Genome-wide association study identifies high-impact susceptibility loci for HCC in North America.

BACKGROUND AND AIMS: Despite the substantial impact of environmental factors, individuals with a family history of liver cancer have an increased risk for HCC. However, genetic factors have not been studied systematically by genome-wide approaches in large numbers of individuals from European descent populations (EDP). APPROACH AND RESULTS: We conducted a 2-stage genome-wide association study (GWAS) on HCC not affected by HBV infections. A total of 1872 HCC cases and 2907 controls were included in the discovery stage, and 1200 HCC cases and 1832 controls in the validation. We analyzed the discovery and validation samples separately and then conducted a meta-analysis. All analyses were conducted in the presence and absence of HCV. The liability-scale heritability was 24.4% for overall HCC. Five regions with significant ORs (95% CI) were identified for nonviral HCC: 3p22.1, MOBP , rs9842969, (0.51, [0.40-0.65]); 5p15.33, TERT , rs2242652, (0.70, (0.62-0.79]); 19q13.11, TM6SF2 , rs58542926, (1.49, [1.29-1.72]); 19p13.11 MAU2 , rs58489806, (1.53, (1.33-1.75]); and 22q13.31, PNPLA3 , rs738409, (1.66, [1.51-1.83]). One region was identified for HCV-induced HCC: 6p21.31, human leukocyte antigen DQ beta 1, rs9275224, (0.79, [0.74-0.84]). A combination of homozygous variants of PNPLA3 and TERT showing a 6.5-fold higher risk for nonviral-related HCC compared to individuals lacking these genotypes. This observation suggests that gene-gene interactions may identify individuals at elevated risk for developing HCC. CONCLUSIONS: Our GWAS highlights novel genetic susceptibility of nonviral HCC among European descent populations from North America with substantial heritability. Selected genetic influences were observed for HCV-positive HCC. Our findings indicate the importance of genetic susceptibility to HCC development.

Effect of HIV and antiretroviral therapy use on body weight changes in a cohort of U.S. veterans living with and without HIV.

OBJECTIVE: People living with HIV have high rates of obesity and obesity-related comorbidities. Our study sought to evaluate weight trajectory in a retrospective cohort of people living with HIV and matched HIV-negative veterans (controls) and to evaluate risk factors for weight gain. METHODS: This was a retrospective database analysis of data extracted from the VA Corporate Data Warehouse that included people living with HIV (n = 22 421) and age-matched HIV-negative controls (n = 63 072). The main outcomes were baseline body weight and weight change from baseline at 1, 2, and 5 years after diagnosis (baseline visit for controls). RESULTS: Body weight at baseline was lower in people living with HIV than in controls. People living with HIV on antiretroviral therapy (ART) gained more weight than did controls. In a sub-analysis of ART-exposed people living with HIV, age >50 years, African American race, body mass index (BMI) <25, CD4 ≤200, and HIV diagnosis year after 2000 were associated with more weight gain at year 1. Nucleoside reverse transcriptase inhibitors (NRTI) plus non-NRTIs (NNRTIs) were associated with less weight gain than NRTIs plus protease inhibitors, NRTIs plus integrase inhibitors, or NRTIs plus other agents at year 1. CONCLUSIONS: Among US veterans, those living with HIV had lower rates of obesity than age-matched HIV-negative controls; however, primarily in the first 2 years after starting ART, people living with HIV gained more weight than did controls.

Risk and incidence of head and neck cancers in veterans living with HIV and matched HIV-negative veterans.

BACKGROUND: Persons living with HIV/AIDS have a higher incidence of virus-related and tobacco/alcohol-related cancers. This study is the first to estimate the effect of HIV versus HIV-negative veterans on the risk of head and neck squamous cell carcinoma incidence in a large retrospective cohort study. METHODS: The authors constructed a retrospective cohort study using patient data from 1999 to 2016 from the National Veterans Administration Corporate Data Warehouse and the VA Central Cancer Registry. This cohort study included 45,052 veterans living with HIV/AIDS and 162,486 HIV-negative patients matched by age, sex, and index visit (i.e., HIV diagnosis date or clinic visit date). The age-standardized incidence rates and estimated adjusted hazard ratios were calculated with a Cox proportional hazards regression for oropharyngeal and nonoropharyngeal head and neck cancer squamous cell carcinoma (HNSCC). The authors also abstracted human papillomavirus (HPV) status from oropharyngeal HNSCC diagnosed after 2010. RESULTS: Veterans living with HIV/AIDS (VLWH) have 1.71 (95% confidence interval [CI], 1.36, 2.14) times the risk of oropharyngeal cancer and 2.06 (95% CI, 1.76, 2.42) times the hazard of nonoropharyngeal cancer compared with HIV-negative veterans. VLWH with oropharyngeal squamous cell carcinoma (OPSCC) were more likely to be HPV-positive (N = 30 [81.1%]) than the HIV-negative veterans with OPSCC (N = 50 [67.6%]), although this difference was not significant (p = .135). For nonoropharyngeal cancer, the increased risk of oral cavity cancer among VLWH drove the increased risk. CONCLUSIONS: The study results suggest that HIV may play a role in virally mediated and nonvirally mediated HNSCC. As the HIV prevalence rises in the United States due to better survival and the incidence of HPV-positive oropharyngeal HNSCC increases, the interaction between HPV and HIV becomes increasingly relevant.

