Extracellular vesicles as biomarkers for AIDS-associated non-Hodgkin lymphoma risk.

Introduction: Extracellular vesicles are membrane-bound structures secreted into the extracellular milieu by cells and can carry bioactive molecules. There is emerging evidence suggesting that EVs play a role in the diagnosis, treatment, and prognosis of certain cancers. In this study, we investigate the association of EVs bearing PD-L1 and molecules important in B-cell activation and differentiation with AIDS-NHL risk. Methods: EVs were isolated from archived serum collected prior to the diagnosis of AIDS-NHL in cases (N = 51) and matched HIV+ controls (N = 52) who were men enrolled in the Los Angeles site of the MACS/WIHS Combined Cohort Study (MWCCS). Serum specimens of AIDS-NHL cases were collected at a mean time of 1.25 years (range of 2 to 36 months) prior to an AIDS-NHL diagnosis. The expression of PD-L1 and other molecules on EVs (CD40, CD40L, TNF-RII, IL-6Rα, B7-H3, ICAM-1, and FasL) were quantified by Luminex multiplex assay. Results and discussion: We observed significantly higher levels of EVs bearing PD-L1, CD40, TNF-RII and/or IL-6Rα in AIDS-NHL cases compared with controls. Using multivariate conditional logistic regression models adjusted for age and CD4+ T-cell count, we found that EVs bearing PD-L1 (OR = 1.93; 95% CI: 1.10 - 3.38), CD40 (OR = 1.97, 95% CI: 1.09 - 3.58), TNF-RII (OR = 5.06; 95% CI: 1.99 - 12.85) and/or IL-6Rα (OR = 4.67; 95% CI: 1.40 - 15.53) were significantly and positively associated with AIDS-NHL risk. In addition, EVs bearing these molecules were significantly and positively associated with non-CNS lymphoma: PD-L1 (OR = 1.94; 95% CI: 1.01 - 3.72); CD40 (OR = 2.66; 95% CI: 1.12 - 6.35); TNF-RII (OR = 9.64; 95% CI: 2.52 - 36.86); IL-6Rα (OR = 8.34; 95% CI: 1.73 - 40.15). These findings suggest that EVs bearing PD-L1, CD40, TNF-RII and/or IL-6Rα could serve as biomarkers for the early detection of NHL in PLWH.

The impact of surgical weight loss procedures on the risk of metachronous colorectal neoplasia: the differential effect of surgery type, sex, and anatomic location.

Patients with prior colorectal polyps are at high risk for metachronous colorectal neoplasia, especially in the presence of obesity. We assessed the impact of 2 common bariatric surgeries, vertical sleeve gastrectomy and roux-n-Y gastric bypass, on the risk of colorectal neoplasia recurrence. This nationally representative analysis included 1183 postbariatric adults and 3193 propensity score-matched controls, who all had prior colonoscopy with polyps and polypectomy. Colorectal polyps reoccurred in 63.8% of bariatric surgery patients and 71.7% of controls at a mean follow-up of 53.1 months from prior colonoscopy. There was a reduced odds of colorectal polyp recurrence after bariatric surgery compared with controls (odds ratio [OR] = 0.70, 95% confidence interval [CI] = 0.58 to 0.83). This effect was most pronounced in men (OR = 0.58, 95% CI = 0.42 to 0.79), and post roux-n-Y gastric bypass (OR = 0.57, 95% CI = 0.41 to 0.79). However, the risk of rectal polyps or colorectal cancer remained consistent between groups. This study is the first to our knowledge to show a reduction in risk of polyp recurrence following bariatric surgery.

Evidence for virus-mediated oncogenesis in bladder cancers arising in solid organ transplant recipients.

