Risk factors for HCC in contemporary cohorts of patients with cirrhosis.

BACKGROUND AND AIMS: Etiological risk factors for cirrhosis have changed in the last decade. It remains unclear to what extent these trends in cirrhosis risk factors have changed HCC risk. APPROACH AND RESULTS: We used data from two contemporary, prospective multiethnic cohorts of patients with cirrhosis: the Texas Hepatocellular Carcinoma Consortium Cohort and the Houston Veterans Administration Cirrhosis Surveillance Cohort. Patients with cirrhosis were enrolled from seven US centers and followed until HCC diagnosis, transplant, death, or June 30, 2021. We calculated the annual incidence rates for HCC and examined the effects of etiology, demographic, clinical, and lifestyle factors on the risk of HCC. We included 2733 patients with cirrhosis (mean age 60.1 years, 31.3% women). At enrollment, 19.0% had active HCV, 23.3% had cured HCV, 16.1% had alcoholic liver disease, and 30.1% had NAFLD. During 7406 person-years of follow-up, 135 patients developed HCC at an annual incidence rate of 1.82% (95% CI, 1.51-2.13). The annual HCC incidence rate was 1.71% in patients with cured HCV, 1.32% in patients with alcoholic liver disease, and 1.24% in patients with NAFLD cirrhosis. Compared to patients with NAFLD, the risk of progression to HCC was 2-fold higher in patients with cured HCV (HR, 2.04; 95% CI, 1.24-3.35). Current smoking (HR, 1.63; 95% CI, 1.01-2.63) and overweight/obesity (HR, 1.79; 95% CI, 1.08-2.95) were also associated with HCC risk. CONCLUSIONS: HCC incidence among patients with cirrhosis was lower than previously reported. HCC risk was variable across etiologies, with higher risk in patients with HCV cirrhosis and lower risk in those with NAFLD cirrhosis. Current smoking and overweight/obesity increased HCC risk across etiologies.

Bayesian Approach to Understand the Association Between Treatment Down-staging and Survival for Patients With Pancreatic Adenocarcinoma.

OBJECTIVE: To evaluate the association between staging concordance, treatment sequencing, and response to neoadjuvant therapy (NAT) on the survival of patients with pancreatic ductal adenocarcinoma (PDAC). SUMMARY OF BACKGROUND DATA: NAT is increasingly utilized in the management of patients with PDAC, but it is unclear whether its benefit is contingent on tumor down-staging. METHODS: This was a cohort study of stage I-III PDAC patients in the National Cancer Database (2006-2015) treated with upfront resection or NAT followed by surgery. We determined staging concordance using patients' clinical and pathological staging data. For NAT patients, we used Bayesian analysis to ascertain staging concordance accounting for down-staging. RESULTS: Among 16,597 patients treated at 979 hospitals, 13,982 had an upfront resection and 2,615 NAT followed by surgery. Overall survival (OS) at 5-years ranged from 26.0% (95% CI 24.9%-27.1%) among cT1-2N0 patients to 18.6% (17.9%-19.2%) among cT1-3N+ ones. Patients with cT3-4 or cN+ tumors had improved OS after NAT compared to upfront surgery (all p< 0.001), while there was no difference among patients with cT1-2N0 (P = 0.16) disease. Relative to accurately staged cT1-2-3N+ or cT4 patients treated with upfront surgery, NAT was associated with a lower risk of death [HR 0.46 (0.37-0.57) for N+; HR 0.56 (0.40-0.77) for T4 disease], even among those without tumor down-staging [HR 0.81 (0.73-0.90) for N+; HR 0.48 (0.39-0.60) for T4]. CONCLUSIONS: NAT is associated with improved survival for PDAC, particularly for patients with more advanced disease and regardless of down-staging. Consideration should be given to recommending NAT for all PDAC patients.

Clinical Understaging, Treatment Response, and Survival Among Esophageal Adenocarcinoma Patients.