Spatial Characteristics of Colonic Mucosa-Associated Gut Microbiota in Humans.

Limited data exist on the spatial distribution of the colonic bacteria in humans. We collected the colonic biopsies from five segments of 27 polyp-free adults and collected feces from 13 of them. We sequenced the V4 region of the bacterial 16S rRNA gene using the MiSeq platform. The sequencing data were assigned to the amplicon sequence variant (ASV) using SILVA. Biodiversity and the relative abundance of the ASV were compared across the colonic segments and between the rectal and fecal samples. Bacterial functional capacity was assessed using Tax4fun. Each individual had a unique bacterial community composition (Weighted Bray-Curtis P value = 0.001). There were no significant differences in richness, evenness, community composition, and the taxonomic structure across the colon segments in all the samples. Firmicutes (47%), Bacteroidetes (39%), and Proteobacteria (6%) were the major phyla in all segments, followed by Verrucomicrobia, Fusobacteria, Desulfobacterota, and Actinobacteria. There were 15 genera with relative abundance > 1%, including Bacteroides, Faecalibacterium, Escherichia/Shigella, Sutterella, Akkermansia, Parabacteroides, Prevotella, Lachnoclostridium, Alistipes, Fusobacterium, Erysipelatoclostridium, and four Lachnospiraceae family members. Intra-individually, the community compositional dissimilarity was the greatest between the cecum and the rectum. There were significant differences in biodiversity and the taxonomic structure between the rectal and fecal bacteria. The bacterial community composition and structure were homogeneous across the large intestine in adults. The inter-individual variability of the bacteria was greater than inter-segment variability. The rectal and fecal bacteria differed in the community composition and structure.

A novel approach to studying early knee osteoarthritis illustrates that bilateral medial tibiofemoral osteoarthritis is a heritable phenotype: an offspring study.

To assess the potential of studying offspring of people with and without knee osteoarthritis to understand the risk factors and heritability for knee osteoarthritis. We selected two groups of Osteoarthritis Initiative (OAI) participants from one clinical site: (1) participants with bilateral radiographic medial tibiofemoral osteoarthritis and (2) those without tibiofemoral osteoarthritis. We then invited biological offspring ≥ 18 years old to complete an online survey that inquired about osteoarthritis risk factors and symptoms. Among the survey respondents, we recruited ten offspring of members from each group for a clinic visit with bilateral knee posterior-anterior radiographs and magnetic resonance imaging of the right knee. We established contact with 269/413 (65%) eligible OAI participants. Most (227/269, 84%) had ≥ 1 eligible biological offspring, and 213 (94%) were willing to share information about the new family study with their offspring. Our survey was completed by 188 offspring from 110 OAI participants: mean age of 43.0 (10.4) years, mean body mass index of 23.7 (5.9) kg/m2, 65% female. Offspring obesity (OR = 2.7, 95% CI 1.0-7.3), hypertension (OR = 3.7, 95% CI 1.2-11.3), and Heberden's nodes (OR = 3.6, 95% CI 1.0-13.2) were associated with parental osteoarthritis status; however, adjusted models were not statistically significant. Radiographic tibiofemoral osteoarthritis (16/18 knees vs. 2/20 knees) and meniscal abnormalities (7/9 vs. 2/10 index knees) were more common among offspring with parental osteoarthritis status than not. We established the potential of a novel offspring study design within the OAI, and our results are consistent with bilateral radiographic medial tibiofemoral osteoarthritis being a heritable phenotype of osteoarthritis.

Validation of the Updated Hepatocellular Carcinoma Early Detection Screening Algorithm in a Community-Based Cohort of Patients With Cirrhosis of Multiple Etiologies.

