Exercise improves surrogate measures of liver histological response in metabolic dysfunction-associated steatotic liver disease.

BACKGROUND AND AIMS: Exercise is recommended for the management of metabolic dysfunction-associated steatotic liver disease (MASLD), yet effects on liver histology remain unknown, especially without significant weight loss. We aimed to examine changes in surrogate measures of liver histological response with exercise training. METHODS: We conducted a post hoc pooled analysis of three randomised controlled trials (duration: 12-20 weeks) comparing aerobic exercise interventions with controls. The primary outcome measure was a ≥30% relative reduction in (MRI-measured) liver fat, as a surrogate measure of liver histological response (the threshold necessary for fibrosis improvement). Secondary outcome measures were changes in other biomarkers of liver fibrosis, anthropometry, body composition and aerobic fitness. RESULTS: Eighty-eight adults (exercise: 54, control: 34; male: 67%) were included with mean (SD) age 51 (11) years and body mass index 33.3 (5.2) kg/m2. Following the intervention, exercise had ~5-fold (OR [95%CI]: 4.86 [1.72, 13.8], p = .002) greater odds of ≥30% relative reduction in MRI-measured liver fat compared with control. This paralleled the improvements in anthropometry (waist and hip circumference reduction), body composition (body fat, visceral and subcutaneous adipose tissue) and aerobic fitness (V̇O2peak, ventilatory threshold and exercise capacity). Importantly, these effects were independent of clinically significant body weight loss (<3% body weight). CONCLUSION: Exercise training led to clinically meaningful improvements in surrogate serum- and imaging-based measures of liver histological change, without clinically meaningful body weight reduction. These data reinforce the weight-neutral benefit of exercise training and suggest that aerobic training may improve liver fibrosis in patients with MASLD.

Patterns of Cancer-Related Healthcare Access across Pennsylvania: Analysis of Novel Census Tract-Level Indicators of Persistent Poverty.

BACKGROUND: Persistent poverty census tracts have had ≥20% of the population living below the federal poverty line for 30+ years. We assessed the relationship between persistent poverty and cancer-related healthcare access across census tracts in Pennsylvania. METHODS: We gathered publicly available census tract-level data on persistent poverty, rurality, and sociodemographic variables, as well as potential access to healthcare (i.e., prevalence of health insurance, last-year check-up), realized access to healthcare (i.e., prevalence of screening for cervical, breast, and colorectal cancers), and self-reported cancer diagnosis. We used multivariable spatial regression models to assess the relationships between persistent poverty and each healthcare access indicator. RESULTS: Among Pennsylvania's census tracts, 2,789 (89.8%) were classified as non-persistent poverty, and 316 (10.2%) were classified as persistent poverty (113 did not have valid data on persistent poverty). Persistent poverty tracts had lower prevalence of health insurance [estimate = -1.70, standard error (SE) = 0.10], screening for cervical cancer (estimate = -4.00, SE = 0.17) and colorectal cancer (estimate = -3.13, SE = 0.20), and cancer diagnosis (estimate = -0.34, SE = 0.05), compared with non-persistent poverty tracts (all P < 0.001). However, persistent poverty tracts had higher prevalence of last-year check-up (estimate = 0.22, SE = 0.08) and screening for breast cancer (estimate = 0.56, SE = 0.15; both P < 0.01). CONCLUSIONS: Relationships between persistent poverty and cancer-related healthcare access outcomes differed in direction and magnitude. Health promotion interventions should leverage data at fine-grained geographic units (e.g., census tracts) to motivate focus on communities or outcomes. IMPACT: Future studies should extend these analyses to other states and outcomes to inform public health research and interventions to reduce geographic disparities.

Exercise training improves serum biomarkers of liver fibroinflammation in patients with metabolic dysfunction-associated steatohepatitis.

