Cognitive function and bladder health among midlife adult women in the Coronary Artery Risk Development in Young Adults (CARDIA) study.

OBJECTIVE: The aim of this study was to examine whether different aspects of women's cognitive function are associated with lower urinary tract symptoms (LUTS) and their impact. METHODS: In 2010-2011, women aged 42 to 57 years in the Coronary Artery Risk Development in Young Adults study completed different tests of cognitive function, including the Digit Symbol Substitution Test, Rey Auditory Verbal Learning Test, and Stroop test. Two years later, data on LUTS and their impact were collected. LUTS/impact, a four-level composite variable ranging from bladder health to mild, moderate, and severe LUTS/impact, was regressed on each cognitive test separately, as well as a cognitive function composite variable. The analytic sample was composed of 1,021 women with complete data. RESULTS: When adjusting for sociodemographic variables (age, race, education) and gynecologic/obstetric variables (parity, menopausal status, hysterectomy, hormonal use), better performance on the cognitive function composite and Digit Symbol Substitution Test were both associated with lower odds of membership to a more severe LUTS/impact category (odds ratio, 0.90 [95% confidence interval, 0.83-0.98] and 0.89 [95% confidence interval, 0.82-0.97], respectively). These associations became nonsignificant when additionally adjusting for mechanisms that might explain an association between cognitive function and LUTS/impact, including health behaviors and health conditions that may covary with cerebral and peripheral vascular health and cognitive function. CONCLUSIONS: In this sample of midlife adult women, a modest association was found between better cognitive function and lower likelihood of LUTS/impact. Longitudinal studies are needed to further investigate the association between cognitive function and LUTS/impact, as well as potential explanatory mechanisms, particularly as women age and cognitive function varies to a greater degree.

Transcriptome-wide association analysis identifies candidate susceptibility genes for prostate-specific antigen levels in men without prostate cancer.

Deciphering the genetic basis of prostate-specific antigen (PSA) levels may improve their utility for prostate cancer (PCa) screening. Using genome-wide association study (GWAS) summary statistics from 95,768 PCa-free men, we conducted a transcriptome-wide association study (TWAS) to examine impacts of genetically predicted gene expression on PSA. Analyses identified 41 statistically significant (p < 0.05/12,192 = 4.10 × 10-6) associations in whole blood and 39 statistically significant (p < 0.05/13,844 = 3.61 × 10-6) associations in prostate tissue, with 18 genes associated in both tissues. Cross-tissue analyses identified 155 statistically significantly (p < 0.05/22,249 = 2.25 × 10-6) genes. Out of 173 unique PSA-associated genes across analyses, we replicated 151 (87.3%) in a TWAS of 209,318 PCa-free individuals from the Million Veteran Program. Based on conditional analyses, we found 20 genes (11 single tissue, nine cross-tissue) that were associated with PSA levels in the discovery TWAS that were not attributable to a lead variant from a GWAS. Ten of these 20 genes replicated, and two of the replicated genes had colocalization probability of >0.5: CCNA2 and HIST1H2BN. Six of the 20 identified genes are not known to impact PCa risk. Fine-mapping based on whole blood and prostate tissue revealed five protein-coding genes with evidence of causal relationships with PSA levels. Of these five genes, four exhibited evidence of colocalization and one was conditionally independent of previous GWAS findings. These results yield hypotheses that should be further explored to improve understanding of genetic factors underlying PSA levels.

Utilization of Pancreatic Endotherapy in Patients with Chronic Pancreatitis: Results From a Multicenter Cohort Study in the United States.

