Research Letter: Relationship of Blood Biomarkers of Inflammation With Acute Concussion Symptoms and Recovery in the CARE Consortium.

OBJECTIVE: Determine the association of inflammatory biomarkers with clinical measures and recovery in participants with concussion. SETTING: Multicenter study in National Collegiate Athletic Association member institutions including military service academies. PARTICIPANTS: Four hundred twenty-two participants with acute concussion. DESIGN: Clinical visits and blood draws were completed preinjury and at multiple visits postconcussion (0-12 hours, 12-36 hours, and 36-60 hours postinjury). Clinical measures included Sport Concussion Assessment Tool (SCAT) symptom severity, Balance Error Scoring System, Standardized Assessment of Concussion (SAC), Brief Symptom Inventory-18 (BSI-18) scores, time to initiation of graduated return-to-play (RTP) protocol, and time to RTP. Interleukin (IL)-6, IL-10, IL-8, IL-1 receptor antagonist (RA), tumor necrosis factor (TNF), c-reactive protein, and vascular endothelial growth factor (VEGF) were measured in serum. Prespecified analyses focused on IL-6 and IL-1RA at 0 to 12 hours; exploratory analyses were conducted with false discovery rate correction. RESULTS: For prespecified analyses, IL-1RA at 0 to 12 hours in female participants was positively associated with more errors on the SAC (B(standard error, SE) = 0.58(0.27), P < .05) and worse SCAT symptom severity (B(SE) = 0.96(0.44), P < .05). For exploratory analyses, higher levels of IL-1RA at 12 to 36 hours were associated with higher global (B(SE) = 0.55(0.14), q < 0.01), depression (B(SE) = 0.45(0.10), q < 0.005), and somatization scores on the BSI (B(SE) = 0.46(0.12), q < 0.01) in participants with concussion; Higher TNF at 12 to 36 hours was associated with fewer errors on the SAC (B(SE) = - 0.46(0.14), q < 0.05). Subanalyses showed similar results for male participants and participants who were athletes. No associations were discovered in nonathlete cadets. Higher IL-8 at 0 to 12 hours was associated with slower RTP in female participants (OR = 14.47; 95% confidence interval, 2.96-70.66, q < 0.05); no other associations with recovery were observed. CONCLUSIONS: Peripheral inflammatory markers are associated with clinical symptoms following concussion and potentially represent one mechanism for psychological symptoms observed postinjury. Current results do not provide strong support for a potential prognostic role for these markers.

Association of Blood Biomarkers of Inflammation With Acute Concussion in Collegiate Athletes and Military Service Academy Cadets.

BACKGROUND AND OBJECTIVES: The objective was to characterize the acute effects of concussion (a subset of mild traumatic brain injury) on serum interleukin (IL)-6 and IL-1 receptor antagonist (RA) and 5 additional inflammatory markers in athletes and military service academy members from the Concussion Assessment, Research, and Education Consortium and to determine whether these markers aid in discrimination of concussed participants from controls. METHODS: Athletes and cadets with concussion and matched controls provided blood at baseline and postinjury visits between January 2015 and March 2020. Linear models investigated changes in inflammatory markers measured using Meso Scale Discovery assays across time points (baseline and 0-12, 12-36, 36-60 hours). Subanalyses were conducted in participants split by sex and injury population. Logistic regression analyses tested whether acute levels of IL-6 and IL-1RA improved discrimination of concussed participants relative to brain injury markers (glial fibrillary acidic protein, tau, neurofilament light, ubiquitin c-terminal hydrolase-L1) or clinical data (Sport Concussion Assessment Tool-Third Edition, Standardized Assessment of Concussion, Balance Error Scoring System). RESULTS: Participants with concussion (total, N = 422) had elevated IL-6 and IL-1RA at 0-12 hours vs controls (n = 345; IL-6: mean difference [MD] (standard error) = 0.701 (0.091), p < 0.0001; IL-1RA: MD = 0.283 (0.042), p < 0.0001) and relative to baseline (IL-6: MD = 0.656 (0.078), p < 0.0001; IL-1RA: MD = 0.242 (0.038), p < 0.0001), 12-36 hours (IL-6: MD = 0.609 (0.086), p < 0.0001; IL-1RA: MD = 0.322 (0.041), p < 0.0001), and 36-60 hours (IL-6: MD = 0.818 (0.084), p < 0.0001; IL-1RA: MD = 0.317 (0.040), p < 0.0001). IL-6 and IL-1RA were elevated in participants with sport (IL-6: MD = 0.748 (0.115), p < 0.0001; IL-1RA: MD = 0.304 (0.055), p < 0.0001) and combative-related concussions (IL-6: MD = 0.583 (0.178), p = 0.001; IL-1RA: MD = 0.312 (0.081), p = 0.0001). IL-6 was elevated in male (MD = 0.734 (0.105), p < 0.0001) and female participants (MD = 0.600 (0.177), p = 0.0008); IL-1RA was only elevated in male participants (MD = 0.356 (0.047), p < 0.0001). Logistic regression showed the inclusion of IL-6 and IL-1RA at 0-12 hours improved the discrimination of participants with concussion from controls relative to brain injury markers (χ2(2) = 17.855, p = 0.0001; area under the receiver operating characteristic curve [AUC] 0.73 [0.66-0.80] to 0.78 [0.71-0.84]), objective clinical measures (balance and cognition; χ2(2) = 40.661, p < 0.0001; AUC 0.81 [0.76-0.86] to 0.87 [0.83-0.91]), and objective and subjective measures combined (χ2(2) = 13.456, p = 0.001; AUC 0.97 [0.95-0.99] to 0.98 [0.96-0.99]), although improvement in AUC was only significantly relative to objective clinical measures. DISCUSSION: IL-6 and IL-1RA (male participants only) are elevated in the early-acute window postconcussion and may aid in diagnostic decisions beyond traditional blood markers and common clinical measures. IL-1RA results highlight sex differences in the immune response to concussion which should be considered in future biomarker work.