BACKGROUND AND AIMS: Exercise training is recommended for all patients with metabolic dysfunction-associated steatotic liver disease and may reverse liver fibrosis. Whether exercise training improves liver fibrosis without body weight loss remains controversial. We further investigated this relationship using serum biomarkers of liver fibroinflammation in a post hoc analysis of an exercise trial where patients did not lose significant body weight. METHODS: In the NASHFit trial, patients with metabolic dysfunction-associated steatohepatitis were randomized to receive either moderate-intensity aerobic exercise training or standard clinical care for 20 weeks. Mediterranean-informed dietary counselling was provided to each group. Change in serum biomarkers was measured and compared between the two groups. RESULTS: Exercise training led to improvement in serum biomarkers of liver fibroinflammation, including (1) ≥17 IU/L reduction in alanine aminotransferase (ALT) in 53% of individuals in the exercise training group compared to 13% in the standard clinical care group (p < 0.001; mean reduction 24% vs. 10% respectively) and (2) improvement in CK18 (-61 vs. +71 ng/mL, p = 0.040). ALT improvement ≥17 IU/L was correlated with ≥30% relative reduction in magnetic resonance imaging-measured liver fat and PNPLA3 genotype. CONCLUSION: Exercise training improves multiple serum biomarkers of liver fibroinflammation at clinically significant thresholds of response without body weight loss. This study provides further evidence that exercise training should be viewed as a weight-neutral intervention for which response to intervention can be readily monitored with widely available non-invasive biomarkers that can be applied at the population level.

LionVu: A Data-Driven Geographical Web-GIS Tool for Community Health and Decision-Making in a Catchment Area.

In 2018, the Penn State Cancer Institute developed LionVu, a web mapping tool to educate and inform community health professionals about the cancer burden in Pennsylvania and its catchment area of 28 counties in central Pennsylvania. LionVu, redesigned in 2023, uses several open-source JavaScript libraries (i.e., Leaflet, jQuery, Chroma, Geostats, DataTables, and ApexChart) to allow public health researchers the ability to map, download, and chart 21 publicly available datasets for clinical, educational, and epidemiological audiences. County and census tract data used in choropleth maps were all downloaded from the sources website and linked to Pennsylvania and catchment area county and census tract geographies, using a QGIS plugin and Leaflet JavaScript. Two LionVu demonstrations are presented, and 10 other public health related web-GIS applications are reviewed. LionVu fills a role in the public health community by allowing clinical, educational, and epidemiological audiences the ability to visualize and utilize health data at various levels of aggregation and geographical scales (i.e., county, or census tracts). Also, LionVu is a novel application that can translate and can be used, for mapping and graphing purposes. A dialog to demonstrate the potential value of web-based GIS to a wider audience, in the public health research community, is needed.

Liver Transplant Outcomes in Young Adults with Cirrhosis Related to Nonalcoholic Fatty Liver Disease.

BACKGROUND: The prevalence of nonalcoholic fatty liver disease (NASH) and cryptogenic cirrhosis (CC) is constantly increasing in adolescents and young adults (AYAs). METHODS: In a retrospective UNOS database evaluation, we analyzed postoperative outcomes of AYAs with nonalcoholic NASH/CC undergoing LT between January 1st, 2003 and March 5th, 2021. After exclusions, 85,970 LT recipients, 393 (47.1%) AYAs with NASH/CC and 441 (52.9%) AYAs with other metabolic conditions, were analyzed. RESULTS: During the study period, the number of LTs performed for AYAs with NASH/CC increased from 4%-7% but decreased from 6.6%-5.3% compared to LTs performed for NASH/CC in all ages. In comparison to AYAs with other metabolic conditions, AYA LT recipients with NASH/CC had a higher prevalence of metabolic syndrome (MetS) components, including diabetes and increased body mass index (P < .0001 for both). Patient and graft survival in AYAs with NASH/CC were significantly lower in comparison to AYAs transplanted for other metabolic conditions (P < .0001) (Hazard Ratio = 1.93, P < .001). Patient survival in AYAs with NASH/CC was significantly better in comparison to older (40-65-year-old) patients with the same diagnosis (P = .01). CONCLUSIONS: Our study found that the overall number of LTs in AYAs with NASH increased significantly, but to a lesser degree compared to the older population with the same diagnosis. Outcomes after LT in AYAs with NASH/CC were worse compared to LT for other metabolic conditions, but significantly better in comparison to older patients. The prevalence of LT for NASH/CC in AYAs is growing. MetS may contribute to worse outcomes in AYAs.