BACKGROUND AND AIMS: Although commonly used for treating complications of chronic pancreatitis (CP), data on the frequency and factors associated with the use of pancreatic endotherapy (PET) are limited. Our aim was to define the utilization and factors predictive for receiving PET in a well-characterized CP cohort. METHODS: This is a cross-sectional analysis of data from PROCEED, a multicenter US cohort study of CP. PET modalities primarily consisted of ERCP. A treatment course was defined as the number of sessions performed for a specific indication. A repeat course was defined as PET >1 year after completion of the last course. Multivariable logistic regression identified predictive factors for receiving PET, and proportional rates model assessed risk factors for repeat PET. RESULTS: Of a total of 681 subjects, 238 (34.9%) received PET. Factors associated with receiving PET included female sex (OR: 1.26, 95% CI: 1.03-1.53), lower education (OR: 1.30, 95% CI: 1.04-1.62), income ≤ $50,000 per year (OR: 1.35, 95% CI: 1.07-1.71) and prior acute pancreatitis (AP) (OR: 1.74, 95% CI: 1.31, 2.32). 103/238 subjects (43.3%) underwent repeat PET at a median duration of 2 years with 23.1% receiving 2 courses, 9.7% receiving 3 courses, and 10.4% receiving 4+ courses. CONCLUSIONS: Nearly half of patients with CP who undergo PET received one or more repeat courses within 2-3 years. In addition to a prior history of AP, demographic and socioeconomic factors were associated with receiving PET.

Circulating immune signatures in chronic pancreatitis with and without preceding acute pancreatitis: A pilot study.

OBJECTIVE: To investigate profiles of circulating immune signatures in healthy controls and chronic pancreatitis patients (CP) with and without a preceding history of acute pancreatitis (AP). METHODS: We performed a phase 1, cross-sectional analysis of prospectively collected serum samples from the PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translation StuDies (PROCEED) study. All samples were collected during a clinically quiescent phase. CP subjects were categorized into two subgroups based on preceding episode(s) of AP. Healthy controls were included for comparison. Blinded samples were analyzed using an 80-plex Luminex assay of cytokines, chemokines, and adhesion molecules. Group and pairwise comparisons of analytes were performed between the subgroups. RESULTS: In total, 133 patients with CP (111 with AP and 22 without AP) and 50 healthy controls were included. Among the 80 analytes studied, CP patients with a history of AP had significantly higher serum levels of pro-inflammatory cytokines (interleukin (IL)-6, IL-8, IL-1 receptor antagonist, IL-15) and chemokines (Cutaneous T-Cell Attracting Chemokine (CTACK), Monokine induced Gamma Interferon (MIG), Macrophage-derived Chemokine (MDC), Monocyte Chemoattractant Protein-1 (MCP-1)) compared to CP without preceding AP and controls. In contrast, CP patients without AP had immune profiles characterized by low systemic inflammation and downregulation of anti-inflammatory mediators, including IL-10. CONCLUSION: CP patients with a preceding history of AP have signs of systemic inflammatory activity even during a clinically quiescent phase. In contrast, CP patients without a history of AP have low systemic inflammatory activity. These findings suggest the presence of two immunologically diverse subtypes of CP.

DNA methylation markers for risk of metastasis in a cohort of men with localized prostate cancer.

Accurately identifying life-threatening prostate cancer (PCa) at time of diagnosis remains an unsolved problem. We evaluated whether DNA methylation status of selected candidate genes can predict the risk of metastasis beyond clinical risk factors in men with untreated PCa. A nested case-control study was conducted among men diagnosed with localized PCa at Kaiser Permanente California between 01/01/1997-12/31/2006 who did not receive curative treatments. Cases were those who developed metastasis within 10 years from diagnosis. Controls were selected using density sampling. Ninety-eight candidate genes were selected from functional categories of cell cycle control, metastasis/tumour suppressors, cell signalling, cell adhesion/motility/invasion, angiogenesis, and immune function, and 41 from pluripotency genes. Cancer DNA from diagnostic biopsy blocks were extracted and analysed. Associations of methylation status were assessed using CpG site level and principal components-based analysis in conditional logistic regressions. In 215 cases and 404 controls, 27 candidate genes were found to be statistically significant in at least one of the two analytical approaches. The agreement between the methods was 25.9% (7 candidate genes, including 2 pluripotency markers). The DNA methylation status of several candidate genes was significantly associated with risk of metastasis in untreated localized PCa patients. These findings may inform future risk prediction models for PCa metastasis beyond clinical characteristics.

Characterizing the spectrum of bladder health and lower urinary tract symptoms among men: Results from the CARDIA study.