BACKGROUND & AIMS: The Hepatocellular carcinoma (HCC) Early detection Screening (HES) algorithm has been proposed to improve the performance of the serum alpha-fetoprotein (AFP) test in surveillance for HCC. The HES algorithm incorporates data on age, level of alanine aminotransferase, platelet count, and rate of AFP change to increase likelihood of earlier detection and thereby reduce HCC-related mortality. We updated the HES algorithm to include etiology of cirrhosis and validated it in a community-based cohort. METHODS: We collected data from the Veterans Health Administration, from 2010 through 2015, on etiologies for HCC, including hepatitis C, hepatitis B, alcoholic liver disease, and non-alcoholic fatty liver disease. We used these data to update the HES algorithm and tested its accuracy using data from patients with cirrhosis in the Kaiser Permanente Northern California healthcare system (validation cohort). RESULTS: Among the 7432 patients with cirrhosis in the validation cohort, 1102 were diagnosed with HCC during a median follow-up time of 3.21 years; 709 patients had early-stage HCC. The HES algorithm identified patients who would receive a diagnosis of early-stage HCC within the next 6 months with 51.20% sensitivity and 90.00% specificity, compared with 46.02% sensitivity for the AFP test alone (5.18% absolute improvement; P = .0015). In HCC screening, a positive result from HES or AFP test leads to follow-up evaluation with more sensitive imaging methods. The number of early-stage HCC cases detected per 1000 imaging analyses were 136.46 with the HES algorithm vs 118.01 with the AFP test alone (P < .0005). The HES algorithm identified 56.00% of patients with HCC in the 6 months before their diagnosis despite no detection of nodules by surveillance ultrasound; the AFP test identified only 50.00% of these patients. CONCLUSIONS: We validated the HES algorithm using data from a diverse community-based cohort of patients with cirrhosis. The algorithm offers a modest but useful advantage over the AFP test alone in detection of early-stage HCC with virtually no added cost.

Post-Traumatic Stress Disorder is Associated with further Increased Parkinson's Disease Risk in Veterans with Traumatic Brain Injury.

OBJECTIVE: Determining if traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) are risk factors for Parkinson's disease (PD). This constitutes a research priority for the Veterans Administration (VA) with implications for screening policy and prevention. METHODS: Population-based, matched case-control study among veterans using VA health care facilities from October 1, 1999, to September 30, 2013. We identified 176,871 PD cases and 707,484 randomly selected PD-free matched controls. PD, TBI, and PTSD were ascertained by validated International Classification of Disease 9th revision (ICD)-9 code-based algorithms. We examined the association between both risk factors and PD using race-adjusted conditional logistic regression. RESULTS: The overall study cohort prevalence for TBImild , TBInon-mild , and PTSD was 0.65%, 0.69%, and 5.5%, respectively. Both TBI and PTSD were significantly associated with PD in single-risk factor race-adjusted analyses (conditional odds ratio [cOR] = 2.99; 95% confidence interval [CI]: 2.69-3.32), 3.82 (95% CI: 3.67-3.97), and 2.71 (95% CI: 2.66-2.77) for TBImild , TBInon-mild , and PTSD, respectively). There was suggestive positive interaction observed with comorbid PTSD/TBI in dual-risk factor analyses, with significant 2.69-fold and 3.70-fold excess relative PD risk in veterans with TBImild and TBInon-mild versus those without TBI when PTSD was present versus 2.17-fold and 2.80-fold excess risk when PTSD was absent. INTERPRETATION: Our study was the first to demonstrate that both TBI and PTSD are independently associated with increased relative PD risk in a diverse nationwide cohort of military service veterans, and the first to suggest a potential modest synergistic excess risk in those with comorbid TBI/PTSD. Longitudinal research is needed to confirm these suggestive findings. ANN NEUROL 2020 ANN NEUROL 2020;88:33-41.

The association between protease inhibitors and anal cancer outcomes in veterans living with HIV treated with definitive chemoradiation: a retrospective study.