INTRODUCTION: Selecting appropriate management for patients with esophageal adenocarcinoma (EA) is predicated on accurate clinical staging information. Inaccurate information could lead to inappropriate treatment and suboptimal survival. We investigated the relationship between staging accuracy, treatment, and survival. METHODS: This was a national cohort study of EA patients in the National Cancer Data Base (2006-2015) treated with upfront resection or neoadjuvant therapy (NAT). Clinical and pathological staging information was used to ascertain staging concordance for each patient. For NAT patients, Bayesian analysis was used to account for potential downstaging. We evaluated the association between staging concordance, receipt of NAT, and survival through hierarchical logistic regression and multivariable Cox regression. RESULTS: Among 7635 EA patients treated at 877 hospitals, 3038 had upfront resection and 4597 NAT followed by surgery. Relative to accurately staged patients, understaging was associated with a lower likelihood (odds ratio [OR] 0.04 95% confidence interval [CI] 0.02-0.05) while overstaging was associated with a greater likelihood of receiving NAT (OR 1.98 [1.53-2.56]). Relative to upfront surgery, treatment of cT1N0 patients with NAT was associated with a higher risk of death (HR 3.08 [2.36-4.02]). For accurately or overstaged cT3-T4 patients, NAT was associated with a lower risk of death whether downstaging occurred (ypN0 disease-HR 0.67 [0.49-0.92]; N+ disease-HR 0.55 [0.45-0.66]) or not (ypN + disease-HR 0.78 [95% CI 0.65-0.93]). CONCLUSIONS: Clinical understaging is associated with receipt of NAT which in turn may have a stage-specific impact on patients' survival regardless of treatment response. Guidelines should account for the possibility of inaccurate clinical staging.

Understanding the association between clinical staging accuracy, treatment response, and survival among gastric cancer patients through Bayesian analysis.

BACKGROUND: Neoadjuvant therapy (NAT) improves survival among patients with locally advanced gastric cancer (GC), but it remains unclear whether its benefit is contingent on treatment response. METHODS: This is a national cohort study of stage Ib-III GC patients in the National Cancer Data Base (2006-2015) treated with upfront resection or NAT followed by surgery. Bayesian analysis was used for NAT patients to ascertain staging concordance and to account for down-staging. We used multivariable Cox regression to evaluate the association between staging concordance, treatment, response to NAT, and survival. RESULTS: The cohort included 13 340 patients treated at 1124 hospitals. Staging concordance ranged from 86.1% for cT3-4N+ to 34.7% for cT2N0 patients. Relative to accurately staged patients treated with upfront surgery, NAT was associated with a decreased risk of death if there was disease down-staging among those with cT1-2N+ (hazard ratio [HR]: 0.43 [0.30-0.61]), cT3-4N0 (HR: 0.69 [0.54-0.88]), and cT3-4N+ (HR: 0.51 [0.48-0.58]) tumors, and in the absence of down-staging among cT3-4N+ patients (HR: 0.83 [0.74-0.92]). Conversely, NAT without down-staging increased the risk of death among those with intermediate-stage disease. CONCLUSIONS: NAT is associated with improved survival for GC, but it seems to be contingent on treatment response among patients with intermediate-stage disease.

Comparative Effectiveness of Neoadjuvant Therapy and Upfront Resection for Patients with Resectable Pancreatic Adenocarcinoma: An Instrumental Variable Analysis.

BACKGROUND: Neoadjuvant therapy (NAT) is increasingly being used in the management of patients with resectable pancreatic ductal adenocarcinoma (PDAC); however, there is a lack of evidence regarding the benefit among these patients. OBJECTIVE: The aim of this study was to evaluate overall survival (OS) in PDAC patients with resectable disease treated with NAT or upfront resection through instrumental variable (IV) analysis. DESIGN: A national cohort study of resectable PDAC patients in the National Cancer Data Base (2007-2015) treated with either upfront surgery or resection after NAT. Using multivariable modeling and IV methods, OS was compared between those treated with NAT and upfront resection. The IV was hospital-level NAT utilization in the most recent year prior to treatment. RESULTS: The cohort included 16,666 patients (14,012 upfront resection; 2654 NAT) treated at 779 hospitals. Among those treated with upfront resection, 59.9% received any adjuvant therapy. NAT patients had higher median (27.9 months, 95% confidence interval [CI] 26.2-29.1) and 5-year OS (24.1%, 95% CI 21.9-26.3%) compared with those treated with upfront surgery (median 21.2 months, 95% CI 20.7-21.6; 5-year survival 20.9%, 95% CI 20.1-21.7%). After multivariable modeling, NAT was associated with an approximately 20% decrease in the risk of death (hazard ratio [HR] 0.78, 95% CI 0.73-0.84), and this effect was magnified in the IV analysis (HR 0.61, 95% CI 0.47-0.79). CONCLUSIONS: In patients with resectable PDAC, NAT is associated with improved survival relative to upfront resection. Given the benefits of multimodality therapy and the challenges in receiving adjuvant therapy, consideration should be given to treating all PDAC patients with NAT.

