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Background. Donation after circulatory death (DCD) allografts might represent one of the largest untapped sources of liver allografts. Our aim was to identify independent recipient risk factors that predict mortality in DCD allograft recipients to preselect optimal candidates for successful transplantation. Furthermore, we compared the application of our newly constructed DCD Recipient Selector Index (RSI) score to previously developed models to determine superiority in predicting recipient survival. Methods. Using the Organ Procurement and Transplantation Network database, we performed univariate and multivariate retrospective analyses on 4228 DCD liver allograft recipients. Results. We identified 8 significant factors and incorporated them into the weighted RSI to predict 3-mo survival following DCD liver transplantation with a C-statistic of 0.6971. The most significant recipient risk factors were recipient serum sodium levels >150 mEq/L at transplant, recipient albumin

Introduction:. Female physicians have been historically underrepresented in orthopaedic surgery residencies. The purpose of this study was to determine whether sex diversity among orthopaedic residency programs and faculty is associated with an increased number of female residents matriculating into that program. In addition, we sought to analyze female resident matriculation trends in the past 5 years. Methods:. The American Medical Association Fellowship and Residency Electronic Interactive Database was used to identify all allopathic orthopaedic surgery residency programs during the 2021 to 2022 academic year. The number of female residents and interns; the number of female faculty, professors, and associate professors; and the number of women in leadership positions were compared with data from the academic year 2016 to 2017. Continuous data were analyzed with independent t-tests, and significance was set at p < 0.05. Results:. A total of 696 female residents (19.2%) were identified from 3,624 orthopaedic residents, an increase from 13.5% in 2016. Programs in the top quartile of female residents had 3 times the number of female residents per program when compared to other quartiles and almost double the number of female interns per program. Programs in the top quartile of female residents had a significantly greater number of female faculty per program than the lower quartiles; 5.76 vs. 4.18. Compared with 2016 to 2017, there were significant increases in female faculty per program from 2.77 to 4.54 along with female full professors from 0.274 to 0.694. These increases contribute to the overall growth in the number of women in leadership positions per program over the past 5 years to 1.01 from 0.35 (p < 0.001). Conclusion:. In the past 5 years, the percentage of female residents has increased from 13.5% to 19.2%. Furthermore, women make up 22.1% of interns. Orthopaedic surgery residency programs with higher percentages of female faculty had higher numbers of female residents. By encouraging programs to promote female representation within leadership and residents, we may continue to see the gap in orthopaedic sex diversity close. Level of Evidence:. III.

Delta-like ligand 3 (DLL3) is expressed in more than 70% of small cell lung cancers (SCLCs) and other neuroendocrine-derived tumor types. SCLC is highly aggressive, and limited therapeutic options lead to poor prognosis for patients. HPN328 is a trispecific T cell-activating construct (TriTAC) consisting of three binding domains: a CD3 binder for T-cell engagement, an albumin binder for half-life extension, and a DLL3 binder for tumor cell engagement. In vitro assays, rodent models, and non-human primates were used to assess the activity of HPN328. HPN328 induces potent dose-dependent killing of DLL3-expressing SCLC cell lines in vitro, concomitant with T-cell activation and cytokine release. In an NCI-H82 xenograft model with established tumors, HPN328 treatment led to T-cell recruitment and anti-tumor activity. In an immunocompetent mouse model expressing a human CD3ε epitope, mice previously treated with HPN328 withstood tumor rechallenge, demonstrating long-term anti-tumor immunity. When repeat doses were administered to cynomolgus monkeys, HPN328 was well tolerated up to 10 mg/kg. Pharmacodynamic changes, such as transient cytokine elevation, were observed, consistent with the expected mechanism of action of T-cell engagers. HPN328 exhibited linear pharmacokinetics in the given dose range with a serum half-life of 78 to 187 hours, supporting weekly or less frequent administration of HPN328 in humans. Preclinical and nonclinical characterization suggests that HPN328 is a highly efficacious, safe, and novel therapeutic candidate. A phase 1/2 clinical trial is currently underway testing safety and efficacy in patients with DLL3-expressing malignancies., (©2024 The Authors; Published by the American Association for Cancer Research.)

Purpose: The purpose of the study is to assess return to play rate and timing of elite athletes treated for multi-ligament knee injuries with modern surgical techniques., Methods: A retrospective review was performed of all professional or national/international level athletes treated for a multi-ligament knee injury by the senior author in the period from February 2001 to October 2019, with a minimum of 2-year follow-up. The study cohort consisted of 136 elite athletes who underwent surgery of two or more knee ligaments. Outcomes measures were return to play (RTP), defined as return to elite level sport, return to play time, and further surgical procedures., Results: One hundred and twenty (88.2%) athletes returned to elite level sport at an average of 12.8 months from operation. In unicruciate injuries, ACL and PCL-based injuries had similar return to play rates (89.1% vs. 87.5% respectfully, n.s.) although mean RTP time was longer in those with PCL-based injuries (15.2 vs. 11.9 months, p < 0.01). Bicruciate injuries had longer RTP times compared to unicruciate injuries (mean RTP 16.0vs. 12.4 months, p < 0.05) but were able to return at a similar rate (83.3% vs. 88.9%, n.s.). Medial and lateral sided injuries had similar RTP rates (89.3% vs. 87.9%, n.s.) though lateral sided injuries took longer before returning to play (13.4 vs. 11.6 months, p < 0.05). Further surgery was required in 54 (39.9%) patients including 25 (18.4%) manipulations under anaesthesia. Four (2.9%) of the athletes underwent revision ligament surgery., Conclusion: Modern surgical techniques used in the treatment of multi-ligament knee injuries can lead to high return to play rates in elite athletes., Level of Evidence: IV., (© 2022. The Author(s) under exclusive licence to European Society of Sports Traumatology, Knee Surgery, Arthroscopy (ESSKA).)