Mobile health lifestyle intervention program leads to clinically significant loss of body weight in patients with NASH.

BACKGROUND AIMS: Lifestyle intervention remains the foundation of clinical care for patients with NASH; however, most patients are unsuccessful in enacting sustained behavioral change. There remains a clear unmet need to develop lifestyle intervention programs to support weight loss. Mobile health (mHealth) programs offer promise to address this need, yet their efficacy remains unexplored. APPROACH RESULTS: We conducted a 16-week randomized controlled clinical trial involving adults with NASH. Patients were randomly assigned (1:1 ratio) to receive Noom Weight (NW), a mHealth lifestyle intervention program, or standard clinical care. The primary end point was a change in body weight. Secondary end points included feasibility (weekly app engagement), acceptability (>50% approached enrolled), and safety. Of 51 patients approached, 40 (78%) were randomly assigned (20 NW and 20 standard clinical care). NW significantly decreased body weight when compared to standard clinical care (-5.5 kg vs. -0.3 kg, p = 0.008; -5.4% vs. -0.4%, p = 0.004). More NW subjects achieved a clinically significant weight loss of ≥5% body weight (45% vs. 15%, p = 0.038). No adverse events occurred, and the majority (70%) of subjects in the NW arm met the feasibility criteria. CONCLUSIONS: This clinical trial demonstrated that NW is not only feasible, acceptable, and safe but also highly efficacious because this mHealth lifestyle intervention program led to significantly greater body weight loss than standard clinical care. Future large-scale studies are required to validate these findings with more representative samples and to determine if mHealth lifestyle intervention programs can lead to sustained, long-term weight loss in patients with NASH.

Serum Fibroblast Growth Factor 21 Is Markedly Decreased following Exercise Training in Patients with Biopsy-Proven Nonalcoholic Steatohepatitis.

BACKGROUND AND AIMS: Exercise remains a key component of nonalcoholic fatty liver disease (NAFLD) treatment. However, mechanisms underpinning the improvements in NAFLD seen with exercise are unclear. Exercise improved liver fat and serum biomarkers of liver fibrosis in the NASHFit trial. We investigated exercise's mechanism of benefit by conducting a post hoc analysis of these data to determine the relationship between serum fibroblast growth factor (FGF) 21, which is implicated in NAFLD development, and exercise. METHODS: In the 20 wk NASHFit trial, patients with nonalcoholic steatohepatitis (NASH) were randomized to receive moderate-intensity aerobic exercise training or standard clinical care. Mediterranean-informed dietary counseling was provided to each group. Change in serum FGF21 was measured after an overnight fast. RESULTS: There was a significant improvement in serum FGF21 with exercise training compared to standard clinical care (p = 0.037) with serum FGF21 reducing by 22% (-243.4 +/-349 ng/mL) with exercise vs. a 34% increase (+88.4 ng/mL +/-350.3 ng/mL) with standard clinical care. There was a large inverse association between change in serum FGF21 and change in cardiorespiratory fitness (VO2peak) (r = -0.62, 95% CI -0.88 to -0.05, p = 0.031), and on multivariable analysis, change in VO2peak remained independently associated with change in FGF21 (ß = -44.5, 95% CI -83.8 to -5.11, p = 0.031). CONCLUSIONS: Serum FGF21 is markedly decreased in response to aerobic exercise training, offering a novel mechanism to explain the observed reduction in liver fat and improvement in serum biomarkers of liver fibrosis in patients with NASH who do exercise.

