a mucosal organ constantly exposed to potentially harmful compounds and pathogens. Beyond their role in gas exchange, they must perform a well-orchestrated protective response against foreign invaders. The lungs identify these foreign compounds, respond to them by eliciting an inflammatory response, and restore tissue homeostasis after inflammation to ensure the lungs continue to function. In addition, lung function can be affected by genetics, environmental exposures, and age, leading to pulmonary diseases that infringe on quality of life. Recent studies indicate that diet can influence pulmonary health including the incidence and/or severity of lung diseases. Specifically, long-chain omega-3 polyunsaturated fatty acids (n-3 PUFAs) have gained attention because of their potential to reduce inflammation and promote resolution of inflammation. Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are two potentially beneficial n-3 PUFAs primarily acquired through dietary intake. Here we review current literature examining the role of n-3 PUFAs and the biological mechanisms by which these fatty acids alter the incidence and pathologies of chronic lung diseases including asthma, chronic obstructive pulmonary disease (COPD), and Interstitial Lung Disease (ILD). We also highlight the role of n-3 PUFAs in vulnerable populations such as pre/post-natal children, those with obesity, and the elderly. Lastly, we review the impact of n-3 PUFA intake and supplementation to evaluate if increasing consumption can mitigate mechanisms driving chronic lung diseases.

Asthma and coronavirus disease 2019-related outcomes in hospitalized patients: A single-center experience.

BACKGROUND: Several chronic conditions have been associated with a higher risk of severe coronavirus disease 2019 (COVID-19), including asthma. However, there are conflicting conclusions regarding risk of severe disease in this population. OBJECTIVE: To understand the impact of asthma on COVID-19 outcomes in a cohort of hospitalized patients and whether there is any association between asthma severity and worse outcomes. METHODS: We identified hospitalized patients with COVID-19 with confirmatory polymerase chain reaction testing with (n = 183) and without asthma (n = 1319) using International Classification of Diseases, Tenth Revision, codes between March 1 and December 30, 2020. We determined asthma maintenance medications, pulmonary function tests, highest historical absolute eosinophil count, and immunoglobulin E. Primary outcomes included death, mechanical ventilation, intensive care unit (ICU) admission, and ICU and hospital length of stay. Analysis was adjusted for demographics, comorbidities, smoking status, and timing of illness in the pandemic. RESULTS: In unadjusted analyses, we found no difference in our primary outcomes between patients with asthma and patients without asthma. However, in adjusted analyses, patients with asthma were more likely to have mechanical ventilation (odds ratio, 1.58; 95% confidence interval [CI], 1.02-2.44; P = .04), ICU admission (odds ratio, 1.58; 95% CI, 1.09-2.29; P = .02), longer hospital length of stay (risk ratio, 1.30; 95% CI, 1.09-1.55; P < .003), and higher mortality (hazard ratio, 1.53; 95% CI, 1.01-2.33; P = .04) compared with the non-asthma cohort. Inhaled corticosteroid use and eosinophilic phenotype were not associated with considerabledifferences. Interestingly, patients with moderate asthma had worse outcomes whereas patients with severe asthma did not. CONCLUSION: Asthma was associated with severe COVID-19 after controlling for other factors.

Tumor mutational burden assessed by targeted NGS predicts clinical benefit from immune checkpoint inhibitors in non-small cell lung cancer.

