William D. Brubaker

Diabetes, body mass index and outcomes in hepatocellular carcinoma patients undergoing liver transplantation

&NA; For many cancers, features of the metabolic syndrome, such as diabetes and obesity, have been associated with both increased risk of cancer development and poor outcomes. Methods We examined a large retrospective cohort of 342 consecutive patients who underwent liver transplantation for hepatocellular carcinoma between January 1999 and July 2010 at our institution. We evaluated the relationship between diabetes, obesity, hepatocellular carcinoma (HCC) recurrence, and overall survival. Results We found that a body mass index (BMI) higher than 30 was an independent predictor of poor overall survival in a multivariable Cox model, approximately doubling the risk of death after transplantation. A BMI higher than 30 was also a predictor of recurrent HCC, although this was of borderline statistical significance (hazard ratio for recurrence, 1.9; 95% confidence interval, 0.9–4.1). We also found increased BMI to be an independent predictor of microvascular invasion within HCC tumors, lending a possible explanation to these results. Those with diabetes showed worsened overall survival compared with those without diabetes in univariate but not multivariable analysis, possibly related to longer wait times. Conclusions Our findings suggest a relationship between higher BMI, tumor vascular invasion, increased recurrence, and worsened overall survival. These findings may help explain why those with high BMI have worse outcomes from their cancers. A better understanding of the role of obesity and diabetes in patients with cancer should help develop better predictors of outcome and improved treatment options for patients with HCC.

Analysis of the Putative Role of CR1 in Alzheimer's Disease: Genetic Association, Expression and Function

Chronic activation of the complement system and induced inflammation are associated with neuropathology in Alzheimer’s disease (AD). Recent large genome wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) in the C3b/C4b receptor (CR1 or CD35) that are associated with late onset AD. Here, anti-CR1 antibodies (Abs) directed against different epitopes of the receptor, were used to localize CR1 in brain, and relative binding affinities of the CR1 ligands, C1q and C3b, were assessed by ELISA. Most Abs tested stained red blood cells in blood vessels but showed no staining in brain parenchyma. However, two monoclonal anti-CR1 Abs labeled astrocytes in all of the cases tested, and this reactivity was preabsorbed by purified recombinant human CR1. Human brain-derived astrocyte cultures were also reactive with both mAbs. The amount of astrocyte staining varied among the samples, but no consistent difference was conferred by diagnosis or the GWAS-identified SNPs rs4844609 or rs6656401. Plasma levels of soluble CR1 did not correlate with diagnosis but a slight increase was observed with rs4844609 and rs6656401 SNP. There was also a modest but statistically significant increase in relative binding activity of C1q to CR1 with the rs4844609 SNP compared to CR1 without the SNP, and of C3b to CR1 in the CR1 genotypes containing the rs6656401 SNP (also associated with the larger isoform of CR1) regardless of clinical diagnosis. These results suggest that it is unlikely that astrocyte CR1 expression levels or C1q or C3b binding activity are the cause of the GWAS identified association of CR1 variants with AD. Further careful functional studies are needed to determine if the variant-dictated number of CR1 expressed on red blood cells contributes to the role of this receptor in the progression of AD, or if another mechanism is involved.

Prevention of de novo hepatitis B in recipients of core antibody-positive livers with lamivudine and other nucleos(t)ides: a 12-year experience.

Background Lamivudine (LAM) has been shown to prevent de novo hepatitis B virus (HBV) infection in recipients of hepatitis B core antibody (HBcAb)–positive liver transplants (LT) but primarily in small studies with limited follow-up. Methods We conducted a retrospective cohort study of HBcAb+ graft recipients at our institution from October 1999 to August 2008. Results One hundred nineteen recipients without prior HBV were identified (median age, 54 years; 70% male), of which 62 received LAM. The median follow-up was 2.6 years overall and 5.3 years in the LAM group. Among LAM recipients, 44% were HBV naïve (HBsAb-/HBcAb-) at LT, of which 6% developed HBsAb+ and 3% developed HBcAb+ after LT. Eight percent developed de novo HBV: two recipients became hepatitis B surface antigen positive at 70 and 23 months and three experienced breakthrough with HBV DNA more than 2000 IU at 1 to 9 months after LT. Sixty percent (3 of 5) were HBV naïve. Four (6%) other recipients also had transiently detectable HBV less than 2000 IU, which did not require any changes to their prophylaxis regimen. When compared with recipients who received other nucleos(t)ide analogues, there was no difference in de novo rates: LAM 8% (5 of 62), adefovir 15% (5 of 33), tenofovir 0% (0 of 3), entecavir 0% (0 of 1), and 5% (1 of 20) for those not given prophylaxis (P=0.59). Conclusions LAM monoprophylaxis was effective in preventing de novo HBV in the vast majority of recipients over long-term follow-up. Adefovir had a higher rate of de novo infections numerically, whereas tenofovir and entecavir had no cases and may be more effective, but this was limited by a small sample size.