Houston hurricane Harvey health (Houston-3H) study: assessment of allergic symptoms and stress after hurricane Harvey flooding.

BACKGROUND: In August 2017, Hurricane Harvey caused unprecedented flooding across the greater Houston area. Given the potential for widespread flood-related exposures, including mold and sewage, and the emotional and mental toll caused by the flooding, we sought to evaluate the short- and long-term impact of flood-related exposures on the health of Houstonians. Our objectives were to assess the association of flood-related exposures with allergic symptoms and stress among Houston-area residents at two time points: within approximately 30 days (T1) and 12 months (T2) after Hurricane Harvey's landfall. METHODS: The Houston Hurricane Harvey Health (Houston-3H) Study enrolled a total of 347 unique participants from four sites across Harris County at two times: within approximately 1-month of Harvey (T1, n = 206) and approximately 12-months after Harvey (T2, n = 266), including 125 individuals who participated at both time points. Using a self-administered questionnaire, participants reported details on demographics, flood-related exposures, and health outcomes, including allergic symptoms and stress. RESULTS: The majority of participants reported hurricane-related flooding in their homes at T1 (79.1%) and T2 (87.2%) and experienced at least one allergic symptom after the hurricane (79.4% at T1 and 68.4% at T2). In general, flood-exposed individuals were at increased risk of upper respiratory tract allergic symptoms, reported at both the T1 and T2 time points, with exposures to dirty water and mold associated with increased risk of multiple allergic symptoms. The mean stress score of study participants at T1 was 8.0 ± 2.1 and at T2, 5.1 ± 3.2, on a 0-10 scale. Participants who experienced specific flood-related exposures reported higher stress scores when compared with their counterparts, especially 1 year after Harvey. Also, a supplementary paired-samples analysis showed that reports of wheezing, shortness of breath, and skin rash did not change between T1 and T2, though other conditions were less commonly reported at T2. CONCLUSION: These initial Houston-3H findings demonstrate that flooding experiences that occurred as a consequence of Hurricane Harvey had lasting impacts on the health of Houstonians up to 1 year after the hurricane.

Underuse of Surgery Accounts for Racial Disparities in Esophageal Cancer Survival Times: A Matched Cohort Study.

BACKGROUND & AIMS: There are racial disparities in survival times of patients with esophageal cancer. We examined the sequential effects of characteristics, diagnosis, and treatment-related factors on the disparity in survival times of black vs white patients with esophageal cancer. METHODS: We identified 1900 black and 15,523 non-Hispanic white (NHW) patients, 65 years or older, diagnosed with esophageal squamous cell carcinoma or esophageal adenocarcinoma from 1994 through 2011 in the Surveillance Epidemiology and End Results (SEER)-Medicare database. Patients were followed up until death or December 31, 2012. Three sets of 1900 NHW patients were matched sequentially to the same set of 1900 black patients, based on demographics (age, sex, year of diagnosis, and SEER site), presentation (demographics plus cancer stage, grade, and comorbidity), and treatment (presentation variables plus surgery, chemotherapy, or radiation therapy). RESULTS: The absolute difference in 5-year survival between black patients (13.3%) and NHW patients (18.4%) was 5.1% (95% CI, 2.3%-7.7%; P = .001) in the demographics match. After we matched for presentation, the difference in 5-year survival was reduced to 2.3% (95% CI, 0.3%-4.8%), but remained statistically significant (P = .04). Additional matching of patients on treatment-related factors eliminated the racial difference in 5-year survival (P = .59). Among patients matched for disease presentation, only 10.8% of black patients underwent surgery, compared with 22.8% of NHW patients (P < .001). Histology, tumor location, socioeconomic status, chemotherapy, and radiation therapy each were associated with the receipt of surgery. None of these factors, however, could explain the racial difference in the receipt of surgery. CONCLUSIONS: In the SEER-Medicare database, underuse of surgical treatment can account for the disparities in survival times between black and NHW patients with esophageal cancer.