Elevations in Tumor Necrosis Factor Alpha and Interleukin 6 From Neuronal-Derived Extracellular Vesicles in Repeated Low-Level Blast Exposed Personnel.

Objective: The purpose of this pilot study was to determine if military service members with histories of hundreds to thousands of low-level blast exposures (i. e., experienced breachers) had different levels of serum and neuronal-derived extracellular vesicle (EV) concentrations of interleukin (IL)-6, IL-10, and tumor necrosis factor alpha (TNFα), compared to matched controls, and if these biomarkers related to neurobehavioral symptoms. Methods: Participants were experienced breachers (n = 20) and matched controls without blast exposures (n = 14). Neuronal-derived EVs were isolated from serum and identified with mouse anti-human CD171. Serum and neuronal-derived EVs were analyzed for IL-6, IL-10, and TNFα using an ultra-sensitive assay. Results: Serum TNFα concentrations were decreased in breachers when compared to control concentrations (p < 0.01). There were no differences in serum concentrations of IL-6, IL-10, or the IL-6/IL-10 ratio between breachers and controls (p's > 0.01). In neuronal-derived EVs, TNFα and IL-6 levels were increased in breachers compared to controls (p's < 0.01), and IL-10 levels were decreased in the breacher group compared to controls (p < 0.01). In breachers the IL-6/IL-10 ratio in neuronal-derived EVs was higher compared to controls, which correlated with higher total Rivermead Post-concussion Questionnaire (RPQ) scores (p's < 0.05). Conclusions: These findings suggest that exposure of personnel to high numbers of low-level blast over a career may result in enduring central inflammation that is associated with chronic neurological symptoms. The data also suggest that peripheral markers of inflammation are not necessarily adequate surrogates for central neuroinflammation.

Extracellular vesicle-associated cytokines in sport-related concussion.

Growing evidence suggests that sport-related concussion results in a robust inflammatory response that can be measured in serum or plasma and is predictive of symptom recovery. Recently, extracellular vesicles (EV) derived from serum or plasma have emerged as a promising source of biomarkers for neurological disorders like concussion because they may better reflect central immunological activity. However, the association of acute concussion with EV-associated cytokines has not yet been systematically studied in humans. We tested the hypothesis that EV-associated cytokines are elevated acutely and predictive of symptom duration following concussion in a cohort of high-school and collegiate football players. Players were enrolled and provided serum samples at a preseason baseline visit (N = 857). An additional blood draw was obtained in players that subsequently suffered a concussion (N = 23) within 6-hours post-injury and in matched, uninjured players (N = 44). Concentrations of Interleukin-6 (IL-6), IL-1ß, IL-1 receptor antagonist (IL-1RA), IL-10, and tumor necrosis factor were measured in EV and EV-depleted serum samples. EV-associated IL-6 was significantly elevated post-injury relative to baseline levels and controls (ps < 0.01). In EV-depleted samples, IL-1RA was significantly elevated post-injury relative to baseline levels and controls (ps < 0.01). Time-to-event analyses showed that post-injury EV-associated IL-6 levels were positively associated with the number of days that injured athletes reported symptoms (p < 0.05). These results highlight the potential of EV-associated cytokines as biomarkers of concussion.