In non-small cell lung cancer (NSCLC), immune checkpoint inhibitors (ICIs) significantly improve overall survival (OS). Tumor mutational burden (TMB) has emerged as a predictive biomarker for patients treated with ICIs. Here, we evaluated the predictive power of TMB measured by the Oncomine™ Tumor Mutational Load targeted sequencing assay in 76 NSCLC patients treated with ICIs. TMB was assessed retrospectively in 76 NSCLC patients receiving ICI therapy. Clinical data (RECIST 1.1) were collected and patients were classified as having either durable clinical benefit (DCB) or no durable benefit (NDB). Additionally, genetic alterations and PD-L1 expression were assessed and compared with TMB and response rate. TMB was significantly higher in patients with DCB than in patients with NDB (median TMB = 8.5 versus 6.0 mutations/Mb, Mann-Whitney p = 0.0244). 64% of patients with high TMB (cut-off = third tertile, TMB ≥ 9) were responders (DCB) compared to 33% and 29% of patients with intermediate and low TMB, respectively (cut-off = second and first tertile, TMB = 5-9 and TMB ≤ 4, respectively). TMB-high patients showed significantly longer progression-free survival (PFS) and OS (log-rank test p = 0.0014 for PFS and 0.0197 for OS). While identifying different subgroups of patients, combining PD-L1 expression and TMB increased the predictive power (from AUC 0.63 to AUC 0.65). Our results show that the TML panel is an effective tool to stratify patients for ICI treatment. A combination of biomarkers might maximize the predictive precision for patient stratification. Our study supports TMB evaluation through targeted NGS in NSCLC patient samples as a tool to predict response to ICI therapy. We offer recommendations for a reliable and cost-effective assessment of TMB in a routine diagnostic setting. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Perceptions of firearms in a cohort of women exposed to intimate partner violence (IPV) in Central Pennsylvania.

BACKGROUND: Almost one-half of U.S. women will experience intimate partner violence (IPV), defined as physical, sexual, or psychological harm by a current or former partner. IPV is associated with an increased risk of homicide, with firearms as the most commonly used weapon. We designed this study to better understand the correlation of interpersonal trauma exposures and demographic factors on firearm perceptions among a cohort of IPV-exposed women. METHODS: Two hundred sixty-seven women in central Pennsylvania with exposure to IPV were surveyed about perceptions of gun access, safety, and gun presence in the home. Trauma variables included IPV type, IPV recency, unwanted sexual exposure, and adverse childhood experiences (ACEs). Multivariable analyses examined three questions examining firearm perceptions controlling for trauma exposures and demographics. RESULTS: Ease of firearm acquisition: Women who were older (mean 44.92 years +/- SD 12.05), compared to women who were younger (40.91 +/- SD 11.81 years) were more likely to describe it as easy or very easy to acquire a gun (aOR 1.05, 95%CI 1.004, 1.10). Perceived safety in the proximity of a gun: Women with the highest ACE score were less likely to feel safe with a gun nearby (aOR 0.31, 95%CI 0.14, 0.67). Odds of guns in the home: Women who were divorced or separated (aOR 0.22, 95%CI 0.09, 0.54), women were widowed or single (aOR0.23, 95%CI 0.08, 0.67), and women who were partnered (aOR 0.45 95%CI 0.20, 0.97) had lower odds of having a gun in the home, compared to married women. There was no significant effect of the trauma variables on the odds of having a gun at home. CONCLUSIONS: Women with more severe childhood trauma felt less safe around firearms, but trauma exposures did not predict the perception of gun prevalence in the local community or gun ownership. Instead, demographic factors of marriage predicted presence of a gun in the home.

Targeting the RhoA-ROCK pathway to reverse T-cell dysfunction in SLE.

OBJECTIVES: Deregulated production of interleukin (IL)-17 and IL-21 contributes to the pathogenesis of autoimmune disorders such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Production of IL-17 and IL-21 can be regulated by ROCK2, one of the two Rho kinases. Increased ROCK activation was previously observed in an SLE cohort. Here, we evaluated ROCK activity in a new SLE cohort, and an RA cohort, and assessed the ability of distinct inhibitors of the ROCK pathway to suppress production of IL-17 and IL-21 by SLE T cells or human Th17 cells. METHODS: ROCK activity in peripheral blood mononuclear cells (PBMCs) from 29 patients with SLE, 31 patients with RA and 28 healthy controls was determined by ELISA. SLE T cells or in vitro-differentiated Th17 cells were treated with Y27632 (a pan-ROCK inhibitor), KD025 (a selective ROCK2 inhibitor) or simvastatin (which inhibits RhoA, a major ROCK activator). ROCK activity and IL-17 and IL-21 production were assessed. The transcriptional profile altered by ROCK inhibitors was evaluated by NanoString technology. RESULTS: ROCK activity levels were significantly higher in patients with SLE and RA than healthy controls. Th17 cells exhibited high ROCK activity that was inhibited by Y27632, KD025 or simvastatin; each also decreased IL-17 and IL-21 production by purified SLE T cells or Th17 cells. Immune profiling revealed both overlapping and distinct effects of the different ROCK inhibitors. CONCLUSIONS: ROCK activity is elevated in PBMCs from patients with SLE and RA. Production of IL-17 and IL-21 by SLE T cells or Th17 cells can furthermore be inhibited by targeting the RhoA-ROCK pathway via both non-selective and selective approaches.