Gene-age interactions in blood pressure regulation: a large-scale investigation with the CHARGE, Global BPgen, and ICBP Consortia.

Although age-dependent effects on blood pressure (BP) have been reported, they have not been systematically investigated in large-scale genome-wide association studies (GWASs). We leveraged the infrastructure of three well-established consortia (CHARGE, GBPgen, and ICBP) and a nonstandard approach (age stratification and metaregression) to conduct a genome-wide search of common variants with age-dependent effects on systolic (SBP), diastolic (DBP), mean arterial (MAP), and pulse (PP) pressure. In a two-staged design using 99,241 individuals of European ancestry, we identified 20 genome-wide significant (p ≤ 5 × 10(-8)) loci by using joint tests of the SNP main effect and SNP-age interaction. Nine of the significant loci demonstrated nominal evidence of age-dependent effects on BP by tests of the interactions alone. Index SNPs in the EHBP1L1 (DBP and MAP), CASZ1 (SBP and MAP), and GOSR2 (PP) loci exhibited the largest age interactions, with opposite directions of effect in the young versus the old. The changes in the genetic effects over time were small but nonnegligible (up to 1.58 mm Hg over 60 years). The EHBP1L1 locus was discovered through gene-age interactions only in whites but had DBP main effects replicated (p = 8.3 × 10(-4)) in 8,682 Asians from Singapore, indicating potential interethnic heterogeneity. A secondary analysis revealed 22 loci with evidence of age-specific effects (e.g., only in 20 to 29-year-olds). Age can be used to select samples with larger genetic effect sizes and more homogenous phenotypes, which may increase statistical power. Age-dependent effects identified through novel statistical approaches can provide insight into the biology and temporal regulation underlying BP associations.

Effects of long-term averaging of quantitative blood pressure traits on the detection of genetic associations.

Blood pressure (BP) is a heritable, quantitative trait with intraindividual variability and susceptibility to measurement error. Genetic studies of BP generally use single-visit measurements and thus cannot remove variability occurring over months or years. We leveraged the idea that averaging BP measured across time would improve phenotypic accuracy and thereby increase statistical power to detect genetic associations. We studied systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP) averaged over multiple years in 46,629 individuals of European ancestry. We identified 39 trait-variant associations across 19 independent loci (p < 5 × 10(-8)); five associations (in four loci) uniquely identified by our LTA analyses included those of SBP and MAP at 2p23 (rs1275988, near KCNK3), DBP at 2q11.2 (rs7599598, in FER1L5), and PP at 6p21 (rs10948071, near CRIP3) and 7p13 (rs2949837, near IGFBP3). Replication analyses conducted in cohorts with single-visit BP data showed positive replication of associations and a nominal association (p < 0.05). We estimated a 20% gain in statistical power with long-term average (LTA) as compared to single-visit BP association studies. Using LTA analysis, we identified genetic loci influencing BP. LTA might be one way of increasing the power of genetic associations for continuous traits in extant samples for other phenotypes that are measured serially over time.

Inhibition of TRPC6 Signal Pathway Alleviates Podocyte Injury Induced by TGF-ß1.