High Social Coping Self-Efficacy Associated With Lower Sweat Interleukin-6 in Older Adults With Chronic Illness.

Inflammation, particularly interleukin-6 (IL-6), is associated with chronic disease in older adults, but not all older adults have the same progression of poor health outcomes. Self-efficacy may play a role in buffering the inflammatory burden in chronic disease. To evaluate associations between self-efficacy and IL-6, 159 community-dwelling older adults (N = 159, Mage = 82 years, SD = 6.3 years) with one or more chronic illnesses were recruited for this cross-sectional study. Sweat IL-6 was collected using a noninvasive sweat patch worn for 72 hrs. Multiple linear regression with bootstrapping showed a significant association between social coping self-efficacy and IL-6 (ß = -0.534, p = .010) after adjustment for age, sex, race, body mass index, financial strain, chronic conditions, and social support. Although preliminary, this study creates a rationale to explore the self-efficacy inflammatory biomarker association further. Enhancing self-efficacy might be a viable nonpharmacological treatment to lower or slow the inflammatory burden in older adults.

17α-Ethinyl estradiol-3-sulfate increases survival and hemodynamic functioning in a large animal model of combined traumatic brain injury and hemorrhagic shock: a randomized control trial.

BACKGROUND: Traumatic brain injury (TBI) and severe blood loss resulting in hemorrhagic shock (HS) represent leading causes of trauma-induced mortality, especially when co-occurring in pre-hospital settings where standard therapies are not readily available. The primary objective of this study was to determine if 17α-ethinyl estradiol-3-sulfate (EE-3-SO4) increases survival, promotes more rapid cardiovascular recovery, or confers neuroprotection relative to Placebo following TBI + HS. METHODS: All methods were approved by required regulatory agencies prior to study initiation. In this fully randomized, blinded preclinical study, eighty (50% females) sexually mature (190.64 ± 21.04 days old; 28.18 ± 2.72 kg) Yucatan swine were used. Sixty-eight animals received a closed-head, accelerative TBI followed by removal of approximately 40% of circulating blood volume. Animals were then intravenously administered EE-3-SO4 formulated in the vehicle at 5.0 mg/mL (dosed at 0.2 mL/kg) or Placebo (0.45% sodium chloride solution) via a continuous pump (0.2 mL/kg over 5 min). Twelve swine were included as uninjured Shams to further characterize model pathology and replicate previous findings. All animals were monitored for up to 5 h in the absence of any other life-saving measures (e.g., mechanical ventilation, fluid resuscitation). RESULTS: A comparison of Placebo-treated relative to Sham animals indicated evidence of acidosis, decreased arterial pressure, increased heart rate, diffuse axonal injury and blood-brain barrier breach. The percentage of animals surviving to 295 min post-injury was significantly higher for the EE-3-SO4 (28/31; 90.3%) relative to Placebo (24/33; 72.7%) cohort. EE-3-SO4 also restored pulse pressure more rapidly post-drug administration, but did not confer any benefits in terms of shock index. Primary blood-based measurements of neuroinflammation and blood brain breach were also null, whereas secondary measurements of diffuse axonal injury suggested a more rapid return to baseline for the EE-3-SO4 group. Survival status was associated with biological sex (female > male), as well as evidence of increased acidosis and neurotrauma independent of EE-3-SO4 or Placebo administration. CONCLUSIONS: EE-3-SO4 is efficacious in promoting survival and more rapidly restoring cardiovascular homeostasis following polytraumatic injuries in pre-hospital environments (rural and military) in the absence of standard therapies. Poly-therapeutic approaches targeting additional mechanisms (increased hemostasis, oxygen-carrying capacity, etc.) should be considered in future studies.

Extracellular Vesicle Proteins and MicroRNAs Are Linked to Chronic Post-Traumatic Stress Disorder Symptoms in Service Members and Veterans With Mild Traumatic Brain Injury.