OBJECTIVES: To operationalize a new definition for bladder health, we examined the distribution and impact of lower urinary tract symptoms (LUTS), along with risk factors, among men in the Coronary Artery Risk Development in Young Adults (CARDIA) study. METHODS: LUTS were defined by American Urologic Association Symptom Index (AUASI) scores and impact on quality of life (QoL). Separate questions assessed urinary incontinence (UI) and postvoid dribbling. We performed cluster analyses using AUASI scores, with and without urine incontinence and postvoid dribbling, and impact collected in 2010-11. We performed analyses to evaluate sociodemographic and cardiovascular risk factors between clusters. RESULTS: Among CARDIA men (mean age: 50.0, SD = 3.6; range: 42-56 years) with complete LUTS data (n = 929), we identified and compared four clusters: men who reported no or very mild symptoms and no impact on well-being (bladder health, n = 696, 75%), men with moderate symptoms and moderate impact on well-being (moderate symptoms/impact, n = 84, 9%), men with high symptoms and high impact on well-being (severe symptoms/impact, n = 117, 13%), and a separate group that reported moderate symptoms and UI with a high impact on well-being (UI + moderate symptoms/severe impact, n = 32, 3%). Exploration of the groupings showed a large percentage of postvoid dribbling across groups (overall 69%). Sociodemographic and cardiovascular risk factors were not associated with symptom/impact groups. CONCLUSIONS: Bladder health clustered into four categories. A majority of middle-aged men in the community showed no or mild bladder symptoms without impact on QoL. Postvoid dribbling is pervasive but did not cluster with a specific LUTS or impact category.

Systemic Neutrophil Gelatinase-Associated Lipocalin Alterations in Chronic Pancreatitis: A Multicenter, Cross-Sectional Study.

INTRODUCTION: Chronic pancreatitis (CP) is a progressive fibroinflammatory disorder lacking therapies and biomarkers. Neutrophil gelatinase-associated lipocalin (NGAL) is a proinflammatory cytokine elevated during inflammation that binds fatty acids (FAs) such as linoleic acid. We hypothesized that systemic NGAL could serve as a biomarker for CP and, with FAs, provide insights into inflammatory and metabolic alterations. METHODS: NGAL was measured by immunoassay, and FA composition was measured by gas chromatography in plasma (n = 171) from a multicenter study, including controls (n = 50), acute and recurrent acute pancreatitis (AP/RAP) (n = 71), and CP (n = 50). Peripheral blood mononuclear cells (PBMCs) from controls (n = 16), AP/RAP (n = 17), and CP (n = 15) were measured by cytometry by time-of-flight. RESULTS: Plasma NGAL was elevated in subjects with CP compared with controls (area under the curve [AUC] = 0.777) or AP/RAP (AUC = 0.754) in univariate and multivariate analyses with sex, age, body mass index, and smoking (control AUC = 0.874; AP/RAP AUC = 0.819). NGAL was elevated in CP and diabetes compared with CP without diabetes ( P < 0.001). NGAL + PBMC populations distinguished CP from controls (AUC = 0.950) or AP/RAP (AUC = 0.941). Linoleic acid was lower, whereas dihomo-γ-linolenic and adrenic acids were elevated in CP ( P < 0.05). Linoleic acid was elevated in CP with diabetes compared with CP subjects without diabetes ( P = 0.0471). DISCUSSION: Elevated plasma NGAL and differences in NGAL + PBMCs indicate an immune response shift that may serve as biomarkers of CP. The potential interaction of FAs and NGAL levels provide insights into the metabolic pathophysiology and improve diagnostic classification of CP.

Circulating immune signatures across clinical stages of chronic pancreatitis: a pilot study.