BACKGROUND: The incidence of anal squamous cell carcinoma has been increasing, particularly in people living with HIV (PLWH). There is concern that radiosensitizing drugs, such as protease inhibitors, commonly used in the management of HIV, may increase toxicities in patients undergoing chemoradiation. This study examines treatment outcomes and toxicities in PLWH managed with and without protease inhibitors who are receiving chemoradiation for anal cancer. METHODS: Patient demographic, HIV management, and cancer treatment information were extracted from multiple Veterans Affairs databases. Patients were also manually chart reviewed. Among PLWH undergoing chemoradiation for anal carcinoma, therapy outcomes and toxicities were compared between those treated with and without protease inhibitors at time of cancer treatment. Statistical analysis was performed using chi-square, Cox regression analysis, and logistic regression. RESULTS: A total of 219 PLWH taking anti-retroviral therapy undergoing chemoradiation for anal cancer were identified and included in the final analysis. The use of protease inhibitors was not associated with any survival outcome including colostomy-free survival, progression-free survival, or overall survival (all adjusted hazard ratio p-values> 0.05). Regarding toxicity, protease inhibitor use was not associated with an increased odds of hospitalizations or non-hematologic toxicities; however, protease inhibitor use was associated with increased hospitalizations for hematologic toxicities, including febrile neutropenia (p < 0.01). CONCLUSION: The use of protease inhibitors during chemoradiation for anal carcinoma was not associated with any clinical outcome or increase in non-hematologic toxicity. Their use was associated with increased hospitalizations for hematologic toxicities. Further prospective research is needed to evaluate the safety and efficacy of protease inhibitors for patients undergoing chemoradiation.

Oral Health and the Altered Colonic Mucosa-Associated Gut Microbiota.

BACKGROUND: Systemic diseases have been associated with oral health and gut microbiota. We examined the association between oral health and the community composition and structure of the adherent colonic gut microbiota. METHODS: We obtained 197 snap-frozen colonic biopsies from 62 colonoscopy-confirmed polyp-free individuals. Microbial DNA was sequenced for the 16S rRNA V4 region using the Illumina MiSeq, and the sequences were assigned to the operational taxonomic unit based on SILVA. We used a questionnaire to ascertain tooth loss, gum disease, and lifestyle factors. We compared biodiversity and relative abundance of bacterial taxa based on the amount of tooth loss and the presence of gum disease. The multivariable negative binomial regression model for panel data was used to estimate the association between the bacterial count and oral health. False discovery rate-adjusted P value (q value) < .05 indicated statistical significance. RESULTS: More tooth loss and gum disease were associated with lower bacterial alpha diversity. The relative abundance of Faecalibacterium was lower (q values < .05) with more tooth loss. The association was significant after adjusting for age, ethnicity, obesity, smoking, alcohol use, hypertension, diabetes, and the colon segment. The relative abundance of Bacteroides was higher in those with gum disease. CONCLUSIONS: Oral health was associated with alteration in the community composition and structure of the adherent gut bacteria in the colon. The reduced anti-inflammatory Faecalibacterium in participants with more tooth loss may indicate systemic inflammation. Future studies are warranted to confirm our findings and investigate the systemic role of Faecalibacterium.

Gout and open-angle glaucoma risk in a veteran population.

PURPOSE: A history of gout, arthritis due to hyperuricemia, has been associated with decreased risk for neurodegenerative diseases such as Parkinson's disease. We performed a population-based case-control study in the US Department of Veterans Affairs (VA) medical centers nationwide to assess if gout or hyperuricemia is similarly associated with the ocular neurodegenerative condition glaucoma. METHODS: We used ICD-9 codes to identify a nationwide cohort of patients examined at VA healthcare eye clinics between 2000 and 2015 with a diagnosis of open-angle glaucoma (OAG) or of glaucoma suspect. We used incidence density matching to choose controls. We used multivariable logistic regression to examine associations between a history of gout and uric acid (UA) levels on relative risk of OAG or glaucoma suspect. RESULTS: There were 1,144,428 OAG or glaucoma suspect cases and 1,144,428 matched controls. Veterans with a history of gout had a small significant decreased risk of OAG compared to controls (ORadjusted(adj) = 0.985, 95% CI: 0.974-0.996). Treated gout was similarly associated with small decreased risk (ORadj = 0.963, 95% CI: 0.950-0.976). A small subset of patients (11.9% of cases and 13.2% of controls) had UA labs available; veterans with the highest median UA levels (> 7.29 mg/dL) did not have statistically significant differences in relative OAG risk (ORadj = 1.014, 95% CI: 0.991-1.036). CONCLUSION: Prospective research in other cohorts is needed to confirm our findings in veterans suggesting a history of gout is associated with a small decreased relative risk of glaucoma.

Ancestry and Risk of Hepatic Fibrosis and Inflammation in Patients With HCV Infection.