A small percentage of bladder cancers in the general population have been found to harbor DNA viruses. In contrast, up to 25% of tumors of solid organ transplant recipients, who are at an increased risk of developing bladder cancer and have an overall poorer outcomes, harbor BK polyomavirus (BKPyV). To better understand the biology of the tumors and the mechanisms of carcinogenesis from potential oncoviruses, we performed whole genome and transcriptome sequencing on bladder cancer specimens from 43 transplant patients. Nearly half of the tumors from this patient population contained viral sequences. The most common were from BKPyV (N=9, 21%), JC polyomavirus (N=7, 16%), carcinogenic human papillomaviruses (N=3, 7%), and torque teno viruses (N=5, 12%). Immunohistochemistry revealed variable Large T antigen expression in BKPyV-positive tumors ranging from 100% positive staining of tumor tissue to less than 1%. In most cases of BKPyV-positive tumors, the viral genome appeared to be clonally integrated into the host chromosome consistent with microhomology-mediated end joining and coincided with focal amplifications of the tumor genome similar to other virus-mediated cancers. Significant changes in host gene expression consistent with the functions of BKPyV Large T antigen were also observed in these tumors. Lastly, we identified four mutation signatures in our cases, with those attributable to APOBEC3 and SBS5 being the most abundant. Mutation signatures associated with an antiviral drug, ganciclovir, and aristolochic acid, a nephrotoxic compound found in some herbal medicines, were also observed. The results suggest multiple pathways to carcinogenesis in solid organ transplant recipients with a large fraction being virus-associated.

Mosaic chromosomal alterations detected in men living with HIV and the relationship to non-Hodgkin lymphoma.

OBJECTIVES: People with HIV (PWH) have an elevated risk of non-Hodgkin lymphoma (NHL) and other diseases. Studying clonal hematopoiesis (CH), the clonal expansion of mutated hematopoietic stem cells, could provide insights regarding elevated NHL risk. DESIGN: Cohort analysis of participants in the Multicenter AIDS Cohort Study ( N  = 5979). METHODS: Mosaic chromosomal alterations (mCAs), a type of CH, were detected from genotyping array data using MoChA. We compared CH prevalence in men with HIV (MWH) to HIV-uninfected men using logistic regression, and among MWH, assessed the associations of CH with NHL incidence and overall mortality using Poisson regression. RESULTS: Comparing MWH to HIV-uninfected men, we observed no difference in the frequency of autosomal mCAs (3.9% vs. 3.6%, P -value = 0.09) or mosaic loss of the Y chromosome (mLOY) (1.4% vs. 2.9%, P -value = 0.13). Autosomal mCAs involving copy-neutral loss of heterozygosity (CN-LOH) of chromosome 14q were more common in MWH. Among MWH, mCAs were not associated with subsequent NHL incidence (autosomal mCA P -value = 0.65, mLOY P -value = 0.48). However, two MWH with diffuse large B-cell lymphoma had overlapping CN-LOH mCAs on chromosome 19 spanning U2AF2 (involved in RNA splicing), and one MWH with Burkitt lymphoma had high-frequency mCAs involving chromosome 1 gain and chromosome 17 CN-LOH (cell fractions 22.1% and 25.0%, respectively). mCAs were not associated with mortality among MWH (autosomal mCA P -value = 0.52, mLOY P -value = 0.93). CONCLUSIONS: We found limited evidence for a relationship between HIV infection and mCAs. Although mCAs were not significantly associated with NHL, mCAs detected in several NHL cases indicate a need for further investigation.

No Association of IFNL4 Genotype With Opportunistic Infections and Cancers Among Men With Human Immunodeficiency Virus 1 Infection.