OBJECTIVE: This pilot study seeks to identify serum immune signatures across clinical stages of patients with chronic pancreatitis (CP). METHODS: We performed a cross-sectional analysis of prospectively collected serum samples from the PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translation StuDies-study. CP subjects were categorised into three clinical stages based on the presence/absence of metabolic complications: (1) CP with no diabetes and exocrine pancreatic dysfunction (EPD), (2) CP with either diabetes or EPD, and (3) CP with diabetes and EPD. Blinded samples were analysed using an 80-plex Luminex assay of cytokines/chemokines/adhesion molecules. Group and pairwise comparisons were performed to characterise immune signatures across CP subgroups. RESULTS: A total of 135 CP subjects (evenly distributed between clinical stages) and 50 controls were studied. Interleukin-6 (IL-6), interleukin-8 (IL-8), and soluble intercellular adhesion molecule 1 (sICAM-1) were significantly elevated in CP subjects compared to controls. The levels of IL-6 and IL-8 increased with advancing disease stages, with the highest levels observed in CP with diabetes and EPD (clinical stage 3). Furthermore, hepatocyte growth factor and macrophage-derived chemokine were significantly increased in clinical stage 3 compared to controls. CONCLUSION: Our study reveals a progressive elevation in pro-inflammatory cytokines and chemokines with advancing clinical stages of CP. These findings indicate potential targets for the development of disease-modifying interventions.

Job strain, occupation, and bladder health among women.

OBJECTIVES: Lower urinary tract symptoms (LUTS) are common among employed women. An underexplored topic is whether characteristics of women's occupations may influence LUTS. The present study examined whether job strain and its individual components (psychological demands, decision latitude) were associated with greater LUTS and their impact and whether, compared to managerial and professional occupations, occupations characterized by manual labor, sales, service, nursing, and teaching were associated with greater LUTS and their impact. METHODS: Coronary Artery Risk Development in Young Adults cohort study data were analyzed. Job strain and occupation were assessed in 1987-88 and 1995-96. In 2012-13, LUTS and their impact were assessed. LUTS/impact category (a composite variable ranging from bladder health to mild, moderate, and severe LUTS/impact) was regressed on job strain and occupation in separate analyses, adjusting for age, race, parity, education, and financial hardship (n = 1006). RESULTS: Job strain and its individual components were not associated with LUTS/impact. In comparison to managerial and professional occupations, service occupations in 1987-88 and 1995-96 were both associated with greater odds of LUTS/impact in proportional odds logistic regression analyses. Employment as a nurse, health assistant, or health aide in 1995-96 was associated with greater odds of any LUTS/impact versus bladder health. Support positions in 1987-88 and sales positions in 1995-96 were associated with greater odds of moderate or severe LUTS/impact versus bladder health or mild LUTS/impact. CONCLUSIONS: Future research should examine characteristics of workplaces that may promote or constrain bladder health (e.g., time and autonomy to void when desired, infrastructure to void).

Financial strain across 25 years and women's bladder health: a life course perspective.

BACKGROUND: A small number of cross-sectional studies have found that financial insecurity-a social determinant of health-is associated with lower urinary tract symptoms. OBJECTIVE: This study aimed to examine (1) whether women in the Coronary Artery Risk Development in Young Adult Study with higher levels of financial strain, assessed at 7 time points across 25 years beginning in 1985-1986, were more likely to report lower urinary tract symptoms and impact after the 2010-2011 financial strain assessment and (2) whether healthcare access and comorbidities mediated potential associations. STUDY DESIGN: This prospective cohort study recruited Black and White participants aged 18 to 30 years at baseline (1985-1986) from the populations of 4 US cities. The analytical sample was composed of women with complete data for analyses involving financial strain trajectories across 7 assessments (n=841) and mediation tests of data collected at 4 assessments (n=886). The outcome variable was previously developed through a cluster analysis of urinary incontinence severity, urinary incontinence impact, other lower urinary tract symptoms severity, and their impact in 2012-2013, which yielded 4 lower urinary tract symptoms and impact cluster categories: women with no symptom or very mild symptoms and no impact vs women with mild, moderate, or severe symptoms and impact. Financial strain was defined as finding it "very hard," "hard," or "somewhat hard" (vs "not very hard") to pay for the very basics, such as food, heating, and medical care. Using proportional odds logistic regression, cluster categories were regressed on the financial strain trajectory group, adjusting for age, race, education, and parity. For mediation analyses, separate financial strain variables (difficulty paying for the very basics, such as food and heating, and difficulty paying for medical care) were created by combining 1995-1996 and 2000-2001 values. Two healthcare access variables (difficulty receiving care and underutilization of care) and a single comorbidity index (smoking, physical inactivity, body mass index, hypertension, diabetes mellitus, and depressive symptoms) were created by combining 2005-2006 and 2010-2011 values. Regression analyses and structural equation modeling were used to test whether healthcare access and comorbidities mediated associations between financial strain and lower urinary tract symptoms and impact cluster categories. RESULTS: In comparison to women who were consistently not financially strained, women who were consistently strained (odds ratio, 2.10; 95% confidence interval, 1.13-3.91), shifted into being strained (odds ratio, 2.00; 95% confidence interval, 1.29-3.10), or experienced >1 shift in strain (odds ratio, 1.99; 95% confidence interval, 1.46-2.71) had roughly twice the odds of reporting greater lower urinary tract symptoms and impact. Underutilization of healthcare and comorbidities mediated the association between difficulty paying for medical care and lower urinary tract symptoms and impact. In the structural equation model, difficulty paying for medical care and underutilization of care were associated (ß=.31; P<.01), as was underutilization of care and greater lower urinary tract symptoms and impact (ß=.09; P<.01). Moreover, difficulty paying for medical care and the comorbidity index were associated (ß=.34; P<.01), as was the comorbidity index and greater lower urinary tract symptoms and impact (ß=.24; P<.01). Collectively, these mediation pathways eliminated a direct association between difficulty paying for medical care and lower urinary tract symptoms and impact. CONCLUSION: Underutilization of healthcare and comorbidities explained an association between financial strain (difficulty paying for medical care) and lower urinary tract symptoms and impact. Research is needed to confirm the findings and examine other mechanisms that may further explain the association. Accumulated evidence may inform future policies and practices.