Worldwide, ∼184 million people have chronic hepatitis C virus (HCV) infection.1 Persistent racial disparities in outcomes are observed among HCV-infected patients. Hispanic patients with chronic HCV are more likely than non-Hispanic white (NHW) patients to develop advanced hepatic fibrosis and inflammation.2,3 Conversely, black patients with HCV infection are at lowest risk. The factors that contribute to this racial disparity are multifactorial, including lifestyle, genetics, and medical care. Limited data in other diseases suggest that genetic ancestry determined using ancestry-informative markers (AIMs) may help explain racial and ethnic differences in disease risk or severity.4 AIMs are sets of single-nucleotide polymorphisms (SNPs) that determine a person's ancestral continent of origin and the genetic ancestry proportions assigned to each individual serves as a proxy for his or her genetic ancestral background. We examined the risk of hepatic fibrosis and inflammation in HCV-infected patients according to both genetic ancestry and self-reported race/ethnicity.

Validation of the Hepatocellular Carcinoma Early Detection Screening (HES) Algorithm in a Cohort of Veterans With Cirrhosis.

BACKGROUND & AIMS: Early detection of hepatocellular carcinoma (HCC) through surveillance reduces mortality associated with this cancer. Guidelines recommend HCC surveillance every 6 months for patients with cirrhosis, via ultrasonography, with or without measurement of serum level of alpha fetoprotein (AFP). METHODS: We previously developed and internally validated an HCC early detection screening (HES) algorithm that included patient's current level of AFP, rate of AFP change, age, level of alanine aminotransferase, and platelet count in a department of Veterans affairs (VA) cohort with active hepatitis C virus-related cirrhosis. HES score was associated with 3.84% absolute improvement in sensitivity of detection of HCC compared with AFP alone, at 90% specificity, within 6 months prior to diagnosis of this cancer. We externally validated the HES algorithm in a cohort of 38,431 patients with cirrhosis of any etiology evaluated at a VA medical center from 2010 through 2015. RESULTS: A total of 4804 cases of HCC developed during a median follow-up time of 3.12 years. At 90% specificity, the HES algorithm identified patients with HCC with 52.56% sensitivity, compared to 48.13% sensitivity for the AFP assay alone, within 6 months prior to diagnosis; this was an absolute improvement of 4.43% (P < .0005). In HCC screening, a positive result leads to follow-up evaluation by computed tomography or magnetic resonance imaging. We estimated that the number of HCC cases detected per 1000 imaging analyses was 198.57 for the HES algorithm vs 185.52 for the AFP assay alone, or detection of 13 additional cases of HCC (P < .0005). CONCLUSION: We validated the HES algorithm in detection of HCC in patients with cirrhosis of any etiology evaluated at VA medical centers. The algorithm offers a modest but useful advantage over AFP alone in HCC surveillance.

Incidence of Hepatocellular Carcinoma in All 50 United States, From 2000 Through 2012.

BACKGROUND & AIMS: The incidence and mortality of hepatocellular carcinoma (HCC) have been reported to be plateauing in the United States. The United States has large racial, ethnic, and regional variation; we collected data from all 50 states to better analyze changes in HCC incidence in the entire United States. METHODS: We collected data from the US Cancer Statistics registry, which covers 97% of the population, and calculated adjusted incidence rates. We assessed annual trends among sociodemographic and geographic subgroups using joinpoint analysis. RESULTS: HCC incidence increased from 4.4/100,000 in 2000 to 6.7/100,000 in 2012, increasing by 4.5% (95% confidence interval [CI], 4.3%-4.7%) annually between 2000 and 2009, but only by 0.7% annually (95% CI, -0.2% to 1.6%) from 2010 through 2012. The average annual percentage change (AAPC) between 2000 and 2012 was higher in men (increase, 3.7%) than in women (increase, 2.7%), and highest in 55- to 59-year-old individuals (AAPC, 8.9%; 95% CI, 7.1%-10.7%) and 60- to 64-year-old individuals (AAPC, 6.4%; 95% CI, 4.7%-8.2%). By 2012, rates in Hispanics surpassed those in Asians, and rates in Texas surpassed those in Hawaii (9.71/100,000 vs 9.68/100,000). Geographic variation within individual race and ethnic groups was observed, but rates were highest in all major race and ethnic groups in Texas. CONCLUSIONS: In an analysis of the incidence of HCC in all 50 US states, we found the rate of increase in HCC to have slowed from 2010 through 2012. However, incidence is increasing in subgroups such as men ages 55 to 64 years old-especially those born in the peak era of hepatitis C virus infection and among whites/Caucasians. Rates in Hispanics have surpassed those in Asian Americans. We observed geographic differences, with Texas having the highest age-adjusted HCC rates nationwide.