Symptoms of post-traumatic stress disorder (PTSD) are common in military populations, and frequently associated with a history of combat-related mild traumatic brain injury (mTBI). In this study, we examined relationships between severity of PTSD symptoms and levels of extracellular vesicle (EV) proteins and miRNAs measured in the peripheral blood in a cohort of military service members and Veterans (SMs/Vs) with chronic mTBI(s). Participants (n = 144) were divided into groups according to mTBI history and severity of PTSD symptoms on the PTSD Checklist for DSM-5 (PCL-5). We analyzed EV levels of 798 miRNAs (miRNAs) as well as EV and plasma levels of neurofilament light chain (NfL), Tau, Amyloid beta (Aß) 42, Aß40, interleukin (IL)-10, IL-6, tumor necrosis factor-alpha (TNFα), and vascular endothelial growth factor (VEGF). We observed that EV levels of neurofilament light chain (NfL) were elevated in participants with more severe PTSD symptoms (PCL-5 ≥ 38) and positive mTBI history, when compared to TBI negative controls (p = 0.024) and mTBI participants with less severe PTSD symptoms (p = 0.006). Levels of EV NfL, plasma NfL, and hsa-miR-139-5p were linked to PCL-5 scores in regression models. Our results suggest that levels of NfL, a marker of axonal damage, are associated with PTSD symptom severity in participants with remote mTBI. Specific miRNAs previously linked to neurodegenerative and inflammatory processes, and glucocorticoid receptor signaling pathways, among others, were also associated with the severity of PTSD symptoms. Our findings provide insights into possible signaling pathways linked to the development of persistent PTSD symptoms after TBI and biological mechanisms underlying susceptibility to PTSD.

Whole blood transcriptome analysis using RNA sequencing in individuals with insomnia disorder and good sleepers: a pilot study.

BACKGROUND: Insomnia is a highly prevalent condition that is associated with negative health outcomes, yet little is known about the underlying molecular mechanisms. METHOD: RNA sequencing was conducted using blood samples from 15 individuals with primary insomnia and 15 age- and gender-matched good sleeper controls. The RNA library was sequenced with 150 base pair paired-ends on the Illumina NovaSeq-6000 platform. Alignment was performed using human reference genome hg38. Differential gene expression analysis was performed using DESeq2 following alignment, using log fold change ±0.50, and had a false discovery rate p-value <0.05. Pathway analysis was performed using Ingenuity Pathway Analysis. RESULTS: We found 288 differentially expressed genes in insomnia patients when compared to controls. Upregulated genes included LINC02224 (Long Intergenic Non-Protein Coding RNA 2224), DUX4L9 (Double Homeobox 4 Like 9), and TUSC3 (Tumor Suppressor Candidate 3) and down regulated genes included CTXN2 (Cortexin 2), CSMD1 (CUB And Sushi Multiple Domains 1), and SLC12A1 (Solute Carrier Family 12 Member 1). Ingenuity® Pathway Analysis (IPA) revealed 3 associated networks (score>40) with genes and hubs related to inflammation (nuclear factor-kB), oxidative stress (Mitochondrial complex 1) and ubiquitination. CONCLUSION: Differentially expressed genes in this analysis are functionally associated with inflammation and immune response, mitochondrial and metabolic processes. Further research into the transcriptomic changes in insomnia is needed to understand related pathways to the disorder and provide new avenues for diagnostics and therapeutics.

Exosomal neurofilament light: A prognostic biomarker for remote symptoms after mild traumatic brain injury?

OBJECTIVE: To measure exosomal and plasma levels of candidate blood biomarkers in veterans with history of mild traumatic brain injury (mTBI) and test their relationship with chronic symptoms. METHODS: Exosomal and plasma levels of neurofilament light (NfL) chain, tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-10, and vascular endothelial growth factor (VEGF) were measured using an ultrasensitive assay in a cohort of 195 veterans, enrolled in the Chronic Effects of Neurotrauma Consortium Longitudinal Study. We examined relationships between candidate biomarkers and symptoms of postconcussive syndrome (PCS), posttraumatic stress disorder (PTSD), and depression. Biomarker levels were compared among those with no traumatic brain injury (TBI) (controls), 1-2 mTBIs, and repetitive (3 or more) mTBIs. RESULTS: Elevated exosomal and plasma levels of NfL were associated with repetitive mTBIs and with chronic PCS, PTSD, and depression symptoms. Plasma TNF-α levels correlated with PCS and PTSD symptoms. The total number of mTBIs correlated with exosomal and plasma NfL levels and plasma IL-6. Increased number of years since the most recent TBI correlated with higher exosomal NfL and lower plasma IL-6 levels, while increased number of years since first TBI correlated with higher levels of exosomal and plasma NfL, as well as plasma TNF-α and VEGF. CONCLUSION: Repetitive mTBIs are associated with elevated exosomal and plasma levels of NfL, even years following these injuries, with the greatest elevations in those with chronic PCS, PTSD, and depression symptoms. Our results suggest a possible neuroinflammatory and axonal disruptive basis for symptoms that persist years after mTBI, especially repetitive.