The economics of nature's healing touch: A systematic review and conceptual framework of green space, pharmaceutical prescriptions, and healthcare expenditure associations.

Green spaces play a crucial role in promoting sustainable and healthy lives. Recent evidence shows that green space also may reduce the need for healthcare, prescription medications, and associated costs. This systematic review provides the first comprehensive assessment of the available literature examining green space exposure and its associations with healthcare prescriptions and expenditures. We applied Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines to search MEDLINE, Scopus, and Web of Science for observational studies published in English through May 6, 2023. A quality assessment of the included studies was conducted using the Office of Health Assessment and Translation (OHAT) tool, and the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) assessment was used to evaluate the overall quality of evidence. Our search retrieved 26 studies that met the inclusion criteria and were included in our review. Among these, 20 studies (77 % of the total) showed beneficial associations of green space exposure with healthcare prescriptions or expenditures. However, most studies had risks of bias, and the overall strength of evidence for both outcomes was limited. Based on our findings and related bodies of literature, we present a conceptual framework to explain the possible associations and complex mechanisms underlying green space and healthcare outcomes. The framework differs from existing green space and health models by including upstream factors related to healthcare access (i.e., rurality and socioeconomic status), which may flip the direction of associations. Additional research with lower risks of bias is necessary to validate this framework and better understand the potential for green space to reduce healthcare prescriptions and expenditures.

Discrimination and bladder health among women in the CARDIA cohort study: Life course and intersectionality perspectives.

OBJECTIVE: This study examines whether discriminatory experiences are associated with lower urinary tract symptoms (LUTS) and their impact among 972 women in the Coronary Artery Risk Development in Young Adults (CARDIA) cohort study, which recruited participants from 4 cities in the United States. METHOD: Exposure to discrimination was assessed 3 times (1992-93, 2000-01, 2010-11) and averaged across assessments. Participants separately reported whether they experienced discrimination on the basis of their gender, race or color, and socioeconomic position or social class. For each social identity, discrimination was assessed in 6-7 settings (e.g., when getting a job, medical care, or housing). At different time points, women who reported discriminatory experiences for a given social identity were asked how frequently the discrimination occurred and how stressful experience(s) were. Following the 2010-11 assessment, data on LUTS and their impact were collected. Women were classified into bladder health versus mild, moderate, or severe symptoms/impact clusters. RESULTS: More Black than White women reported discriminatory experiences across all social identities and most settings. Perceived stress of discriminatory experiences did not differ between Black and White women. In analyses stratified by race and social identity, White women reported LUTS/impact with discriminatory experiences in more settings, more frequent discriminatory experiences across settings, and each additional social identity for which discrimination was experienced. Black women reported LUTS/impact with more frequent discriminatory experiences across settings. For Black women, greater perceived stress of both gender and race discrimination were associated with LUTS/impact. For White women, only greater perceived stress of race discrimination was associated with LUTS/impact. CONCLUSIONS: This is one of the first studies to examine discrimination in relation to LUTS/impact. Additional research is needed to better understand differences in how discriminatory experiences based on potentially intersecting identities may be related to bladder health among women.