BACKGROUND: IFNL4 genetic variants that are strongly associated with clearance of hepatitis C virus have been linked to risk of certain opportunistic infections (OIs) and cancers, including Kaposi sarcoma, cytomegalovirus infection, and herpes simplex virus infection. As the interferon (IFN) λ family plays a role in response to viral, bacterial, and fungal infections, IFNL4 genotype might affect risk for a wide range of OIs/cancers. METHODS: We examined associations between genotype for the functional IFNL4 rs368234815 polymorphism and incidence of 16 OIs/cancers among 2310 men with human immunodeficiency virus (2038 white; 272 black) enrolled in the Multicenter AIDS Cohort Study during 1984-1990. Our primary analyses used Cox proportional hazards models adjusted for self-reported racial ancestry to estimate hazard ratios with 95% confidence intervals, comparing participants with the genotypes that generate IFN-λ4 and those with the genotype that abrogates IFN-λ4. We censored follow-up at the introduction of highly effective antiretroviral therapies. RESULTS: We found no statistically significant association between IFNL4 genotype and the incidence of Kaposi sarcoma (hazard ratio, 0.92 [95% confidence interval, .76-1.11]), cytomegalovirus infection (0.94 [.71-1.24]), herpes simplex virus infection (1.37 [.68-2.93]), or any other OI/cancer. We observed consistent results using additive genetic models and after controlling for CD4 cell count through time-dependent adjustment or restriction to participants with a low CD4 cell count. CONCLUSIONS: The absence of associations between IFNL4 genotype and these OIs/cancers provides evidence that this gene does not affect the risk of disease from opportunistic pathogens.

Cardiovascular and hepatic disease associations by magnetic resonance imaging: A retrospective cohort study.

Background: Hepatic disease is linked to cardiovascular events but the independent association between hepatic and cardiovascular disease remains unclear, given shared risk factors. Methods: This was a retrospective study of consecutive patients with a clinical cardiac MRI (CMR) and a serological marker of hepatic fibrosis, the FIB-4 score, within one year of clinical imaging. We assessed the relations between FIB-4 scores grouped based on prior literature: low (< 1.3), moderate (1.3-3.25), and high (>3.25), and abnormalities detected by comprehensive CMR grouped into 4 domains: cardiac structure (end diastolic volumes, atrial dimensions, wall thickness); cardiac function (ejection fractions, wall motion abnormalities, cardiac output); vascular structure (ascending aortic and pulmonary arterial sizes); and cardiac composition (late gadolinium enhancement, T1 and T2 times). We used Poisson regression to examine the association between the conventionally defined FIB-4 category (low <1.3, moderate 1.3-3.25, and high >3.25) and any CMR abnormality while adjusting for demographics and traditional cardiovascular risk factors. Results: Of the 1668 patients studied (mean age: 55.971 ± 7.28, 901 [54%] male), 85.9% had ≥1 cardiac abnormality with increasing prevalence seen within the low (82.0%) to moderate (88.8%) to high (92.3%) FIB-4 categories. Multivariable analyses demonstrated the presence of any cardiac abnormality was significantly associated with having a high-range FIB-4 (prevalence ratio 1.07, 95% CI: 1.01-1.13); notably, the presence of functional cardiac abnormalities were associated with being in the high FIB-4 range (1.41, 1.21-1.65) and any vascular abnormalities with being in the moderate FIB-4 range (1.22, 1.01-1.47). Conclusions: Elevated FIB-4 was associated with cardiac functional and vascular abnormalities even after adjustment for shared risk factors in a cohort of patients with clinically referred CMR. These CMR findings indicate that cardiovascular abnormalities exist in the presence of subclinical hepatic fibrosis, irrespective of shared risk factors, underscoring the need for further studies of the heart-liver axis.

Association of Cardiometabolic Disease With Cancer in the Community.

Background: Obesity and cardiometabolic dysfunction have been associated with cancer risk and severity. Underlying mechanisms remain unclear. Objectives: The aim of this study was to examine associations of obesity and related cardiometabolic traits with incident cancer. Methods: FHS (Framingham Heart Study) and PREVEND (Prevention of Renal and Vascular End-Stage Disease) study participants without prevalent cancer were studied, examining associations of obesity, body mass index (BMI), waist circumference, visceral adipose tissue (VAT) and subcutaneous adipose tissue depots, and C-reactive protein (CRP) with future cancer in Cox models. Results: Among 20,667 participants (mean age 50 years, 53% women), 2,619 cancer events were observed over a median follow-up duration of 15 years. Obesity was associated with increased risk for future gastrointestinal (HR: 1.30; 95% CI: 1.05-1.60), gynecologic (HR: 1.62; 95% CI: 1.08-2.45), and breast (HR: 1.32; 95% CI: 1.05-1.66) cancer and lower risk for lung cancer (HR: 0.62; 95% CI: 0.44-0.87). Similarly, waist circumference was associated with increased risk for overall, gastrointestinal, and gynecologic but not lung cancer. VAT but not subcutaneous adipose tissue was associated with risk for overall cancer (HR: 1.22; 95% CI: 1.05-1.43), lung cancer (HR: 1.92; 95% CI: 1.01-3.66), and melanoma (HR: 1.56; 95% CI: 1.02-2.38) independent of BMI. Last, higher CRP levels were associated with higher risk for overall, colorectal, and lung cancer (P < 0.05 for all). Conclusions: Obesity and abdominal adiposity are associated with future risk for specific cancers (eg, gastrointestinal, gynecologic). Although obesity was associated with lower risk for lung cancer, greater VAT and CRP were associated with higher lung cancer risk after adjusting for BMI.