Breastfeeding in patients with peripartum cardiomyopathy: clinical outcomes and physician counseling.

BACKGROUND: Peripartum cardiomyopathy (PPCM) is a form of heart failure occurring towards the end of pregnancy or in the months following delivery. Concerns regarding the role of prolactin (the polypeptide hormone responsible for lactation) driving the pathogenesis of PPCM have led experts to discourage patients from breastfeeding; however, limited clinical data exist. We sought to (1) determine whether lactation was associated with less cardiac recovery and (2) assess the counseling about breastfeeding given to patients at the time of their initial diagnosis. METHODS: Patients diagnosed with PPCM from 1999 to 2019 were identified through detailed chart review and demographic characteristics, comorbidities, outcomes, and lactation status were collected. Cardiac recovery was defined as left ventricular ejection fraction (LVEF) 55% or higher. A survey about breastfeeding and patient experience was administered by mail. Patients were only included in this analysis if definitive information about lactation status was documented. RESULTS: Of 220 patients with confirmed PPCM, lactation status was known definitively in 54 patients; of these, 18 (33%) had breastfed for at least 6 weeks and 36 (67%) did not breastfeed. There were no significant differences in the breastfeeding and non-breastfeeding groups related to baseline LVEF, age, race, gestational diabetes, smoking, hypertensive disorders of pregnancy, and medication treatments. Despite similar baseline LVEF at the time of diagnosis, there was no statistically significant difference in cardiac recovery based on lactation status. In a subset of patients with severe cardiac dysfunction at the time of diagnosis, there remained no significant differences in recovery based on lactation status. Of the 34 survey respondents, 62% were told not to breastfeed due to their diagnosis or concerns regarding safety of medications, and none were encouraged to breastfeed. CONCLUSION: In this retrospective cohort, lactation was not associated with lower rates of myocardial recovery. Importantly, a majority of patients had received counseling that they should not breastfeed. Future studies of the role of lactation in PPCM are needed in order to better understand the impact of breastfeeding and improve patient counseling.

Longitudinal transcriptomic analysis reveals persistent enrichment of iron homeostasis and erythrocyte function pathways in severe COVID-19 ARDS.

Introduction: The acute respiratory distress syndrome (ARDS) is a common complication of severe COVID-19 and contributes to patient morbidity and mortality. ARDS is a heterogeneous syndrome caused by various insults, and results in acute hypoxemic respiratory failure. Patients with ARDS from COVID-19 may represent a subgroup of ARDS patients with distinct molecular profiles that drive disease outcomes. Here, we hypothesized that longitudinal transcriptomic analysis may identify distinct dynamic pathobiological pathways during COVID-19 ARDS. Methods: We identified a patient cohort from an existing ICU biorepository and established three groups for comparison: 1) patients with COVID-19 ARDS that survived hospitalization (COVID survivors, n = 4), 2) patients with COVID-19 ARDS that did not survive hospitalization (COVID non-survivors, n = 5), and 3) patients with ARDS from other causes as a control group (ARDS controls, n = 4). RNA was isolated from peripheral blood mononuclear cells (PBMCs) at 4 time points (Days 1, 3, 7, and 10 following ICU admission) and analyzed by bulk RNA sequencing. Results: We first compared transcriptomes between groups at individual timepoints and observed significant heterogeneity in differentially expressed genes (DEGs). Next, we utilized the likelihood ratio test to identify genes that exhibit different patterns of change over time between the 3 groups and identified 341 DEGs across time, including hemoglobin subunit alpha 2 (HBA1, HBA2), hemoglobin subunit beta (HBB), von Willebrand factor C and EGF domains (VWCE), and carbonic anhydrase 1 (CA1), which all demonstrated persistent upregulation in the COVID non-survivors compared to COVID survivors. Of the 341 DEGs, 314 demonstrated a similar pattern of persistent increased gene expression in COVID non-survivors compared to survivors, associated with canonical pathways of iron homeostasis signaling, erythrocyte interaction with oxygen and carbon dioxide, erythropoietin signaling, heme biosynthesis, metabolism of porphyrins, and iron uptake and transport. Discussion: These findings describe significant differences in gene regulation during patient ICU course between survivors and non-survivors of COVID-19 ARDS. We identified multiple pathways that suggest heme and red blood cell metabolism contribute to disease outcomes. This approach is generalizable to larger cohorts and supports an approach of longitudinal sampling in ARDS molecular profiling studies, which may identify novel targetable pathways of injury and resolution.