Genome-wide association study of prostate-specific antigen levels in 392,522 men identifies new loci and improves cross-ancestry prediction.

We conducted a multi-ancestry genome-wide association study of prostate-specific antigen (PSA) levels in 296,754 men (211,342 European ancestry; 58,236 African ancestry; 23,546 Hispanic/Latino; 3,630 Asian ancestry; 96.5% of participants were from the Million Veteran Program). We identified 318 independent genome-wide significant (p≤5e-8) variants, 184 of which were novel. Most demonstrated evidence of replication in an independent cohort (n=95,768). Meta-analyzing discovery and replication (n=392,522) identified 447 variants, of which a further 111 were novel. Out-of-sample variance in PSA explained by our new polygenic risk score reached 16.9% (95% CI=16.1%-17.8%) in European ancestry, 9.5% (95% CI=7.0%-12.2%) in African ancestry, 18.6% (95% CI=15.8%-21.4%) in Hispanic/Latino, and 15.3% (95% CI=12.7%-18.1%) in Asian ancestry, and lower for higher age. Our study highlights how including proportionally more participants from underrepresented populations improves genetic prediction of PSA levels, with potential to personalize prostate cancer screening.

Genome-wide methylation profiling of diagnostic tumor specimens identified DNA methylation markers associated with metastasis among men with untreated localized prostate cancer.

BACKGROUND: We used a genome-wide discovery approach to identify methylation markers associated with metastasis in men with localized prostate cancer (PCa), as better identification of those at high risk of metastasis can inform treatment decision-making. METHODS: We identified men with localized PCa at Kaiser Permanente California (January 1, 1997-December 31, 2006) who did not receive curative treatment and followed them for 10 years to determine metastasis status. Cases were chart review-confirmed metastasis, and controls were matched using density sampling. We extracted DNA from the cancerous areas in the archived diagnostic tissue blocks. We used Illumina's Infinium MethylationEPIC BeadChip for methylation interrogation. We used conditional logistic regression and Bonferroni's correction to identify methylation markers associated with metastasis. In a separate validation cohort (2007), we evaluated the added predictive utility of the methylation score beyond clinical risk score. RESULTS: Among 215 cases and 404 controls, 31 CpG sites were significantly associated with metastasis status. Adding the methylation score to the clinical risk score did not meaningfully improve the c-statistic (0.80-0.81) in the validation cohort, though the score itself was statistically significant (p < 0.01). In the validation cohort, both clinical risk score alone and methylation marker score alone are well calibrated for predicted 10-year metastasis risks. Adding the methylation score to the clinical risk score only marginally improved predictive risk calibration. CONCLUSION: Our findings do not support the use of these markers to improve clinical risk prediction. The methylation markers identified may inform novel hypothesis in the roles of these genetic regions in metastasis development.

Real-World Use of Electronic Patient-Reported Outcome (ePRO) Tools Integrated in the Electronic Medical Record During Radiation Therapy for Head and Neck Cancer: Feasibility Study.

Purpose Use of electronic patient-reported outcome (ePRO) tools in routine oncology practice can be challenging despite evidence showing they can improve survival, improve patient and practitioner satisfaction, and reduce medical resource utilization. Head and neck cancer (HNC) patients receiving radiation therapy (RT) may be a group that would particularly benefit from interventions focused on early symptom management. Methods Patients undergoing definitive RT for HNC were enrolled in a feasibility study and received ePRO surveys integrated within the electronic medical record (EMR) on a weekly basis during RT. After completion of each ePRO survey, a radiation oncology registered nurse documented the findings and subsequent interventions within the EMR. Results Thirty-four patients with HNC who received curative RT at a single center were enrolled. The total number of surveys completed was 194 with a median of 7 surveys per patient (range 1-8). There was a total of 887 individual abnormal findings reported on the ePROs, and the authors found that all 887 had a corresponding documented intervention. Post-treatment practitioner questionnaires highlighted that ePROs were felt to be helpful for the care team in providing care to HNC patients. Conclusion For patients with HNC receiving RT, ePROs can be effectively utilized to address patient symptoms within an integrated health care system. Creating an infrastructure for the use of ePROs integrated within the EMR in routine care requires an approach that accounts for local workflows and buy-in from patients and the entire care team.