How useful are body mass index and history of diabetes in COVID-19 risk stratification?

OBJECTIVE: This study examines the value of risk stratification by documented diagnosis of diabetes and objectively measured height and weight (BMI) in COVID-19 severity and mortality in a large sample of patients in an urban hospital located in Southern California. METHODS: Data from a retrospective cohort study of COVID-19 patients treated at Cedars-Sinai Medical Center between March 8, 2020, and January 25, 2021, was analyzed. Sociodemographic characteristics and pre-existing conditions were extracted from electronic medical records. Univariable and multivariable logistic regression models identified associated risk factors, and a regression causal mediation analysis examined the role of diabetes in the association between obesity and illness severity. All analyses were stratified by age (<65 and ≥65). RESULTS: Among individuals <65yo, diabetes accounted for 19-30% of the associations between obesity and COVID-19 illness severity. Among patients ≥65yo, having a BMI <18.5 was a risk factor for mortality regardless of diabetes history. CONCLUSION: Our findings have clinical implications in documenting which patients may be at elevated risk for adverse outcomes. More in-depth prospective studies are needed to capture how glycemic regulation may influence prognosis.

Cancer Screening Practices Among Healthcare Workers During the COVID-19 Pandemic.

The COVID-19 pandemic has the potential to impact long-standing efforts to increase adherence to cancer screening guidelines. Healthcare workers (HCWs) experienced significant hardship, but generally have greater access to preventive services, making them a particularly relevant population in which to understand cancer screening behaviors during the pandemic. We report data from 794 HCWs enrolled in the NCI-funded Serological Sciences Network for Coronavirus Associations and Longitudinal Evaluation Study from December 2020 to April 2021. Participants reported lifestyle and screening behaviors during relevant look-back periods which included the pandemic timeframe. Among women between the ages of 40 and 74, 25.7% were overdue for mammographic breast cancer screening. Among participants 50-75 years old, 38.9% were overdue for colorectal cancer screening. The proportion over-due varied according to race/ethnicity. Lifetime low-dose computed tomography lung cancer screening among HCWs age 50-80 years who were smokers was 10.9%. Strategies to address screening disruptions are needed to minimize the impact of later stage of diagnosis.

Duodenal Microbiome and Serum Metabolites Predict Hepatocellular Carcinoma in a Multicenter Cohort of Patients with Cirrhosis.