BACKGROUND/AIMS: Transforming growth factor beta 1 (TGF-ß1) plays a critical role in the pathogenesis of glomerulosclerosis. The purpose of this study was to examine the effects of inhibition of transient receptor potential cation channel C6 (TRPC6) on podocyte injury induced by TGF-ß1 via nephrin and desmin mechanisms. METHODS: A rat model of nephropathy was first induced by intravenous injections of adriamycin to determine TRPC6 signal pathway engaged in glomerulosclerosis in vivo. Conditionally immortalized podocytes were cultured in vitro and they were divided into four groups: control; TGF-ß1 treatment; TGF-ß1 with TRPC6 knockdown and TGF-ß1 without TRPC6 knockdown. Real time RT-PCR and Western blot analysis were employed to determine the mRNA and protein of expression of nephrin, desmin and caspase-9, respectively. Flow cytometry was used to examine the apoptotic rate of podocytes and DAPI fluorescent staining was used to determine apoptotic morphology. RESULTS: In vivo experiment, adriamycin significantly upregulated the protein expression of TGF-ß1, TRPC6, desmin and caspase-9, and decreased nephrin. Consistent with the latter results, in vitro experiment mRNA and protein expression of desmin and caspase-9 was increased in cultured TGF-ß1-treated podocytes, whereas nephrin was declined as compared with the control group. Importantly, TRPC6 knockdown significantly attenuated the upregulated desmin and caspase-9, and alleviated impairment of nephrin induced by TGF-ß1. Moreover, typical morphologic features were presented in apoptotic podocytes. The number of apoptotic podocytes was increased after exposure to TGF-ß1 and this was alleviated after TRPC6 knockdown. TRPC6 knockdown also decreased an apoptosis rate of TGF-ß1-treated podocytes. Note that negative TRPC6 transfection control failed to alter an increase of the apoptosis rate in TGF-ß1-treated podocytes. CONCLUSIONS: TGF-ß1 induced by glomerulosclerosis impairs the protein expression of nephrin and amplifies the protein expression of desmin and caspase -9 via TRPC6 signal pathway. Inhibition of TRPC6 alleviates these changes in podocytes-treated with TGF-ß1 and attenuated apoptosis of podocytes. Our data suggest that TRPC6 signal plays an important role in mediating TGF-ß1-induced podocyte injury via nephrin, desmin and caspase-9. Results of the current study also indicate that blocking TRPC6 signal pathway has a protective effect on podocyte injury. Targeting one or more of these signaling molecules may present new opportunities for treatment and management of podocyte injury observed in glomerulosclerosis.

Role of MiR-155 Signal Pathway in Regulating Podocyte Injury Induced by TGF-ß1.

BACKGROUND/AIMS: Transforming growth factor beta 1 (TGF-ß1) plays a critical role in the pathogenesis of glomerulosclerosis. The purpose of this study was to examine the effects of inhibition of miR-155 on podocyte injury induced by TGF-ß1 and to determine further molecular mediators involved in the effects of miR-155. METHODS: Conditionally immortalized podocytes were cultured in vitro and they were divided into four groups: control; TGF-ß1 treatment; TGF-ß1 with miR-155 knockdown [using antisense oligonucleotides against miR-155 (ASO-miR-155)] and TGF-ß1 with negative control antisense oligonucleotides (ASO-NC). Real time RT-PCR and Western blot analysis were employed to determine the mRNA and protein expression of nephrin, desmin and caspase-9, respectively. Flow cytometry was used to examine the apoptotic rate of podocytes and DAPI fluorescent staining was used to determine apoptotic morphology. In addition, we examined the levels of miR-155, TGF-ß1, nephrin, desmin and caspase-9 in glomerular tissues of nephropathy induced by intravenous injections of adriamycin in rats. RESULTS: mRNA and protein expression of desmin and caspase-9 was increased in cultured TGF-ß1-treated podocytes, whereas nephrin was decreased as compared with the control group. Importantly, miR-155 knockdown significantly attenuated upregulation of desmin and caspase-9, and alleviated impairment of nephrin induced by TGF-ß1. Moreover, the number of apoptotic podocytes was increased after exposure to TGF-ß1 and this was alleviated after miR-155 knockdown. Knocking down miR-155 also decreased an apoptosis rate of TGF-ß1-treated podocytes. Note that negative control antisense oligonucleotides failed to alter an increase of the apoptosis rate in TGF-ß1-treated podocytes. Consistent with in vitro results, expression of miR-155, TGF-ß1, desmin and caspase-9 was increased and nephrin was decreased in glomerular tissues with nephropathy in vivo experiments. CONCLUSIONS: TGF-ß1 impairs the protein expression of nephrin and amplifies the protein expression of desmin and caspase -9 via miR-155 signal pathway. Inhibition of miR-155 alleviates these changes in podocytes-treated with TGF-ß1 and attenuated apoptosis of podocytes. Our data suggest that miR-155 plays a role in mediating TGF-ß1-induced podocyte injury via nephrin, desmin and caspase-9. Results of the current study also indicate that blocking miR-155 signal has a protective effect on podocyte injury. Targeting one or more of these signaling molecules may present new opportunities for treatment and management of podocyte injury observed in glomerulosclerosis.