Interleukin-6 is associated with acute concussion in military combat personnel.

BACKGROUND: Concussion is the most common type of TBI, yet reliable objective measures related to these injuries and associated recovery processes remain elusive, especially in military personnel. The purpose of this study was to characterize the relationship between cytokines and recovery from acute brain injury in active duty service members. Inflammatory cytokines (IL-6, IL-10, and TNFα) were measured acutely in blood samples within 8 h following a medically diagnosed concussion and then 24 h later. METHODS: Participants (n = 94) were categorized into two groups: 1) military personnel who sustained provider-diagnosed concussion, without other major medical diagnosis (n = 45) and 2) healthy control participants in the same deployment environment who did not sustain concussion or other illness or injuries (n = 49). IL-6, IL-10, and TNFα concentrations were measured using an ultrasensitive single-molecule enzyme-linked immunosorbent assay. Differences in cytokine levels between concussed and healthy groups were evaluated at two time points (time point 1 ≤ 8 h after injury; time point 2 = 24 h following time point 1). RESULTS: At time point 1, IL-6 median (IQR) concentrations were 2.62 (3.62) in the concussed group, which was greater compared to IL-6 in the healthy control group (1.03 (0.90); U = 420.00, z = - 5.12, p < 0.001). Compared to healthy controls, the concussed group did not differ at time point 1 in IL-10 or TNFα concentrations (p's > 0.05). At time point 2, no differences were detected between concussed and healthy controls for IL-6, IL-10, or TNFα (p's > 0.05). The median difference between time points 1 and 2 were compared between the concussed and healthy control groups for IL-6, IL-10, and TNFα. Change in IL-6 across time was greater for the concussed group than healthy control (- 1.54 (3.12); U = 315.00, z = - 5.96, p < 0.001), with no differences between groups in the change of IL-10 or TNFα (p's > 0.05). CONCLUSION: Reported here is a significant elevation of IL-6 levels in concussed military personnel less than 8 h following injury. Future studies may examine acute and chronic neurological symptomology associated with inflammatory cytokine levels, distinguish individuals at high risk for developing neurological complications, and identify underlying biological pathways to mitigate inflammation and improve outcomes.

Mild traumatic brain injuries with loss of consciousness are associated with increased inflammation and pain in military personnel.

Mild traumatic brain injuries (mTBI) are a pervasive concern for military personnel. Determining the impact of injury severity, including loss of consciousness (LOC) may provide important insights into the risk of psychological symptoms and inflammation commonly witnessed in military personnel and veterans following mTBI. US military personnel and veterans were categorized into three groups; TBI with LOC (n = 36), TBI without LOC (n = 25), Controls (n = 82). Participants reported their history of mTBI, psychological symptoms (post-traumatic stress disorder [PTSD] and depression), health-related quality of life (HRQOL), and underwent a blood draw. ANCOVA models which controlled for insomnia status and combat exposure indicated that both mTBI groups (with/without LOC) reported significantly greater depression and PTSD symptoms compared to controls; however, they did not differ from each other. The mTBI with LOC did report greater pain than both controls and mTBI without LOC. The TBI with LOC group also had significantly elevated IL-6 concentrations than both TBI without LOC and control groups. Within the mTBI groups, increased TNFα concentrations were associated with greater PTSD symptoms. These findings indicate that sustaining an mTBI, with or without LOC is detrimental for psychological wellbeing. However, LOC may be involved in perceptions of pain and concentrations of IL-6.

Gene expression differences in PTSD are uniquely related to the intrusion symptom cluster: A transcriptome-wide analysis in military service members.