BACKGROUND: Hepatocellular carcinoma (HCC) is rapidly increasing in the U.S. and is a leading cause of mortality for patients with cirrhosis. Discovering novel biomarkers for risk stratification of HCC is paramount. We examined biomarkers of the gut-liver axis in a prospective multicenter cohort. METHODS: Patients with cirrhosis without a history of HCC were recruited between May 2015 and March 2020 and prospectively followed at 3 tertiary care hospitals in Los Angeles. Microbiome analysis was performed on duodenal biopsies and metabolomic analysis was performed on serum samples, collected at the time of enrollment. Optimal microbiome-based survival analysis and Cox proportional hazards regression analysis were used to determine microbiota and metabolite associations with HCC development, respectively. RESULTS: A total of 227 participants with liver cirrhosis contributed a total of 459.58 person-years of follow-up, with 14 incident HCC diagnoses. Male sex (HR = 7.06, 95% CI = 1.02-54.86) and baseline hepatic encephalopathy (HE, HR = 4.65, 95% CI = 1.60-13.52) were associated with developing HCC over follow-up. Adjusting for age, sex, baseline HE, and alkaline phosphatase, an increased risk of HCC were observed for participants with the highest versus lowest three quartiles for duodenal Alloprevotella (HR = 3.22, 95% CI = 1.06-9.73) and serum taurocholic acid (HR = 6.87, 95% CI = 2.32-20.27), methionine (HR = 9.97, 95% CI = 3.02-32.94), and methioninesulfoxide (HR = 5.60, 95% CI = 1.84-17.10). Being in the highest quartile for Alloprevotella or methionine had a sensitivity and specificity for developing HCC of 85.71% and 60.56%, respectively, with an odds ratio of 10.92 (95% CI = 2.23-53.48). CONCLUSION: Alloprevotella and methionine, methioninesulfoxide, and taurocholic acid predicted future HCC development in a high-risk population of participants with liver cirrhosis.

Symptomology following mRNA vaccination against SARS-CoV-2.

Despite demonstrated efficacy of vaccines against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of coronavirus disease-2019 (COVID-19), widespread hesitancy to vaccination persists. Improved knowledge regarding frequency, severity, and duration of vaccine-associated symptoms may help reduce hesitancy. In this prospective observational study, we studied 1032 healthcare workers who received both doses of the Pfizer-BioNTech SARS-CoV-2 mRNA vaccine and completed post-vaccine symptom surveys both after dose 1 and after dose 2. We defined appreciable post-vaccine symptoms as those of at least moderate severity and lasting at least 2 days. We found that symptoms were more frequent following the second vaccine dose than the first (74% vs. 60%, P < 0.001), with >80% of all symptoms resolving within 2 days. The most common symptom was injection site pain, followed by fatigue and malaise. Overall, 20% of participants experienced appreciable symptoms after dose 1 and 30% after dose 2. In multivariable analyses, female sex was associated with greater odds of appreciable symptoms after both dose 1 (OR, 95% CI 1.73, 1.19-2.51) and dose 2 (1.76, 1.28-2.42). Prior COVID-19 was also associated with appreciable symptoms following dose 1, while younger age and history of hypertension were associated with appreciable symptoms after dose 2. We conclude that most post-vaccine symptoms are reportedly mild and last <2 days. Appreciable post-vaccine symptoms are associated with female sex, prior COVID-19, younger age, and hypertension. This information can aid clinicians in advising patients on the safety and expected symptomatology associated with vaccination.

Specimen Collection and Analysis of the Duodenal Microbiome.

Shifts in the microbiome have been correlated with the physiology and pathophysiology of many organ systems both in humans and in mouse models. The gut microbiome has been typically studied through fecal specimen collections. The ease of obtaining fecal samples has resulted in many studies that have revealed information concerning the distal luminal gastrointestinal tract. However, few studies have addressed the importance of the microbiome in the proximal gut. Given that the duodenum is a major site for digestion and absorption, its microbiome is relevant to nutrition and liver disease and warrants further investigation. Here we detail a novel method for sampling the proximal luminal and mucosal gut microbiome in human subjects undergoing upper endoscopy by obtaining duodenal aspirate and biopsies. Specimen procurement is facile and unaffected by artifacts such as patient preparatory adherence, as might be the case in obtaining colonic samples during colonoscopy. The preliminary results show that the luminal and mucosal microbiomes differ significantly, which is likely related to environmental conditions and barrier functions. Therefore, a combination of duodenal aspirate and biopsies reveal a more comprehensive picture of the microbiome in the duodenum. Biopsies are obtained from the descending and horizontal segments of the duodenum, which are anatomically close to the liver and biliary tree. This is important in studying the role of bile acid biology and the gut-liver axis in liver disease. Biopsies and aspirate can be used for 16S ribosomal RNA sequencing, metabolomics, and other similar applications.