Activation of TLR5 induces podocyte apoptosis.

The apoptosis plays a critical role in a number of inflammatory disorders. Bacterial infection is one of the causes inducing apoptosis. This study aims to investigate the mechanism by which activation of TLR5 induces podocyte apoptosis. In this study, a podocyte cell line was cultured in RPMI1640 medium. The expression of TLR5 was assessed by real-time PCR and Western blotting. The Fas ligand gene transcription was assessed by immunoprecipitation and chromatin immunoprecipitation assay. The results showed that the expression of TLR5 was observed in the podocytes at both mRNA and protein levels. Exposure to TLR5 ligand, flagellin, induced Fas ligand expression and podocyte apoptosis. p300, one of the histone acetyltransferases, mediated the Fas ligand gene transcription in podocytes. In conclusion, TLR5 activation plays an important role in the induction of podocyte apoptosis.

Genome-wide joint meta-analysis of SNP and SNP-by-smoking interaction identifies novel loci for pulmonary function.

Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV(1)), and its ratio to forced vital capacity (FEV(1)/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV(1) and FEV(1)/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest P(JMA = )5.00×10(-11)), HLA-DQB1 and HLA-DQA2 (smallest P(JMA = )4.35×10(-9)), and KCNJ2 and SOX9 (smallest P(JMA = )1.28×10(-8)) were associated with FEV(1)/FVC or FEV(1) in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects.

Genetic loci associated with plasma phospholipid n-3 fatty acids: a meta-analysis of genome-wide association studies from the CHARGE Consortium.

Long-chain n-3 polyunsaturated fatty acids (PUFAs) can derive from diet or from α-linolenic acid (ALA) by elongation and desaturation. We investigated the association of common genetic variation with plasma phospholipid levels of the four major n-3 PUFAs by performing genome-wide association studies in five population-based cohorts comprising 8,866 subjects of European ancestry. Minor alleles of SNPs in FADS1 and FADS2 (desaturases) were associated with higher levels of ALA (p = 3 x 10⁻64) and lower levels of eicosapentaenoic acid (EPA, p = 5 x 10⁻58) and docosapentaenoic acid (DPA, p = 4 x 10⁻¹54). Minor alleles of SNPs in ELOVL2 (elongase) were associated with higher EPA (p = 2 x 10⁻¹²) and DPA (p = 1 x 10⁻4³) and lower docosahexaenoic acid (DHA, p = 1 x 10⁻¹5). In addition to genes in the n-3 pathway, we identified a novel association of DPA with several SNPs in GCKR (glucokinase regulator, p = 1 x 10⁻8). We observed a weaker association between ALA and EPA among carriers of the minor allele of a representative SNP in FADS2 (rs1535), suggesting a lower rate of ALA-to-EPA conversion in these subjects. In samples of African, Chinese, and Hispanic ancestry, associations of n-3 PUFAs were similar with a representative SNP in FADS1 but less consistent with a representative SNP in ELOVL2. Our findings show that common variation in n-3 metabolic pathway genes and in GCKR influences plasma phospholipid levels of n-3 PUFAs in populations of European ancestry and, for FADS1, in other ancestries.

Functional variants of OCTN cation transporter genes are associated with Crohn disease.

Crohn disease is a chronic, inflammatory disease of the gastrointestinal tract. A locus of approximately 250 kb at 5q31 (IBD5) was previously associated with susceptibility to Crohn disease, as indicated by increased prevalence of a risk haplotype of 11 single-nucleotide polymorphisms among individuals with Crohn disease, but the pathogenic lesion in the region has not yet been identified. We report here that two variants in the organic cation transporter cluster at 5q31 (a missense substitution in SLC22A4 and a G-->C transversion in the SLC22A5 promoter) form a haplotype associated with susceptibility to Crohn disease. These variants alter transcription and transporter functions of the organic cation transporters and interact with variants in another gene associated with Crohn disease, CARD15, to increase risk of Crohn disease. These results suggest that SLC22A4, SLC22A5 and CARD15 act in a common pathogenic pathway to cause Crohn disease.