Evaluating screening approaches for hepatocellular carcinoma in a cohort of HCV related cirrhosis patients from the Veteran's Affairs Health Care System.

BACKGROUND: Hepatocellular carcinoma (HCC) has limited treatment options in patients with advanced stage disease and early detection of HCC through surveillance programs is a key component towards reducing mortality. The current practice guidelines recommend that high-risk cirrhosis patients are screened every six months with ultrasonography but these are done in local hospitals with variable quality leading to disagreement about the benefit of HCC surveillance. The well-established diagnostic biomarker α-Fetoprotein (AFP) is used widely in screening but the reported performance varies widely across studies. We evaluate two biomarker screening approaches, a six-month risk prediction model and a parametric empirical Bayes (PEB) algorithm, in terms of their ability to improve the likelihood of early detection of HCC compared to current AFP alone when applied prospectively in a future study. METHODS: We used electronic medical records from the Department of Veterans Affairs Hepatitis C Clinical Case Registry to construct our analysis cohort, which consists of serial AFP tests in 11,222 cirrhosis control patients and 902 HCC cases prior to their HCC diagnosis. The six-month risk prediction model incorporates routinely measured laboratory tests, age, the rate of change in AFP over the past year with the current AFP. The PEB algorithm incorporates prior AFP screening values to identify patients with a significant elevated level of AFP at their current screen. We split the analysis cohort into independent training and validation datasets. All model fitting and parameter estimation was performed using the training data and the algorithm performance was assessed by applying each approach to patients in the validation dataset. RESULTS: When the screening-level false positive rate was set at 10%, the patient-level true positive rate using current AFP alone was 53.88% while the patient-level true positive rate for the six-month risk prediction model was 58.09% (4.21% increase) and PEB approach was 63.64% (9.76% increase). Both screening approaches identify a greater proportion of HCC cases earlier than using AFP alone. CONCLUSIONS: The two approaches show greater potential to improve early detection of HCC compared to using the current AFP only and are worthy of further study.

Role of Non-hepatic Medical Comorbidity and Functional Limitations in Predicting Mortality in Patients with HCV.

BACKGROUND: Medical comorbidities and functional status limitations are determinants of mortality in many chronic diseases. The extent to which survival in the rapidly aging cohort of patients with HCV is affected by these competing causes of mortality remains unclear. AIM: We sought to determine the effect of medical/functional comorbidities on survival after adjusting for liver disease severity in a cohort of patients with HCV infection. METHODS: We prospectively recruited consecutive patients from an HCV clinic 2009-2014. We calculated an index of survival (Schonberg Index, SI) based on age, gender, medical comorbidities, and functional status variables. We defined cirrhosis with the FibroSure test (F3/4-F4). We used multivariable Cox modeling to assess association between functional/survival measure and survival after adjustment for severity of liver disease. RESULTS: The cohort consisted of 1052 HCV patients. The average age was 56.8 years; 36 % had cirrhosis. The mean SI was 8.2 (SD = 2.7). During a mean follow-up of 5610 person-years, 102 (9.7 %) patients died. In unadjusted analysis, higher baseline SI predicted mortality (HR 1.17; 95 % CI 1.09-1.25). SI similarly predicted mortality in cirrhotic patients (HR 1.23, 95 % CI 1.13-1.34) and non-cirrhotic patients (HR 1.21, 95 % CI 1.08-1.36). This did not change after adjusting for age, drug use, or coronary artery disease. DISCUSSION: Comorbidities and functional limitations predict higher mortality in patients with HCV; this relationship is independent of cirrhosis. Use of general prognostic indices may help identify HCV patients at high risk for mortality, which could further guide clinical care in a manner not achievable with assessment of liver disease alone.

Efficacy of Psychosocial Interventions in Inducing and Maintaining Alcohol Abstinence in Patients With Chronic Liver Disease: A Systematic Review.

