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AbstractChronic lung disease (CLD) is the second leading cause of pulmonary hypertension (PH) and is associated with significant morbidity and mortality. Although PH associated with CLD (PH‐CLD) leads to impaired health‐related quality of life (HRQOL), there are no validated tools to assess HRQOL in PH‐CLD. The Pulmonary Arterial Hypertension–Symptoms and Impact Questionnaire (PAH‐SYMPACT) is an HRQOL instrument aimed at assessing the symptoms and impact of PH on overall function and well‐being. We performed a single‐center prospective cohort study using PAH‐SYMPACT scores to compare symptoms, exercise capacity and HRQOL in patients with PAH and PH‐CLD. One hundred and twenty‐five patients (99 patients with idiopathic/heritable PAH and 26 with PH‐CLD) completed the PAH‐SYMPACT questionnaire which consists of 22 questions that assess HRQOL across four domains: cardiopulmonary (CP) symptoms, cardiovascular (CV) symptoms, physical impact (PI), and cognitive/emotional (CE) impact. Higher scores indicate worse HRQOL. We compared patients with PAH and PH‐CLD using a Wilcoxon rank sum or chi‐squared test as appropriate. Multivariate linear regression analysis was used to assess the relationship between PH classification and SYMPACT scores. Compared to PAH, patients with PH‐CLD were older, more likely to use oxygen and had worse functional class and exercise capacity. While there was no significant difference between the two groups in CP, CV, or CE domain scores, patients with PH‐CLD had significantly worse PI scores by univariate (1.79 vs. 1.13, p < 0.001) and multivariate analysis (1.61 vs. 1.17, p = 0.02) and overall worse SYMPACT scores (1.19 vs. 0.91, p = 0.03). In conclusion, patients with PH‐CLD have worse HRQOL as assessed by the PAH‐SYMPACT questionnaire versus patients with PAH. Although PAH‐SYMPACT has not been validated in PH‐CLD, the results of this study can guide clinicians in understanding the symptoms and impact of PH‐CLD relative to PAH.

AbstractPulmonary rehabilitation (PR) is a supervised exercise program for patients with chronic lung disease. Among patients with pulmonary hypertension (PH), PR has been shown to improve both quality of life and exercise capacity. The purpose of this study was to assess the prevalence of PR participation among PH patients, patient perspectives regarding PR, and to identify potential barriers to PR participation. We performed a cross‐sectional survey of patients with self‐reported PH who attended the Pulmonary Hypertension Association (PHA) conference in June 2022 in Atlanta, Georgia, and patients within the PHA listserv. A total of 429 participants completed the survey and were enrolled in the study. The average age of participants was 61 ± 14 years with 83% of participants identifying as female, 51% of patients self‐reported as having group 1 PH. Among patients who completed the survey, 41% had previously attended a PR program. Of those who had completed a PR program, 83% reported being satisfied or very satisfied with the program and 86% reported that they would recommend PR to other PH patients. After completion of a PR program, 76% of patients reported an improvement in their quality of life and 88% reported improvement in exercise capacity. Among the patients who had not previously participated in PR (n = 254), 63% reported an interest in participation while 64% cited a lack of discussion from their treatment team as the primary reason for the lack of PR participation. Limitations of the study include sampling and response bias. According to this cross‐sectional survey, the majority of PH patients who have participated in PR report improvement in both quality of life and exercise capacity and would recommend PR to other PH patients. The majority of PH patients who have not participated in PR were interested in participation and cited a lack of discussion with their treatment team as one of the primary reasons for the lack of participation. PR is associated with self‐reported improvements in quality of life and exercise capacity but remains underutilized among patients with PH.