Endogenous sex steroid hormones and risk of liver cancer among US men: Results from the Liver Cancer Pooling Project.

Background & Aims: Incidence rates of liver cancer in most populations are two to three times higher among men than women. The higher rates among men have led to the suggestion that androgens are related to increased risk whereas oestrogens are related to decreased risk. This hypothesis was investigated in the present study via a nested case-control analysis of pre-diagnostic sex steroid hormone levels among men in five US cohorts. Methods: Concentrations of sex steroid hormones and sex hormone-binding globulin were quantitated using gas chromatography-mass spectrometry and a competitive electrochemiluminescence immunoassay, respectively. Multivariable conditional logistic regression was used to calculate odds ratios (ORs) and 95% CIs for associations between hormones and liver cancer among 275 men who subsequently developed liver cancer and 768 comparison men. Results: Higher concentrations of total testosterone (OR per one-unit increase in log2 = 1.77, 95% CI = 1.38-2.29), dihydrotestosterone (OR = 1.76, 95% CI = 1.21-2.57), oestrone (OR = 1.74, 95% CI = 1.08-2.79), total oestradiol (OR = 1.58, 95% CI=1.22-20.05), and sex hormone-binding globulin (OR = 1.63, 95% CI = 1.27-2.11) were associated with increased risk. Higher concentrations of dehydroepiandrosterone (DHEA), however, were associated with a 53% decreased risk (OR = 0.47, 95% CI = 0.33-0.68). Conclusions: Higher concentrations of both androgens (testosterone, dihydrotestosterone) and their aromatised oestrogenic metabolites (oestrone, oestradiol) were observed among men who subsequently developed liver cancer compared with men who did not. As DHEA is an adrenal precursor of both androgens and oestrogens, these results may suggest that a lower capacity to convert DHEA to androgens, and their subsequent conversion to oestrogens, confers a lower risk of liver cancer, whereas a greater capacity to convert DHEA confers a greater risk. Impact and implications: This study does not fully support the current hormone hypothesis as both androgen and oestrogen levels were associated with increased risk of liver cancer among men. The study also found that higher DHEA levels were associated with lower risk, thus suggesting the hypothesis that greater capacity to convert DHEA could be associated with increased liver cancer risk among men.

Adipose tissue and skeletal muscle wasting precede clinical diagnosis of pancreatic cancer.

Patients with pancreatic cancer commonly develop weight loss and muscle wasting. Whether adipose tissue and skeletal muscle losses begin before diagnosis and the potential utility of such losses for earlier cancer detection are not well understood. We quantify skeletal muscle and adipose tissue areas from computed tomography (CT) imaging obtained 2 months to 5 years before cancer diagnosis in 714 pancreatic cancer cases and 1748 matched controls. Adipose tissue loss is identified up to 6 months, and skeletal muscle wasting is identified up to 18 months before the clinical diagnosis of pancreatic cancer and is not present in the matched control population. Tissue losses are of similar magnitude in cases diagnosed with localized compared with metastatic disease and are not correlated with at-diagnosis circulating levels of CA19-9. Skeletal muscle wasting occurs in the 1-2 years before pancreatic cancer diagnosis and may signal an upcoming diagnosis of pancreatic cancer.

Serum Biomarkers of Nociceptive and Neuropathic Pain in Chronic Pancreatitis.