BACKGROUND & AIMS: We conducted a systematic review of efficacy of psychosocial interventions in inducing or maintaining alcohol abstinence in patients with chronic liver disease (CLD) and alcohol use disorder (AUD). METHODS: We performed structured keyword searches in PubMed, PsychINFO, and MEDLINE for original research articles that were published from January 1983 through November 2014 that evaluated the use of psychosocial interventions to induce or maintain alcohol abstinence in patients with CLD and AUD. RESULTS: We identified 13 eligible studies that comprised 1945 patients; 5 were randomized controlled trials (RCTs). Delivered therapies included motivational enhancement therapy, cognitive behavioral therapy (CBT), motivational interviewing, supportive therapy, and psychoeducation either alone or in combination in the intervention group and general health education or treatment as usual in the control group. All studies of induction of abstinence (4 RCTs and 6 observational studies) reported an increase in abstinence among participants in the intervention and control groups. Only an integrated therapy that combined CBT and motivational enhancement therapy with comprehensive medical care, delivered during a period of 2 years, produced a significant increase in abstinence (74% increase in intervention group vs 48% increase in control group, P = .02), which was reported in 1 RCT. All studies of maintenance of abstinence (1 RCT and 2 observational studies) observed recidivism in the intervention and control groups. Only an integrated therapy that combined medical care with CBT produced a significantly smaller rate of recidivism (32.7% in integrated CBT group vs 75% in control group, P = .03), which was reported from 1 observational study. However, data were not collected for more than 2 years on outcomes of patients with CLD and AUD. CONCLUSIONS: In a systematic analysis of studies of interventions to induce or maintain alcohol abstinence in patients with CLD and AUD, integrated combination psychotherapy with CBT, motivational enhancement therapy, and comprehensive medical care increased alcohol abstinence. No psychosocial intervention was successful in maintaining abstinence, but an integrated therapy with CBT and medical care appears to reduce recidivism.

Genetic Variants in Interleukin-28B Are Associated with Diabetes and Diabetes-Related Complications in Patients with Chronic Hepatitis C Virus Infection.

BACKGROUND: Few studies have shown that host interleukin-28B (IL28B) genetic polymorphisms are associated with insulin resistance in patients with chronic hepatitis C virus (HCV) infection. However, the clinical relevance of this relationship is unclear. AIMS: We examined the association between IL28B genotype for rs12980275 and risk of type 2 diabetes and diabetes-related complications. METHODS: We used a cross-sectional study of prospectively recruited male veterans with chronic HCV. We employed logistic regression analysis and adjusted for patients' age, race, body mass index, and hepatic fibrosis. RESULTS: A total of 528 participants were recruited (mean age 59.1 years; 38.5 % African-American; 40.3 % advanced fibrosis). Of these, 36.1 % were homozygous for favorable AA allele for rs12980275, 49.0 % were heterozygous (AG), and 14.0 % were homozygous for the unfavorable allele (GG). Prevalence of diabetes was significantly lower in patients with both favorable alleles (AA) than that with at least one unfavorable IL28B G allele (21.1 vs. 30.2 %, p = 0.02). Similarly, patients who were homozygous for the favorable alleles had lower prevalence of diabetes-related complications than patients with any unfavorable IL28B allele (5.7 vs. 12.2 %, p = 0.01). This association did not change after adjusting for sociodemographic characteristics, body mass index, and stage of hepatic fibrosis (adjusted ORdiabetes 0.56, 95 % CI 0.35-0.89; ORdiabetes-related complications 0.47, 95 % CI 0.23-0.96). CONCLUSIONS: Patients who have favorable AA IL28B alleles have a lower prevalence of diabetes and related complications compared with patients with unfavorable IL28B rs12980275 genotype. IL28B genotype information may be used to counsel HCV patients regarding their individualized risk of diabetes and diabetes-related complications.

Many patients with interleukin 28B genotypes associated with response to therapy are ineligible for treatment because of comorbidities.

BACKGROUND & AIMS: Interleukin (IL)-28B (interferon-λ 3) genotype is the strongest predictor of response of patients with hepatitis C virus (HCV) infection to antiviral therapy. However, patients with HCV infection often have physical or mental comorbidities that contraindicate or complicate treatment, regardless of their genotype. The potential role of IL28B genotype within the context of patients' clinical and social environment is therefore unclear. METHODS: We characterized the IL28B genotype (for rs12980275 and rs8099917) in 308 patients (mean age, 56 y; 25% African American; 38% with advanced-stage fibrosis) with genotype 1 HCV infection seen at the Michael E. DeBakey Veterans Administration Medical Center in Houston, Texas, from May 1, 2009, through April 1, 2012. We evaluated their eligibility for antiviral treatment based on clinical and social factors such as physical or mental health comorbidity, ongoing alcohol or drug use, and noncompliance with treatment evaluation. RESULTS: Of the 308 subjects, 40% were homozygous for rs12980275 (associated with response to therapy), 46% were heterozygous, and 15% were homozygous for alleles associated with reduced response to therapy. Overall, 36% of patients were considered to be ineligible for treatment; of these, 40% had the rs12980275 genotype. More than half of the patients with rs12980275 who were ineligible for treatment were excluded because of mental health comorbidities; one-third of these patients had advanced fibrosis. The reason(s) for treatment exclusion resolved in only 8% of patients during a mean 1.5 years of follow-up evaluation. CONCLUSIONS: In a well-characterized cohort of patients with HCV, a large proportion (40%) with IL28B polymorphisms associated with response to therapy is ineligible for treatment because of contraindications. One potential role of IL28B genotype analysis could be to identify patients who, although not currently eligible for antiviral treatment, could become so by modifying fixable exclusions to treatment.