Peripheral complement interactions with amyloid β peptide: Erythrocyte clearance mechanisms

Although amyloid β peptide (Aβ) is cleared from the brain to cerebrospinal fluid and the peripheral circulation, mechanisms for its removal from blood remain unresolved. Primates have uniquely evolved a highly effective peripheral clearance mechanism for pathogens, immune adherence, in which erythrocyte complement receptor 1 (CR1) plays a major role.

Increased risk of autoimmune disorders in infertile men: analysis of US claims data

Aberrations in reproductive fitness may be a harbinger of medical diseases in men. Existing data suggest that female infertility is associated with autoimmune disorders; however, this has not been examined in men. As immune surveillance and hormonal factors can impact male fertility and autoimmunity, we sought to determine the association between male infertility and incident autoimmune disorders. We analyzed subjects from the Truven Health MarketScan claims database from 2001 to 2008. Infertile men were identified through diagnosis and treatment codes. We examined the most common immune disorders, which were identified by ICD9 diagnosis codes. Men diagnosed with an immune disorder at baseline or within 1 year of follow‐up were excluded. Infertile men were compared to vasectomized men (i.e., men who are likely fertile) and to age‐matched control (10 : 1) group using Cox regression analysis. A total of 33,077 infertile men (mean age of 33 years), 77,693 vasectomized men (mean age 35), and 330,770 age‐matched control men (mean age 33) were assembled with a total follow‐up of 1.49 M person‐years. Overall, immune disorders were rare in the group with the individual conditions occurring in <0.1% of men. However, infertile men displayed the highest risk of many conditions. Infertile men had a higher risk of developing rheumatoid arthritis compared to both vasectomized men (HR 1.56, 95% CI 1.19–2.05) and age‐matched controls (HR 1.29, 95% CI 1.02–1.62). Additionally, this higher risk was seen in general immune disorders (under which systemic lupus erythematosus is categorized) compared to vasectomized men (HR 3.11, 95% CI 2.00–4.86) and age‐matched men (HR 2.12, 95% CI 1.52–2.96). This same risk trend was seen in psoriasis, when compared to vasectomized men (HR 1.28, 95% CI 1.09–1.50) and age‐matched controls (HR 1.20, 95% CI 1.04–1.37). A similar trend was seen in the analysis comparing infertile men and vasectomized men in developing multiple sclerosis (HR 1.91, 95% CI 1.10–3.31) and Graves disease (HR 1.46, 95% CI 1.10–1.92), as well as the higher risk of infertile men compared to the age‐matched group at developing thyroiditis (HR 1.60, 95% CI 1.02–2.52). The current analysis shows that infertile men have a higher risk of developing certain autoimmune disorders in the years following an infertility evaluation. Specifically, infertile men had higher rates of developing rheumatoid arthritis, multiple sclerosis, psoriasis, thyroiditis, and Graves disease. Given these findings, further research should focus on confirmation of these associations and elucidation of the pathways between fertility and immunity.

Peripheral complement interactions with amyloid β peptide in Alzheimer's disease: 2. Relationship to Aβ immunotherapy

Our previous studies have shown that amyloid β peptide (Aβ) is subject to complement‐mediated clearance from the peripheral circulation, and that this mechanism is deficient in Alzheimers disease. The mechanism should be enhanced by Aβ antibodies that form immune complexes (ICs) with Aβ, and therefore may be relevant to current Aβ immunotherapy approaches.

Adherence to hepatitis B immunoglobulin (HBIG) after liver transplantation.