Durable and rechargeable antimicrobial cotton driven by enhanced UV stability and real-time detection of biocidal factors.

In this study, graphene oxide/N-halamine nanocomposite was synthesized through Pickering miniemulsion polymerization, which was then coated on cotton surface. The modified cotton exhibited excellent superhydrophobicity, which could effectively prevent microbial infestation and reduce the probability of hydrolysis of active chlorine, with virtually no active chlorine released in water after 72 h. Deposition of reduced graphene oxide nanosheets endowed cotton with ultraviolet-blocking properties, attributing to enhanced UV adsorption and long UV paths. Moreover, encapsulation of polymeric N-halamine resulted in improved UV stability, thus extending the life of N-halamine-based agents. After 24 h of irradiation, 85 % of original biocidal component (active chlorine content) was retained, and approximately 97 % of initial chlorine could be regenerated. Modified cotton has been proven to be an effective oxidizing material against organic pollutants and a potential antimicrobial substance. Inoculated bacteria were completely killed after 1 and 10 min of contact time, respectively. An innovative and simple scheme for determination of active chlorine content was also devised, and real-time inspection of bactericidal activity could be achieved to assure antimicrobial sustainability. Moreover, this method could be utilized to evaluate hazard classification of microbial contamination in different locations, thus broadening the application scope of N-halamine-based cotton fabrics.

Risk stratification for hepatocellular cancer among patients with cirrhosis using a hepatic fat polygenic risk score.

BACKGROUND: Polygenic risk scores (PRS) hold the promise to refine prognostication in hepatocellular cancer (HCC). The few available HCC PRS include germline risk variants identified among individuals of mostly European ancestry, but data are lacking on the transportability of these PRS in multiethnic U.S patients with cirrhosis from multiple etiologies. METHODS: We used data from 1644 patients with cirrhosis enrolled in two prospective cohort studies in the U.S. Patients were followed until HCC diagnosis, death, liver transplantation, or last study visit through June 30, 2021. The high-risk variants in PNPLA3-MBOAT7-TM6SF2-GCKR were combined in a PRS and we evaluated its association with HCC. Discriminatory accuracy was assessed using the C-statistic. RESULTS: During 4,759 person-years of follow-up, 93 patients developed HCC. Mean age was 59.8 years, 68.6% were male, 27.2% Hispanic, 25.1% non-Hispanic Black, 25.7% had NAFLD, 42.1% had heavy alcohol use, and 19.5% had active HCV. HCC risk increased by 134% per unit increase in PRS (HR = 2.30; 95% CI, 1.35-3.92). Compared to cirrhosis patients in the lowest tertile of the PRS, those in the highest tertile had 2-fold higher risk of HCC (HR = 2.05; 95% CI, 1.22-3.44). The PRS alone had modest discriminatory ability (C-statistic = 0.58; 95% CI, 0.52-0.63); however, adding PRS to a predictive model with traditional HCC risk factors had a C-statistic of 0.70 (95% CI, 0.64-0.76), increasing from 0.68 without the PRS (p = 0.0012). CONCLUSIONS: Our findings suggest that PRS may enhance risk prediction for HCC in contemporary U.S. cirrhosis patients.

Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants.