Genetic variation at the transmembrane protein 106B gene ( TMEM106B) has been linked to risk of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) through an unknown mechanism. We found that presence of the TMEM106B rs3173615 protective genotype was associated with longer survival after symptom onset in a postmortem FTLD-TDP cohort, suggesting a slower disease course. The seminal discovery that filaments derived from TMEM106B is a common feature in aging and, across a range of neurodegenerative disorders, suggests that genetic variants in TMEM106B could modulate disease risk and progression through modulating TMEM106B aggregation. To explore this possibility and assess the pathological relevance of TMEM106B accumulation, we generated a new antibody targeting the TMEM106B filament core sequence. Analysis of postmortem samples revealed that the TMEM106B rs3173615 risk allele was associated with higher TMEM106B core accumulation in patients with FTLD-TDP. In contrast, minimal TMEM106B core deposition was detected in carriers of the protective allele. Although the abundance of monomeric full-length TMEM106B was unchanged, carriers of the protective genotype exhibited an increase in dimeric full-length TMEM106B. Increased TMEM106B core deposition was also associated with enhanced TDP-43 dysfunction, and interactome data suggested a role for TMEM106B core filaments in impaired RNA transport, local translation, and endolysosomal function in FTLD-TDP. Overall, these findings suggest that prevention of TMEM106B core accumulation is central to the mechanism by which the TMEM106B protective haplotype reduces disease risk and slows progression.

Abstract Background: Clinical, molecular, and genetic epidemiology studies displayed remarkable differences between ever- and never-smoking lung cancer. Methods: We conducted a stratified multi-population (European, East Asian, and African descent) association study on 44,823 ever-smokers and 20,074 never-smokers to identify novel variants that were missed in the non-stratified analysis. Functional analysis including expression quantitative trait loci (eQTL) colocalization and DNA damage assays, and annotation studies were conducted to evaluate the functional roles of the variants. We further evaluated the impact of smoking quantity on lung cancer risk for the variants associated with ever-smoking lung cancer. Results: Five novel independent loci, GABRA4, intergenic region 12q24.33, LRRC4C, LINC01088, and LCNL1 were identified with the association at two or three populations (P &lt; 5 × 10−8). Further functional analysis provided multiple lines of evidence suggesting the variants affect lung cancer risk through excessive DNA damage (GABRA4) or cis-regulation of gene expression (LCNL1). The risk of variants from 12 independent regions, including the well-known CHRNA5, associated with ever-smoking lung cancer was evaluated for never-smokers, light-smokers (packyear ≤ 20), and moderate-to-heavy-smokers (packyear &gt; 20). Different risk patterns were observed for the variants among the different groups by smoking behavior. Conclusions: We identified novel variants associated with lung cancer in only ever- or never-smoking groups that were missed by prior main-effect association studies. Impact: Our study highlights the genetic heterogeneity between ever- and never-smoking lung cancer and provides etiologic insights into the complicated genetic architecture of this deadly cancer.

AbstractBackgroundHigher blood pressure (BP) is associated with greater white matter hyperintensity (WMH) volume, but research is limited in recently menopausal and postmenopausal women. Postmenopausal women have a greater burden of WMH than men and premenopausal women, but whether hormone therapy (HT) modifies the association between systolic and diastolic BP (SBP, DBP) and WMH is unknown. We investigated the association of SBP and DBP in recently postmenopausal women who participated in an HT trial with WMH volumes measured 14 years later and explored whether HT modified the results.MethodWomen with good cardiovascular (CV) health, who were previously enrolled in a randomized placebo‐controlled HT trial, the Kronos Early Estrogen Prevention Study (KEEPS), participated in the current observational KEEPS continuation (n = 212; median age = 67; range 58‐72). SBP and DBP were measured at KEEPS baseline (median age = 54 years; range 44‐59) and continuation. Antihypertensive users were excluded (baseline, n = 34; continuation, n = 61). Approximately 10 years after the end of KEEPS HT versus placebo 4‐year interventions, automated WMH volumes were measured from 3D‐FLAIR MRI. Associations of KEEPS baseline and continuation SBP and DBP with log WMH volume at KEEPS continuation were tested using linear regression analyses adjusting for covariates in model 1 (age, total intracranial volume, study site) and model 2 (model 1 plus cardiovascular risk factors (CVRF)).ResultHigher KEEPS baseline SBP and DBP were associated with greater WMH volume measured 14 years later, and after adjusting for CVRF (p≤0.01). Similarly, in KEEPS continuation, higher SBP and DBP were associated with greater WMH volume measured concurrently and after adjusting for CVRF (p<0.001). We did not find statistically significant evidence that HT versus placebo modified these associations. Topographically, higher SBP and DBP were associated with greater periventricular WMH in the frontal and parietal lobes after adjusting for age (Figure).ConclusionHigher SBP and DBP in recently menopausal women with good CV health were associated with greater WMH volumes more than a decade later after adjusting for CVRF, independent of randomization to HT. Our results show the importance of blood pressure control in recently menopausal women, that may reduce the white matter injury later in life.