BACKGROUND Ensuring a good match between donor and recipient is critically important to achieve acceptable graft outcomes after living-donor liver transplantation (LDLT). Our objective was to evaluate the product of donor age and Model for End-stage Liver Disease score (D-MELD) as a predictor of graft survival after LDLT. METHODS We retrospectively evaluated the records of 355 adults who underwent LDLT for chronic liver disease and explored the relationship between D-MELD and graft outcome. RESULTS High MELD score and advanced donor age were significantly associated with graft survival; D-MELD had the strongest association with in-hospital mortality. Receiver operating characteristic curve analysis showed that a D-MELD score of 462 had the highest sensitivity for predicting in-hospital mortality. Patients were allocated to three groups based on D-MELD (Class A [≤449; n=142], Class B [450-899; n=163], and Class C [≥900; n=50]) and were found to have stratified cumulative 2-year graft survivals of 94.1%, 85.3%, and 63.1%, respectively (P<0.01). Although D-MELD Class C patients had larger graft volume-to-standard liver volume ratio (P<0.01) and received right lobe grafts more often (P<0.01), they still exhibited significantly higher rates of primary graft dysfunction (P<0.01) and in-hospital mortality (P<0.01). Outcomes in D-MELD Class C were significantly worse in hepatitis C-positive patients (P<0.05). CONCLUSIONS The D-MELD score is a simple and reliable predictor of early graft survival that assists the matching of donors and recipients in LDLT in adults.Background Ensuring a good match between donor and recipient is critically important to achieve acceptable graft outcomes after living-donor liver transplantation (LDLT). Our objective was to evaluate the product of donor age and Model for End-stage Liver Disease score (D-MELD) as a predictor of graft survival after LDLT. Methods We retrospectively evaluated the records of 355 adults who underwent LDLT for chronic liver disease and explored the relationship between D-MELD and graft outcome. Results High MELD score and advanced donor age were significantly associated with graft survival; D-MELD had the strongest association with in-hospital mortality. Receiver operating characteristic curve analysis showed that a D-MELD score of 462 had the highest sensitivity for predicting in-hospital mortality. Patients were allocated to three groups based on D-MELD (Class A [⩽449; n=142], Class B [450–899; n=163], and Class C [≥900; n=50]) and were found to have stratified cumulative 2-year graft survivals of 94.1%, 85.3%, and 63.1%, respectively (P<0.01). Although D-MELD Class C patients had larger graft volume-to-standard liver volume ratio (P<0.01) and received right lobe grafts more often (P<0.01), they still exhibited significantly higher rates of primary graft dysfunction (P<0.01) and in-hospital mortality (P<0.01). Outcomes in D-MELD Class C were significantly worse in hepatitis C–positive patients (P<0.05). Conclusions The D-MELD score is a simple and reliable predictor of early graft survival that assists the matching of donors and recipients in LDLT in adults.

Peripheral complement interactions with amyloid β peptide in Alzheimer's disease: Polymorphisms, structure, and function of complement receptor 1

Genome‐wide association studies consistently show that single nucleotide polymorphisms (SNPs) in the complement receptor 1 (CR1) gene modestly but significantly alter Alzheimers disease (AD) risk. Follow‐up research has assumed that CR1 is expressed in the human brain despite a paucity of evidence for its function there. Alternatively, erythrocytes contain >80% of the bodys CR1, where, in primates, it is known to bind circulating pathogens.

Payer Type, Race/Ethnicity, and the Timing of Surgical Management of Urinary Stone Disease

PURPOSE Surgery for upper tract urinary stone disease is often reserved for symptomatic patients and those whose stone does not spontaneously pass after a trial of passage. Our objective was to determine whether payer type or race/ethnicity is associated with the timeliness of kidney stone surgery. MATERIALS AND METHODS A population-based cohort study was conducted using the California Office of Statewide Health Planning and Development dataset from 2010 to 2012. We identified patients who were discharged from an emergency department (ED) with a stone diagnosis and who subsequently underwent a stone surgery. Primary outcome was time from ED discharge to urinary stone surgery in days. Secondary outcomes included potential harms resulting from delayed stone surgery. RESULTS Over the study period, 15,193 patients met the inclusion criteria. Median time from ED discharge to stone surgery was 28 days. On multivariable analysis patients with Medicaid, Medicare, and self-pay coverage experienced adjusted mean increases of 46%, 42%, and 60% in time to surgery, respectively, when compared with those with private insurance. In addition, patients of Black and Hispanic race/ethnicity, respectively, experienced adjusted mean increases of 36% and 20% in time to surgery relative to their White counterparts. Before a stone surgery, underinsured patients were more likely to revisit an ED three or more times, undergo two or more CT imaging studies, and receive upper urinary tract decompression. CONCLUSIONS Underinsured and minority patients are more likely to experience a longer time to stone surgery after presenting to an ED and experience potential harm from this delay.