Seroprevalence of antibodies to SARS-CoV-2 in healthcare workers: a cross-sectional study.

OBJECTIVE: We sought to determine the extent of SARS-CoV-2 seroprevalence and the factors associated with seroprevalence across a diverse cohort of healthcare workers. DESIGN: Observational cohort study of healthcare workers, including SARS-CoV-2 serology testing and participant questionnaires. SETTINGS: A multisite healthcare delivery system located in Los Angeles County. PARTICIPANTS: A diverse and unselected population of adults (n=6062) employed in a multisite healthcare delivery system located in Los Angeles County, including individuals with direct patient contact and others with non-patient-oriented work functions. MAIN OUTCOMES: Using Bayesian and multivariate analyses, we estimated seroprevalence and factors associated with seropositivity and antibody levels, including pre-existing demographic and clinical characteristics; potential COVID-19 illness-related exposures; and symptoms consistent with COVID-19 infection. RESULTS: We observed a seroprevalence rate of 4.1%, with anosmia as the most prominently associated self-reported symptom (OR 11.04, p<0.001) in addition to fever (OR 2.02, p=0.002) and myalgias (OR 1.65, p=0.035). After adjusting for potential confounders, seroprevalence was also associated with Hispanic ethnicity (OR 1.98, p=0.001) and African-American race (OR 2.02, p=0.027) as well as contact with a COVID-19-diagnosed individual in the household (OR 5.73, p<0.001) or clinical work setting (OR 1.76, p=0.002). Importantly, African-American race and Hispanic ethnicity were associated with antibody positivity even after adjusting for personal COVID-19 diagnosis status, suggesting the contribution of unmeasured structural or societal factors. CONCLUSION AND RELEVANCE: The demographic factors associated with SARS-CoV-2 seroprevalence among our healthcare workers underscore the importance of exposure sources beyond the workplace. The size and diversity of our study population, combined with robust survey and modelling techniques, provide a vibrant picture of the demographic factors, exposures and symptoms that can identify individuals with susceptibility as well as potential to mount an immune response to COVID-19.

Risk of smoking-related cancers among women and men living with and without HIV.

OBJECTIVES: We investigated whether the effect of smoking on the incidence of smoking-related cancers differs by HIV-infection status, if sex modifies the impact of risk factors for smoking-related cancers, and the sex-specific attributable risk of smoking on cancer incidence. DESIGN: Data from two large prospective studies in the United States were analyzed: 6789 men in the Multicenter AIDS Cohort Study from 1984 through 2018 and 4423 women in the Women's Interagency HIV Study from 1994 through 2018. METHODS: Incidence rates, relative risks, and adjusted population attributable fractions (PAFs) were calculated for smoking-related cancers. RESULTS: During study follow-up, there were 214 incident smoking-related cancers in the men and 192 in the women. The age-adjusted incidence ratess for smoking-related cancers were higher in the women (392/100 000) than for the men (198/100 000; P < 0.01) and higher for people living with HIV (PLWH, 348/100 000) than for those without HIV (162/100 000; P < 0.01). Unadjusted incidence rates in PLWH were higher than in those without HIV when stratifying by cumulative pack-years of smoking (all P values <0.01). In adjusted interaction models, the effects of cumulative pack-years of smoking were significantly stronger in women. The adjusted PAFs for smoking-related cancers were nonsignificantly higher in the women than in the men (39 vs. 28%; P = 0.35). CONCLUSION: HIV looks to be an independent risk factor for smoking-related cancers and women appear to have a greater risk than men. These results highlight the need for interventions to help PLWH, especially women, quit smoking and sustain cessation to reduce their risk of smoking-related cancers.

Genetic variation near CXCL12 is associated with susceptibility to HIV-related non-Hodgkin lymphoma.