Posttraumatic stress disorder (PTSD) is associated with wide-spread immune dysregulation; however, little is known about the gene expression differences attributed to each PTSD symptom cluster. This is an important consideration when identifying diagnostic and treatment response markers in highly comorbid populations with mental and physical health conditions that share symptoms. To this aim, we utilized a transcriptome-wide analysis of differential gene expression in peripheral blood by comparing military service members: (1) with vs. without PTSD, (2) with high vs. low PTSD cluster symptom severity, and (3) with improved vs. not improved PTSD symptoms following 4-8 weeks of evidenced-based sleep treatment. Data were analyzed at a ±2.0-fold change magnitude with subsequent gene ontology-based pathway analysis. In participants with PTSD (n = 39), 89 differentially expressed genes were identified, and 94% were upregulated. In participants with high intrusion symptoms (n = 22), 1040 differentially expressed genes were identified, and 98% were upregulated. No differentially expressed genes were identified for the remaining two PTSD symptom clusters. Ten genes (C5orf24, RBAK, CREBZF, CD69, PMAIP1, AGL, ZNF644, ANKRD13C, ESCO1, and ZCCHC10) were upregulated in participants with PTSD and high intrusion symptoms at baseline and downregulated in participants with improved PTSD symptoms following treatment. Pathway analysis identified upregulated immune response systems and metabolic networks with a NF-kB hub, which were downregulated with symptom reduction. Molecular biomarkers implicated in intrusion symptoms and PTSD symptom improvement may inform the development of therapeutic targets for precise treatment of PTSD.

Antiangiogenic mechanisms and factors in breast cancer treatment.

Breast cancer is known to metastasize in its latter stages of existence. The different angiogenic mechanisms and factors that allow for its progression are reviewed in this article. Understanding these mechanisms and factors will allow researchers to design drugs to inhibit angiogenic behaviors and control the rate of tumor growth.

Women in recovery from PTSD have similar inflammation and quality of life as non-traumatized controls.

OBJECTIVE: Post-traumatic stress disorder (PTSD) is associated with greater concentrations of inflammatory biomarkers as well as substantial medical burden; however, it is not clear if these morbidity risks change following recovery from PTSD. In this study we compare women who have recovered from PTSD, to those with current PTSD, and healthy controls on their perceived health and inflammatory and metabolic biomarkers. METHODS: We studied 3 groups of women: those with current PTSD, those who reported recovery from PTSD, and healthy non-traumatized controls, which were determined using standard diagnostic instruments. We obtained a morning blood sample and examined concentrations of inflammatory biomarkers of: interleukin 6 (IL-6) and c-reactive protein (CRP), and lipid concentrations. Lastly, we evaluated health related quality of life (HRQOL). RESULTS: Women who had recovered from PTSD had a similar HRQOL and inflammatory biomarkers as non-traumatized controls. Their concentrations of inflammatory biomarkers were lower than women with current PTSD, and similar to non-traumatized controls. CONCLUSION: Health perception as well as biological indicators of health significantly differ in women in recovery from PTSD, compared to those who remain symptomatic. These findings suggest that the psychological recovery is associated with normal levels of inflammatory biomarkers and HRQOL.

Hepatitis C progressing to hepatocellular carcinoma: the HCV dialysis patient in dilemma.

Approximately 3.2 million people in the United States have chronic hepatitis C virus (HCV) infection; the primary cause for adult liver transplantation and a significant burden on healthcare resources. The role of HCV and other risk factors in development of HCC in patients with chronic kidney disease is not well defined. We studied predictors of hepatocellular carcinoma (HCC) in dialysis patients with chronic HCV by analyzing factors associated with its development. Data were extracted from the United States Renal Database System (USRDS) using ICD-9 codes. Variables included were gender, race, duration on dialysis and co-morbidities (alcohol abuse, drug abuse, HIV, hepatitis B, diabetes and/or presence of cirrhosis). Among the 32 806 HCV infected subjects, 262 cases had HCC. HCC was 12 times more likely in subjects with cirrhosis (P < 0.001), three times more likely in subjects with alcohol abuse (P < 0.001), and 1.3 times more likely in subjects with diabetes (P = 0.04). Asians were three times more likely (P < 0.001) to have HCC. Females were less likely to have HCC compared to males (P = 0.002). The likelihood of having HCC increased with age (P =0.001). This population-based study demonstrates that among subjects with HCV on dialysis, those with cirrhosis, Asian race and history of alcohol abuse are at highest risk for development of HCC. Furthermore, these findings indicate links between HCV and HCC which are valuable in case management for identifying; monitoring, and managing dialysis patients with HCC.