Risk and predictors of penile cancer in US Veterans with HIV.

OBJECTIVES: People with HIV (PWH) may have an increased burden of penile cancer. We aimed to evaluate the risk of penile cancer in PWH compared with that of the general population. DESIGN: We conducted a nationwide retrospective matched cohort study of penile cancer incidence among veterans with HIV (VWH) compared with veterans without HIV. METHODS: We compared penile cancer incidence rates in 44 173 VWH to those of veterans without HIV ( N  = 159 443; 4 : 1 matched in age). We used Cox regression models to estimate hazard ratios and 95% confidence intervals (CIs) for associations with HIV infection and for penile cancer risk factors. RESULTS: HIV positivity was associated with an increased risk of penile cancer, with adjusted hazard ratios of 2.63 (95% CI 1.64-4.23) when adjusting for age, race/ethnicity, baseline BMI, smoking and alcohol use, economic means test, and history of condyloma. The risk increased to hazard ratio = 4.25 (95% CI 2.75-6.57) when adjusting for all factors except history of condyloma. Risk factors for penile cancer in VWH included lower nadir CD4 + count, less than 50% of follow-up time with undetectable HIV viral load, and history of condyloma. CONCLUSION: VWH - particularly those with low CD4 + counts, detectable HIV viral loads, or history of condyloma - are at increased risk of penile cancer, suggesting the penile cancer prevention activities are needed in this population.

Irritable Bowel Syndrome in Veterans with Gulf War Illness Evaluated at VA's War-Related Illness and Injury Study Center.

INTRODUCTION: Excess rates of Gulf War illness (GWI) and irritable bowel syndrome (IBS), two chronic multisymptom illnesses, have long been documented among nearly 700,000 veterans who served in the 1990-1991 Persian Gulf War. We sought to report the prevalence, characteristics, and association of GWI and IBS decades after the war in a clinical cohort of deployed Gulf War veterans (GWVs) who were evaluated at the Department of Veterans Affairs' War Related Illness and Injury Study Center (WRIISC) for unexplained chronic symptoms. MATERIALS AND METHODS: We analyzed data gathered from clinical intake questionnaires of deployed GWVs who were evaluated at WRIISC clinics between 2008 and 2020. We applied Centers for Disease Control (CDC) criteria to determine the prevalence of severe GWI. IBS was identified using Rome IV diagnostic criteria (current IBS) and veterans' self-reported "history of physician-diagnosed IBS." We examined associations between IBS and GWI using bivariate analyses and multivariable logistic regression. RESULTS: Among the N = 578 GWVs evaluated by the WRIISC, severe GWI (71.8%), history of physician-diagnosed IBS (50.3%) and current IBS (42.2%) were all highly prevalent. Nearly half of GWVs with severe GWI met Rome criteria for IBS (45.8%), and over half reported a history of physician-diagnosed IBS (56.1%). In multivariable models, severe GWI was significantly associated both with current IBS (adjusted odds ratio (aOR): 1.68, 95% CI: 1.11, 2.54) and with veteran-reported history of physician-diagnosed IBS (aOR: 2.15, 95% CI: 1.43, 2.23). IBS with diarrhea (IBS-D) was the most common subtype among GWVs with current IBS (61.1%). However, IBS-mixed affected a significantly greater proportion of veterans with severe GWI, compared to veterans who did not have severe GWI (P = .03). CONCLUSIONS: More than 20 years after the Persian Gulf War, our findings indicate a high degree of comorbidity between severe GWI and IBS among deployed GWVs seeking care for unexplained illnesses. Our results suggest GWVs with GWI should be screened for IBS for which evidence-based treatments are available and could potentially reduce symptom burden. Conversely, symptoms of IBS should trigger additional evaluation for non-gastrointestinal symptoms in deployed Gulf War veterans to identify possible GWI and ensure a comprehensive approach to care.