Human immunodeficiency virus (HIV) infection is associated with an increased risk of non-Hodgkin lymphoma (NHL). Even in the era of suppressive antiretroviral treatment, HIV-infected individuals remain at higher risk of developing NHL compared to the general population. To identify potential genetic risk loci, we performed case-control genome-wide association studies and a meta-analysis across three cohorts of HIV+ patients of European ancestry, including a total of 278 cases and 1924 matched controls. We observed a significant association with NHL susceptibility in the C-X-C motif chemokine ligand 12 (CXCL12) region on chromosome 10. A fine mapping analysis identified rs7919208 as the most likely causal variant (P = 4.77e-11), with the G>A polymorphism creating a new transcription factor binding site for BATF and JUND. These results suggest a modulatory role of CXCL12 regulation in the increased susceptibility to NHL observed in the HIV-infected population.

Effect of Statin Use on Inflammation and Immune Activation Biomarkers in HIV-Infected Persons on Effective Antiretroviral Therapy.

Immune activation and inflammation are hallmarks of chronic HIV infection and are etiologically linked to major causes of morbidity and mortality among HIV-infected persons, including coronary artery disease and cancer. Systemic immune activation is dampened, but not resolved, with use of combination antiretroviral therapy (cART). Statins are cardioprotective drugs that also appear to have immunomodulatory and anti-inflammatory properties. We sought to understand the association between statin use, cART, and levels of circulating immune markers in a longitudinal cohort study. From 2004 to 2009, statin use was ascertained in male participants of the Multicenter AIDS Cohort Study (MACS) using interviewer-administered questionnaires. Twenty-four circulating markers of immune activation and inflammation were measured in archived serial samples from a subset of cohort members using multiplex assays. Propensity-adjusted generalized gamma models were used to compare biomarkers' distributions by statin use, and multivariable linear regression models were used to assess the effect of initiating statin on these biomarkers. Overall, 1,031 cART-exposed individuals with HIV infection were included in this study. Statin use was reported by 31.5% of cART-exposed participants. Compared to nonstatin users on cART, statin users on cART had lower levels of IP-10, IL-10, and IL-12p70, and the effect of statin use was decreased in participants using lipophilic statins (atorvastatin, simvastatin, fluvastatin, or lovastatin); these results were statistically significant (p < .05). Among cART users not on aspirin, starting statins decreased levels of high sensitivity c-reactive protein (hsCRP), IL-12p70, and IL-6. Statin therapy is associated with reduced levels of certain biomarkers of immune activation and inflammation in cART users, which may contribute to a lower burden of disease.

Emerging risk factors for nonalcoholic fatty liver disease associated hepatocellular carcinoma.

Worldwide, nonalcoholic fatty liver disease (NAFLD) has reached epidemic proportions and in parallel, hepatocellular carcinoma (HCC) has become one of the fastest growing cancers. Epidemiological studies have not only shed light on the prevalence and incidence of the disease but have also unmasked important environmental risk factors, including the role of diabetes and dyslipidemia in disease pathogenesis. Genetic association studies have identified single nucleotide polymorphisms implicated in NAFLD-HCC, many of which are part of lipid metabolism pathways. Through these clinical studies and subsequently, translational and basic research, the role of statins as a chemoprotective agent has also emerged with ongoing clinical trials assessing their utility in HCC prevention and treatment. In this review, we summarize the recent epidemiological studies describing the burden of NAFLD-HCC in different patient populations and countries. We discuss the genetic and environmental risk factors for NAFLD-HCC and highlight the chemoprotective role of statins and aspirin. We also summarize what is known about NAFLD-HCC in the cirrhosis and non-cirrhosis populations and briefly address the role of surveillance in NAFLD-HCC patients.

Improved survival after treatments of patients with nonalcoholic fatty liver disease associated hepatocellular carcinoma.