Robust assessment of tumor mutational burden in cytological specimens from lung cancer patients.

OBJECTIVES: Tumor mutational burden (TMB) has emerged as a promising predictive biomarker for immune checkpoint inhibitor therapy. While the feasibility of TMB analysis on formalin-fixed paraffin-embedded (FFPE) samples has been thoroughly evaluated, only limited analyses have been performed on cytological samples, and no dedicated study has investigated concordance of TMB between different sample types. Here, we assessed TMB on matched histological and cytological samples from lung cancer patients and evaluated the accuracy of TMB estimation in these sample types. MATERIALS AND METHODS: We analyzed mutations and resulting TMB in FFPE samples and matched ethanol-fixed cytological smears (n = 12 matched pairs) by using a targeted next-generation sequencing assay (Oncomine™ Tumor Mutational Load). Two different variant allele frequency (VAF) thresholds were used to estimate TMB (VAF = 5% or 10%). RESULTS: At 5% VAF threshold, 73% (107/147) of mutations were concordantly detected in matched histological and cytological samples. Discordant variants were mainly unique to FFPE samples (34/40 discordant variants) and mostly C:G > T:A transitions with low allelic frequency, likely indicating formalin fixation artifacts. Increasing the VAF threshold to 10% clearly increased the number of concordantly detected mutations in matched histological and cytological samples to 96% (100/106 mutations), and drastically reduced the number of FFPE-only mutations (from 34 to 4 mutations). In contrast, cytological samples showed consistent mutation count and TMB values at both VAF thresholds. Using FFPE samples, 2 out of 12 patients were classified as TMB-high at VAF cutoff of 5% but TMB-low at 10%, whereas cytological specimens allowed consistent patient classification independently from VAF cutoff. CONCLUSION: Our results show that cytological smears provide more consistent TMB values due to high DNA quality and lack of formalin-fixation induced artifacts. Therefore, cytological samples should be the preferred sample type for robust TMB estimation.

Factors Associated with New Uptake of Long-Acting Reversible Contraceptives Since the Affordable Care Act Among Privately Insured Women in Pennsylvania.

BACKGROUND: The Affordable Care Act eliminated out-of-pocket costs for contraceptives, including highly effective long-acting reversible contraception (LARC), for most insured women. Patient characteristics associated with new LARC uptake after the Affordable Care Act have not been well-studied. We hypothesized that awareness of no-cost intrauterine device (IUD) coverage would be associated with new LARC use. METHODS: Data included were from 883 women not using a LARC at baseline who participated in the MyNewOptions study, a 2-year study of privately insured women in Pennsylvania. Multivariable analysis assessed whether the following baseline characteristics predicted new LARC use over 2 years: awareness of no-cost IUD coverage, future pregnancy intention, baseline contraceptive use, contraceptive attitudes, and sociodemographic characteristics. RESULTS: At baseline, 54.4% of participants were using prescription methods; 21.1% nonprescription methods; 12.1% natural family planning, withdrawal, or spermicide alone; and 12.5% no method. A minority (7.2%) was aware of no-cost coverage for IUDs. Over 2 years, 7.2% of participants became new LARC users, but awareness of no-cost coverage for IUDs was not associated with new LARC use (adjusted odds ratio, 0.84; 95% confidence interval, 0.27-2.55). New LARC use was associated with already using prescription methods, not intending pregnancy within the next 5 years, prior unintended pregnancy, and desire to change method if cost were not a factor. CONCLUSIONS: Among privately insured women, wanting to switch methods if cost were not a factor was associated with new LARC uptake, although awareness of no-cost IUD coverage was not. Providing women with information about their contraceptive coverage benefits may help women to seek and obtain the methods better aligned with their personal needs.