AbstractBackgroundHigher blood pressure (BP) is associated with greater white matter hyperintensity (WMH) volume, but research is limited in recently menopausal and postmenopausal women. Postmenopausal women have a greater burden of WMH than men and premenopausal women, but whether hormone therapy (HT) modifies the association between systolic and diastolic BP (SBP, DBP) and WMH is unknown. We investigated the association of SBP and DBP in recently postmenopausal women who participated in an HT trial with WMH volumes measured 14 years later and explored whether HT modified the results.MethodWomen with good cardiovascular (CV) health, who were previously enrolled in a randomized placebo‐controlled HT trial, the Kronos Early Estrogen Prevention Study (KEEPS), participated in the current observational KEEPS continuation (n = 212; median age = 67; range 58‐72). SBP and DBP were measured at KEEPS baseline (median age = 54 years; range 44‐59) and continuation. Antihypertensive users were excluded (baseline, n = 34; continuation, n = 61). Approximately 10 years after the end of KEEPS HT versus placebo 4‐year interventions, automated WMH volumes were measured from 3D‐FLAIR MRI. Associations of KEEPS baseline and continuation SBP and DBP with log WMH volume at KEEPS continuation were tested using linear regression analyses adjusting for covariates in model 1 (age, total intracranial volume, study site) and model 2 (model 1 plus cardiovascular risk factors (CVRF)).ResultHigher KEEPS baseline SBP and DBP were associated with greater WMH volume measured 14 years later, and after adjusting for CVRF (p = 0.01). Similarly, in KEEPS continuation, higher SBP and DBP were associated with greater WMH volume measured concurrently and after adjusting for CVRF (p<0.001). We did not find statistically significant evidence that HT versus placebo modified these associations. Topographically, higher SBP and DBP were associated with greater periventricular WMH in the frontal and parietal lobes after adjusting for age (Figure).ConclusionHigher SBP and DBP in recently menopausal women with good CV health were associated with greater WMH volumes more than a decade later after adjusting for CVRF, independent of randomization to HT. Our results show the importance of blood pressure control in recently menopausal women, that may reduce the white matter injury later in life.

Introduction: US rural areas have a disproportionate burden of CVD and hypertension. Physical inactivity is a major risk factor, with 25% prevalence in US adults. However, rural disparities in physical inactivity are incompletely described. The aim was to evaluate differences in prevalence of physical inactivity based on county-level rurality. Methods: We used CDC county-level data for adults aged ≥20 years, 2004–2019, available for 97.6% of US counties (n=3148/3226). CDC defined physical inactivity as self-reported lack of leisure time physical activity in the month preceding the survey. Rurality was based on six categories ordered from least rural (large central metro) to most rural (noncore). We used weighted least squares regression to compare prevalence by rurality level, adjusting for 13 county-level sociodemographic factors; results reported as prevalence ratios (95% CI) with partial F -tests and P -values. Results: In age and sex ratio adjusted analysis (model 1), we observed a gradient in the prevalence of physical inactivity across levels of rurality, with significantly higher rates in small metro (1.03 [1.00–1.06]), micropolitan (1.05 [1.02–1.07]), and noncore (1.05 [1.02–1.08]) compared with large central metro counties ( F -statistic=7.5; P <.001). With further adjustment for other sociodemographic factors (model 2), the relative differences were negated in noncore counties (0.99 [0.97-1.02]), attenuated in intermediate counties, and accentuated in large fringe metro counties (1.06 [1.04-1.08]) ( F -statistic=14.3; P <.001). Further adjustment for obesity (model 3) largely attenuated the association of rurality with physical inactivity, resulting in no significant differences relative to large central metro counties ( F -statistic=4.8; P <.001). Conclusions: County-level rurality was associated with prevalence of physical inactivity. These disparities were largely accounted for by obesity, which may be targeted for intervention.