Worldwide, nonalcoholic fatty liver disease (NAFLD) has reached epidemic proportions and in parallel, hepatocellular carcinoma (HCC) has become one of the fastest growing cancers. Despite the rise in these disease entities, detailed long-term outcomes of large NAFLD-associated HCC cohorts are lacking. In this report, we compared the overall and recurrence-free survival rates of NAFLD HCC cases to patients with HBV and HCV-associated HCC cases. Distinguishing features of NAFLD-associated HCC patients in the cirrhosis and non-cirrhosis setting were also identified. We conducted a retrospective study of 125 NAFLD, 170 HBV and 159 HCV HCC patients, utilizing clinical, pathological and radiographic data. Multivariate regression models were used to study the overall and recurrence-free survival. The overall survival rates were significantly higher in the NAFLD-HCC cases compared to HBV-HCC (HR = 0.35, 95% CI 0.15-0.80) and HCV-HCC (HR = 0.37, 95% CI 0.17-0.77) cases. The NAFLD-HCC patients had a trend for higher recurrence-free survival rates compared to HBV and HCV-HCC cases. Within the NAFLD group, 18% did not have cirrhosis or advanced fibrosis; Hispanic ethnicity (OR = 12.34, 95% CI 2.59-58.82) and high BMI (OR = 1.19, 95% CI 1.07-1.33) were significantly associated with having cirrhosis. NAFLD-HCC cases were less likely to exhibit elevated serum AFP (p < 0.0001). After treatments, NAFLD-related HCC patients had longer overall but not recurrence-free survival rates compared to patients with viral-associated HCC. Non-Hispanic ethnicity and normal BMI differentiated non-cirrhosis versus cirrhosis NAFLD HCC. Further studies are warranted to identify additional biomarkers to stratify NAFLD patients without cirrhosis who are at risk for HCC.

The Role of Microbial Translocation and Immune Activation in AIDS-Associated Non-Hodgkin Lymphoma Pathogenesis: What Have We Learned?

Human immunodeficiency virus (HIV) infection is associated with greatly increased risk for development of non-Hodgkin lymphoma (NHL). Nearly all acquired immunodeficiency syndrome (AIDS)-associated NHL (AIDS-NHL) is of B-cell origin. Two major mechanisms are believed to contribute to the genesis of AIDS-NHL: (1) loss of immunoregulation of Epstein-Barr virus (EBV)+ B cells, resulting from impaired T-cell function late in the course of HIV disease and (2) chronic B-cell activation, leading to DNA-modifying events that contribute to oncogene mutations/ translocations. HIV infection has long been known to be associated with chronic inflammation and polyclonal B-cell activation, and more recently, microbial translocation. Microbial translocation is bacterial product leakage from gut lumen into the peripheral circulation, resulting in high levels of lipopolysaccharide (LPS) in the peripheral circulation, leading to chronic immune activation and inflammation. We review recent literature linking microbial translocation to lymphom-agenesis. This includes epidemiological studies of biomarkers of microbial translocation with risk of AIDS-NHL and emerging data on the mechanisms by which microbial translocation may lead to AIDS-NHL development.

Dietary Protein, Fiber and Coffee Are Associated with Small Intestine Microbiome Composition and Diversity in Patients with Liver Cirrhosis.

: The gut microbiome is a key factor in chronic liver disease progression. In prior research, we found that the duodenal microbiome was associated with sex, ethnicity, and cirrhosis complications. Here, we examined the association between diet and the duodenal microbiome in patients with liver cirrhosis. This study included 51 participants who completed a detailed food frequency questionnaire and donated duodenal biopsies for microbiome characterization by 16S ribosomal RNA gene sequencing. Data were analyzed for alpha diversity, beta diversity, and association of taxa abundance with diet quality and components using QIIME 2 pipelines. Diet quality was assessed through calculation of the Healthy Eating Index 2010. Participants with higher adherence to protein recommendations exhibited increased microbial richness and evenness (p = 0.03) and a different microbial profile compared to those with lower adherence (p = 0.03). Prevotella-9 and Agathobacter were increased in association with increased protein adherence. Fiber consumption was also associated with the duodenal microbial profile (p = 0.01), with several taxa exhibiting significantly decreased or increased abundance in association with fiber intake. Coffee drinking was associated with microbial richness and evenness (p = 0.001), and there was a dose-response association between coffee drinking and relative abundance of Veillonella (p = 0.01). We conclude that protein, fiber, and coffee are associated with diversity and composition of the duodenal microbiome in liver cirrhosis.