Debilitating abdominal pain is a common symptom affecting most patients with chronic pancreatitis (CP). There are multiple underlying mechanisms that contribute to CP-related pain, which makes successful treatment difficult. The identification of biomarkers for subtypes of pain could provide viable targets for nonopioid interventions and the development of mechanistic approaches to pain management in CP. Nineteen inflammation- and nociception-associated proteins were measured in serum collected from 358 subjects with definite CP enrolled in PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translational StuDies, a prospective observational study of pancreatitis in US adult subjects. First, serum levels of putative biomarkers were compared between CP subjects with and without pain. Only platelet-derived growth factor B (PDGF-B) stood out, with levels significantly higher in the CP pain group as compared to subjects with no pain. Subjects with pain were then stratified into 4 pain subtypes (Neuropathic, Nociceptive, Mixed, and Unclassified). A comparison of putative biomarker concentration among 5 groups (no pain and 4 pain subtypes) identified unique proteins that were correlated with pain subtypes. Serum transforming growth factor beta 1 (TGFß1) level was significantly higher in the Nociceptive pain group compared to the No pain group, suggesting that TGFß1 may be a biomarker for nociceptive pain. The Neuropathic pain only group was too small to detect statistical differences. However, glycoprotein 130 (GP130), a coreceptor for interleukin 6, was significantly higher in the Mixed pain group compared to the groups lacking a neuropathic pain component. These data suggest that GP130 may be a biomarker for neuropathic pain in CP. PERSPECTIVE: Serum TGFß1 and GP130 may be biomarkers for nociceptive and neuropathic CP pain, respectively. Preclinical data suggest inhibiting TGFß1 or GP130 reduces CP pain in rodent models, indicating that additional translational and clinical studies may be warranted to develop a precision medicine approach to the management of pain in CP.

Genetically adjusted PSA levels for prostate cancer screening.

Prostate-specific antigen (PSA) screening for prostate cancer remains controversial because it increases overdiagnosis and overtreatment of clinically insignificant tumors. Accounting for genetic determinants of constitutive, non-cancer-related PSA variation has potential to improve screening utility. In this study, we discovered 128 genome-wide significant associations (P < 5 × 10-8) in a multi-ancestry meta-analysis of 95,768 men and developed a PSA polygenic score (PGSPSA) that explains 9.61% of constitutive PSA variation. We found that, in men of European ancestry, using PGS-adjusted PSA would avoid up to 31% of negative prostate biopsies but also result in 12% fewer biopsies in patients with prostate cancer, mostly with Gleason score <7 tumors. Genetically adjusted PSA was more predictive of aggressive prostate cancer (odds ratio (OR) = 3.44, P = 6.2 × 10-14, area under the curve (AUC) = 0.755) than unadjusted PSA (OR = 3.31, P = 1.1 × 10-12, AUC = 0.738) in 106 cases and 23,667 controls. Compared to a prostate cancer PGS alone (AUC = 0.712), including genetically adjusted PSA improved detection of aggressive disease (AUC = 0.786, P = 7.2 × 10-4). Our findings highlight the potential utility of incorporating PGS for personalized biomarkers in prostate cancer screening.

Narcolepsy risk loci outline role of T cell autoimmunity and infectious triggers in narcolepsy.

Narcolepsy type 1 (NT1) is caused by a loss of hypocretin/orexin transmission. Risk factors include pandemic 2009 H1N1 influenza A infection and immunization with Pandemrix®. Here, we dissect disease mechanisms and interactions with environmental triggers in a multi-ethnic sample of 6,073 cases and 84,856 controls. We fine-mapped GWAS signals within HLA (DQ0602, DQB1*03:01 and DPB1*04:02) and discovered seven novel associations (CD207, NAB1, IKZF4-ERBB3, CTSC, DENND1B, SIRPG, PRF1). Significant signals at TRA and DQB1*06:02 loci were found in 245 vaccination-related cases, who also shared polygenic risk. T cell receptor associations in NT1 modulated TRAJ*24, TRAJ*28 and TRBV*4-2 chain-usage. Partitioned heritability and immune cell enrichment analyses found genetic signals to be driven by dendritic and helper T cells. Lastly comorbidity analysis using data from FinnGen, suggests shared effects between NT1 and other autoimmune diseases. NT1 genetic variants shape autoimmunity and response to environmental triggers, including influenza A infection and immunization with Pandemrix®.