Decline in Functional Status While on the Waiting List Predicts Worse Survival After Lung Transplantation.

OBJECTIVES: To determine if decreases in the Karnofsky Performance Score (KPS) while on the waitlist predict decreased survival after lung transplantation (LTx). DESIGN: A retrospective evaluation of the United Network for Organ Sharing database. The KPS was evaluated at the time of listing for transplant and at the time of transplantation. Group I consisted of patients having a decrease in KPS during the time on the waiting list (from the time of listing to the time of transplant), and Group II consisted of patients whose KPS stayed the same or increased during the same period. The authors used propensity-score weighting for comparisons of these groups. SETTING: Retrospective observational database review. PARTICIPANTS: Adult patients undergoing lung transplantation. INTERVENTIONS: None. Patients were stratified according to a change in their KPS. MEASUREMENTS AND MAIN RESULTS: Patient and graft survival of patients with decreasing or not decreasing KPS were compared. Of the 27,558 subjects included in the analysis, 17,986 (65%) had worsening KPS, which was associated with worse graft (p = 0.0003) and patient (p = 0.0019) survival after LTx. Using multivariate regression, a decrease in KPS of ≥40 was associated with decreased survival, and an increase of ≥40 was associated with improved survival (HR = 1.245, 95% CI [1.181-1.312], p < 0.0001 and HR = 0.866, 95% CI [0.785, 0.955], respectively). Among patients with a KPS <40 at the time of transplant, those with a decrease in KPS of ≥40 had decreased graft and patient survival compared with those with a smaller decrease (p = 0.0002 and p = 0.0021, respectively). CONCLUSIONS: Deterioration of KPS on the waiting list for LTx is associated with significantly greater postoperative mortality in patients after LTx. These results should be taken into consideration when allocating organs. Strategies to increase or to prevent a decrease in KPS before LTx should be evaluated.

Ambient air exposures to arsenic and cadmium and overall and prostate cancer-specific survival among prostate cancer cases in Pennsylvania, 2004 to 2014.

BACKGROUND: Exposures to arsenic (As) and cadmium (Cd) have been associated with higher prostate cancer (PC) mortality; however, these associations have been inconsistent. The authors investigated whether higher ambient air concentrations of As and Cd are associated with lower overall and PC-specific survival among PC cases in Pennsylvania. METHODS: Incident PC cases of patients, aged 40 years or older, with a clinical diagnosis and nonmetastatic disease were identified in the 2004 to 2014 Pennsylvania Cancer Registry. Demographic, clinical, and pathologic information were extracted from the Pennsylvania Cancer Registry. The 3- and 5-year average and cumulative air concentrations of As and Cd were extracted from the Environmental Protection Agency's Toxics Release Inventory database. Spatial-temporal hierarchical accelerated failure time models were used to examine the associations between air concentrations of As and Cd and overall and PC-specific survival for the total population and stratified by geographical region defined by rurality and Appalachia status, after adjusting for confounders. RESULTS: There were 78,914 PC cases included. Increasing 3- and 5-year average and cumulative air concentrations of As and Cd were significantly associated with lower overall and PC-specific survival among cases, after adjusting for confounders, for the total population, and stratified by geographical region for most of the estimates. CONCLUSIONS: Data suggest that increasing ambient air exposures to As and Cd may play a role in overall and PC-specific mortality risk among PC cases. Exposures to As and Cd are modifiable and may provide insight into potential strategies to improve PC health outcomes. LAY SUMMARY: Arsenic and cadmium exposures linked to increased prostate cancer deaths remain unclear. We investigated whether air levels of arsenic and cadmium reported to be released from industries decrease overall and prostate cancer-specific survival among prostate cancer cases identified in the 2004 to 2014 Pennsylvania Cancer Registry. Among the 78,914 prostate cancer cases, increasing air levels of arsenic and cadmium are found to be associated with lower overall and prostate cancer-specific survival for the total population and within rural and urban Appalachia and urban non-Appalachia counties in Pennsylvania. Reducing exposures to arsenic and cadmium have the potential to decrease prostate cancer deaths.