BACKGROUND: Primary biliary cirrhosis is a chronic granulomatous cholangitis, characteristically associated with antimitochondrial antibodies. Twin and family aggregation data suggest that there is a significant genetic predisposition to primary biliary cirrhosis, but the susceptibility loci are unknown. METHODS: To identify genetic loci conferring a risk for primary biliary cirrhosis, we carried out a genomewide association analysis in which DNA samples from 2072 Canadian and U.S. subjects (536 patients with primary biliary cirrhosis and 1536 controls) were genotyped for more than 300,000 single-nucleotide polymorphisms (SNPs). Sixteen of the SNPs most strongly associated with primary biliary cirrhosis were genotyped in two independent replication sets. We carried out fine-mapping studies across three loci associated with primary biliary cirrhosis. RESULTS: We found significant associations between primary biliary cirrhosis and 13 loci across the HLA class II region; the HLA-DQB1 locus (encoding the major histocompatibility complex class II, DQ beta chain 1) had the strongest association (P=1.78x10(-19); odds ratio for patients vs. controls, 1.75). Primary biliary cirrhosis was also significantly and reproducibly associated with two SNPs at the IL12A locus (encoding interleukin-12alpha), rs6441286 (P=2.42x10(-14); odds ratio, 1.54) and rs574808 (P=1.88x10(-13); odds ratio, 1.54), and one SNP at the IL12RB2 locus (encoding interleukin-12 receptor beta2), rs3790567 (P=2.76x10(-11); odds ratio, 1.51). Fine-mapping analysis showed that a five-allele haplotype in the 3' flank of IL12A was significantly associated with primary biliary cirrhosis (P=1.15x10(-34)). We found a modest genomewide association (P<5.0x10(-5)) with the risk of disease for SNPs at the STAT4 locus (encoding signal transducer and activator of transcription 4) and the CTLA4 locus (encoding cytotoxic T-lymphocyte-associated protein 4) and 10 other loci. CONCLUSIONS: Our data show significant associations between primary biliary cirrhosis and common genetic variants at the HLA class II, IL12A, and IL12RB2 loci and suggest that the interleukin-12 immunoregulatory signaling axis is relevant to the pathophysiology of primary biliary cirrhosis. (ClinicalTrials.gov number, NCT00242125.)

Staging Concordance and Guideline-Concordant Treatment for Esophageal Adenocarcinoma.

BACKGROUND: Treatment selection for patients with esophageal adenocarcinoma is predicated on clinical staging information, which is inaccurate in 20% to 30% of cases and could impact the delivery of guideline-concordant treatment. We aimed to evaluate the association between staging concordance at the patient and hospital levels with the delivery of guideline-concordant treatment among esophageal adenocarcinoma patients. METHODS: This was a national cohort study of resected esophageal adenocarcinoma patients in the National Cancer Data Base (2006 to 2015) treated either with upfront resection or neoadjuvant therapy followed by surgery. Patient- and hospital-level clinical and pathologic staging concordance and deviations from treatment guidelines were ascertained. For neoadjuvant therapy patients, staging concordance was predicted through Bayesian analysis. Reliability adjustment was used when evaluating hospital-level concordance. RESULTS: Among 9393 esophageal adenocarcinoma patients treated at 927 hospitals, 41% had upfront surgery. Among upfront surgery patients, staging concordance was 85.1% for T1N0 and 86.9% for T3-T4N+ disease, but less than 50% for all others. Among patients treated with neoadjuvant therapy, treatment downstaging was observed in 33.9%. Deviations from treatment guidelines were identified in 38.5% of upfront surgery patients and 3.3% of neoadjuvant therapy patients. The proportion of concordantly staged patients ranged from 60.1% to 87.9%, and deviations from treatment guidelines were observed among 14.9% to 22.7% of the patients. Patient staging concordance increased, and deviations from guidelines decreased, as hospital-level concordance increased (trend test, P values less than .001 for all). CONCLUSIONS: Deviations from treatment guidelines in esophageal adenocarcinoma patients appear to be a function of inaccurate clinical staging information, which should be a new focus for quality improvement efforts.

A modified forward multiple regression in high-density genome-wide association studies for complex traits.

Genome-wide association studies (GWAS) have been widely used to identify genetic effects on complex diseases or traits. Most currently used methods are based on separate single-nucleotide polymorphism (SNP) analyses. Because this approach requires correction for multiple testing to avoid excessive false-positive results, it suffers from reduced power to detect weak genetic effects under limited sample size. To increase the power to detect multiple weak genetic factors and reduce false-positive results caused by multiple tests and dependence among test statistics, a modified forward multiple regression (MFMR) approach is proposed. Simulation studies show that MFMR has higher power than the Bonferroni and false discovery rate procedures for detecting moderate and weak genetic effects, and MFMR retains an acceptable-false positive rate even if causal SNPs are correlated with many SNPs due to population stratification or other unknown reasons.