Introduction: US rural, compared with nonrural, counties have a higher burden of CVD. Obesity is a major CVD risk factor with 40% prevalence in adults. However, the rural-nonrural disparities in obesity are incompletely described. We aimed to evaluate differences in prevalence of obesity by county-level rurality. Methods: We used CDC county-level data for adults aged ≥20 years, 2004–2019, available for 97.6% of US counties (n=3148/3226). CDC defined obesity (body mass index ≥30 kg/m 2 ) using self-reported weight and height. Rurality was based on six levels from large central metro (most urban) to noncore (most rural). We compared prevalence by rurality level using weighted least squares regression, adjusting for 13 county-level sociodemographic measures, and reported prevalence ratios (95% CI). Results: Counties with increasing rurality reflected older populations, as indicated by higher median age (from 35.6 years to 42.4 years). Also, increasing rurality was associated with differences in income and proportion uninsured. In age and sex ratio adjusted analysis (model 1), obesity prevalence was 1.05- to 1.06-fold higher in medium metro, small metro, and micropolitan counties compared with large central metro counties (global test, P <.001). With further adjustment for sociodemographic measures (model 2; model 1 covariates plus race, state, income, proportion uninsured) these relative differences were preserved but attenuated (each 1.03-fold higher), while a greater difference was revealed for large fringe metro (1.06-fold higher) counties. In both models, differences in obesity prevalence between noncore and large central metro counties were minimal. (Table) Conclusion: Counties with intermediate rurality were associated with higher obesity prevalence. The association was partly accounted for by nonmodifiable and modifiable sociodemographic measures, which may be targeted to reduce rural-nonrural disparities in obesity.

AbstractBackgroundHow variations predicted by pharmacogenomic testing to alter drug metabolism and therapeutic response affect outcomes for patients with disorders of gut‐ brain interaction is unclear.AimsTo assess the prevalence of pharmacogenomics‐predicted drug‐gene interactions and symptom outcomes for patients with disorders of gut‐brain interaction.MethodsPatients who were treated in our clinical practice for functional dyspepsia/bowel disorder underwent pharmacogenomic testing. The change in symptoms from baseline to 6 months was compared for patients with variations in CYP2D6 and CYP2C19, which metabolize neuromodulators, and SLC6A4, which encodes the sodium‐ dependent serotonin transporter.ResultsAt baseline, 79 of 94 participants (84%) had at least one predicted major drug‐ gene interaction, and all 94 (100%) had at least one predicted moderate interaction. For the 44 participants who completed a survey of their symptoms at 6 months, the mean (SD) irritable bowel syndrome‐symptom severity score decreased from 284 (71) at baseline to 231 (95) at 6 months (p < 0.001). Among patients taking selective serotonin reuptake inhibitors, the decrease in symptom severity (p = 0.03) and pain (p = 0.002) scores from baseline to 6 months was greater for patients with a homozygous SLC6A4 long/long genotype (n = 30) (ie, increased serotonin transporter activity) than for patients with homozygous short/short or heterozygous long/short genotypes (n = 64). Symptom outcomes were not affected by CYP2D6 or CYP2C19 variations.ConclusionsThe homozygous SLC6A4 long/long genotype confers better symptom resolution for patients with disorders of gut‐brain interaction who take selective serotonin reuptake inhibitors than do the homozygous short/short or heterozygous long/short genotypes.