A decline in functional status while awaiting liver transplantation is predictive of increased post-transplantation mortality.

BACKGROUND: Functional status (FS) is dynamic and changes over time. We examined how changes in FS while awaiting liver transplantation influence post-transplant outcomes. METHODS: Data on adult liver transplants performed in the United States during the MELD era were obtained through September 2020. Patient and graft survival were compared between groups with no change or improved FS, and those with worsening FS. RESULTS: Of the 90,210 transplant recipients included in the analysis, 39,193 (43%) had worsening FS, which was associated with longer waiting-list time (187 vs. 329 days, p < 0.001) and worse patient survival after liver transplant (1858 vs. 1727 days, p < 0.001). A consistent and dose-dependent relationship was observed for each 10-point decrease in Karnofsky Performance Score and post-transplant survival. Multivariable regression analysis confirmed that a decline in FS was associated with worse patient survival (HR 1.15, p < 0.001). Similar findings were observed for graft survival. CONCLUSION: A decline in FS on the waiting-list is associated with significantly greater post-liver transplant mortality in recipients. These results should be taken into consideration when allocating organs and determining transplant candidacy. Strategies to optimize FS prior to transplantation should be prioritized as even subtle decreases in FS are associated with inferior post-transplantation outcomes.

Vitamin D and family history of hypertension in relation to hypertension status among college students.

Hypertension and vitamin D concentrations have heritable components, although these factors remain uninvestigated in young adults. The objective of this study was to investigate hypertension risk among young adults with respect to family history of hypertension, adjusting for vitamin D status. Resting blood pressure (BP) was measured in 398 individuals aged 18-35 and classified according to the 2017 American Heart Association criteria. Plasma vitamin D metabolite (25(OH)D3; 24,25(OH)2D3; 1,25(OH)2D3) concentrations were determined using liquid chromatography tandem mass spectrometry (LC-MS/MS). Stepwise logistic regression was used to select covariates. Participants' mean age was 21, 30.3% had hypertension, and nearly all unaware of their hypertensive status (90.7%). Compared with no parental history, the adjusted odds ratio (AOR) for hypertension was elevated among participants with two parents having hypertension (AOR = 4.5, 95% CI: 1.70-11.76), adjusting for sex, body mass index, physical activity, and plasma 25(OH)D3. Results for systolic hypertension (SH) were similar but more extreme (two parents AOR = 7.1, 95% CI: 2.82, 17.66), although dihydroxy metabolites (1,25(OH)2D3 and 24,25(OH)2D3) were significant. There was a strong, independent association with dual parental history and hypertension status, regardless of vitamin D status. Hypertension was prevalent in nearly one-third of the sample and underscores the need for targeted prevention for young adults.

Spatial patterns in prostate Cancer-specific mortality in Pennsylvania using Pennsylvania Cancer registry data, 2004-2014.

BACKGROUND: Spatial heterogeneity of prostate cancer-specific mortality in Pennsylvania remains unclear. We utilized advanced geospatial survival regressions to examine spatial variation of prostate cancer-specific mortality in PA and evaluate potential effects of individual- and county-level risk factors. METHODS: Prostate cancer cases, aged ≥40 years, were identified in the 2004-2014 Pennsylvania Cancer Registry. The 2018 County Health Rankings data and the 2014 U.S. Environmental Protection Agency's Environmental Quality Index were used to extract county-level data. The accelerated failure time models with spatial frailties for geographical correlations were used to assess prostate cancer-specific mortality rates for Pennsylvania and by the Penn State Cancer Institute (PSCI) 28-county catchment area. Secondary assessment based on estimated spatial frailties was conducted to identify potential health and environmental risk factors for mortality. RESULTS: There were 94,274 cases included. The 5-year survival rate in PA was 82% (95% confidence interval, CI: 81.1-82.8%), with the catchment area having a lower survival rate 81% (95% CI: 79.5-82.6%) compared to the non-catchment area rate of 82.3% (95% CI: 81.4-83.2%). Black men, uninsured, more aggressive prostate cancer, rural and urban Appalachia, positive lymph nodes, and no definitive treatment were associated with lower survival. Several county-level health (i.e., poor physical activity) and environmental factors in air and land (i.e., defoliate chemical applied) were associated with higher mortality rates. CONCLUSIONS: Spatial variations in prostate cancer-specific mortality rates exist in Pennsylvania with a higher risk in the PSCI's catchment area, in particular, rural-Appalachia. County-level health and environmental factors may contribute to spatial heterogeneity in prostate cancer-specific mortality.

Prostate Cancer Incidence and Aggressiveness in Appalachia versus Non-Appalachia Populations in Pennsylvania by Urban-Rural Regions, 2004-2014.

BACKGROUND: Few studies have examined prostate cancer incidence and aggressiveness in urban-rural Appalachian populations. We examined these rates in urban-rural Appalachia and non-Appalachia Pennsylvania (PA), and the association between these areas and more aggressive prostate cancer at diagnosis. METHODS: Men, ages ≥ 40 years with a primary prostate cancer diagnosis, were identified from the 2004-2014 Pennsylvania Cancer Registry. Age-adjusted incidence rates for prostate cancer and more aggressive prostate cancer at diagnosis were calculated by urban-rural Appalachia status. Multivariable Poisson regressions were conducted. Multiple logistic regressions were used to examine the association between the geographic areas and more aggressive prostate cancer, after adjusting for confounders. RESULTS: There were 94,274 cases, ages 40-105 years, included. Urban non-Appalachia had the highest 2004-2014 age-adjusted incidence rates of prostate cancer and more aggressive prostate cancer (293.56 and 96.39 per 100,000 men, respectively) and rural Appalachia had the lowest rates (256.48 and 80.18 per 100,000 men, respectively). Among the cases, urban Appalachia were more likely [OR = 1.12; 95% confidence interval (CI) = 1.08-1.17] and rural Appalachia were less likely (OR = 0.92; 95% CI = 0.87-0.97) to have more aggressive prostate cancer at diagnosis compared with urban non-Appalachia. CONCLUSIONS: Lower incidence rates and the proportion of aggressive disease in rural Appalachia may be due to lower prostate cancer screening rates. More aggressive prostate cancer at diagnosis among the cases in urban Appalachia may be due to exposures that are prevalent in the region. IMPACT: Identifying geographic prostate cancer disparities will provide information to design programs aimed at reducing risk and closing the disparity gap.

LionVu 2.0 Usability Assessment for Pennsylvania, United States.

The Penn State Cancer Initiative implemented LionVu 1.0 (Penn State University, United States) in 2017 as a web-based mapping tool to educate and inform public health professionals about the cancer burden in Pennsylvania and 28 counties in central Pennsylvania, locally known as the catchment area. The purpose of its improvement, LionVu 2.0, was to assist investigators answer person-place-time questions related to cancer and its risk factors by examining several data variables simultaneously. The primary objective of this study was to conduct a usability assessment of a prototype of LionVu 2.0 which included area- and point-based data. The assessment was conducted through an online survey; 10 individuals, most of whom had a masters or doctorate degree, completed the survey. Although most participants had a favorable view of LionVu 2.0, many had little to no experience with web mapping. Therefore, it was not surprising to learn that participants wanted short 10-15-minute training videos to be available with future releases, and a simplified user-interface that removes advanced functionality. One unexpected finding was the suggestion of using LionVu 2.0 for teaching and grant proposals. The usability study of the prototype of LionVu 2.0 provided important feedback for its future development.