MT-3724, a novel engineered toxin body comprised of an anti-CD20 single-chain variable fragment genetically fused to Shiga-like Toxin A subunit, is capable of binding to and internalizing against CD20, inducing cell killing via permanent ribosomal inactivation. This study evaluated MT-3724 in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (r/rNHL). This open-label, multiple-dose phase Ia/b trial included a dose escalation in patients with r/rNHL according to a standard 3+3 design. Primary objectives were to determine the MTD and pharmacokinetics/pharmacodynamics. In a dose expansion study at MTD in serum rituximab-negative patients with diffuse large B-cell lymphoma (DLBCL), primary objectives were safety, tolerability, and pharmacokinetics/pharmacodynamics. Twenty-seven patients enrolled. MTD was 50 μg/kg/dose with 6,000 μg/dose cap. Thirteen patients experienced at least one grade ≥3 treatment-related adverse events; the most common grade ≥3 event was myalgia (11.1%). Two patients (75 μg/kg/dose) experienced grade 2 treatment-related capillary leak syndrome. Overall objective response rate was 21.7%. In serum rituximab-negative patients with DLBCL or composite DLBCL ( n = 12), overall response rate was 41.7% (complete response, n = 2; partial response, n = 3). In patients with detectable baseline peripheral B cells, treatment resulted in dose-dependent B-cell depletion. The proportion of patients with anti-drug antibodies (ADA) increased during treatment and the majority appeared to be neutralizing based on an in vitro assay; nevertheless, tumor regression and responses were observed. MT-3724 demonstrated efficacy at the MTD in this population of previously treated patients with r/rDLBCL, with mild-to-moderate immunogenic safety events., Significance: This work describes the safety and efficacy of a new pharmaceutical pathway that could provide a treatment option for a subset of patients with a critical unmet therapeutic need. The study drug, MT-3724, is capable of targeting B-cell lymphomas via a unique, potent cell-killing mechanism that appears to be promising., Competing Interests: P.A. Hamlin reports personal fees from Calithera, Karyopharm, Sandoz, and personal fees from Juno Therapeutics outside the submitted work. V. Musteata reports other from ARENSIA EM during the conduct of the study. S.I. Park reports grants and personal fees from BMS and Seattle Genetics; non-financial support from Rafael Pharma; personal fees from G1 Therapeutics, Teva, Gilead, Morphosys, and personal fees from Epizyme outside the submitted work; grants from Takeda. C. Burnett was a paid employee of Molecular Templates at the time the work was performed. K. Dabovic reports employment with the sponsor, Molecular Templates. T. Strack reports personal fees from Molecular Templates during the conduct of the study and personal fees from Molecular Templates outside the submitted work. E.T. Williams was employed by Molecular Templates for these efforts. J.P. Higgins reports grants from Cancer Prevention & Research Institute of Texas during the conduct of the study; personal fees from Molecular Templates outside the submitted work. D. Persky reports personal fees from Morphosys, Debiopharm, Karyopharm, Cellectar, Epizyme, ADC Therapeutics, Genentech, Beigene, Eli Lilly, Abbvie, and personal fees from TG Therapeutics outside the submitted work. No other disclosures were reported., (© 2022 The Authors; Published by the American Association for Cancer Research.)

Early diagnosis and ultrahigh sample throughput screening are the need of the hour to control the geological spread of the COVID-19 pandemic. Traditional laboratory tests such as enzyme-linked immunosorbent assay (ELISA), reverse transcription polymerase chain reaction (RT-PCR) and computed tomography are implemented for the detection of COVID-19. However, they are limited by the laborious sample collection and processing procedures, longer wait time for test results and skilled technicians to operate sophisticated facilities. In this context, the point of care (PoC) diagnostic platform has proven to be the prospective approach in addressing the abovementioned challenges. This review emphasizes the mechanism of viral infection spread detailing the host-virus interaction, pathophysiology, and the recent advances in the development of affordable PoC diagnostic platforms for rapid and accurate diagnosis of COVID-19. First, the well-established optical and electrochemical biosensors are discussed. Subsequently, the recent advances in the development of PoC biosensors, including lateral flow immunoassays and other emerging techniques, are highlighted. Finally, a focus on integrating nanotechnology with wearables and smartphones to develop smart nanobiosensors is outlined, which could promote COVID-19 diagnosis accessible to both individuals and the mass population at patient care., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 Elsevier B.V. All rights reserved.)

Background: This article provides a detailed narrative review on the history and current concepts surrounding ligamentous repair techniques in athletic patients. In particular, we will focus on the anterior cruciate ligament (ACL) as a case study in ligament injury and ligamentous repair techniques. PubMed (MEDLINE), EMBASE and Cochrane Library databases for papers relating to primary anterior cruciate ligament reconstruction were searched by all participating authors. All relevant historical papers were included for analysis. Additional searches of the same databases were made for papers relating to biological enhancement of ligament healing., Current Standard: The poor capacity of the ACL to heal is one of the main reasons why the current gold standard surgical treatment for an ACL injury in an athletic patient is ACL reconstruction with autograft from either the hamstrings or patella tendon. It is hypothesised that by preserving and repairing native tissues and negating the need for autograft that primary ACL repair may represent a key step change in the treatment of ACL injuries., History of Primary Acl Repair: The history of primary ACL repair will be discussed and the circumstances that led to the near-abandonment of primary ACL repair techniques will be reviewed., New Primary Repair Techniques: There has been a recent resurgence in interest with regards to primary ACL repair. Improvements in imaging now allow for identification of tear location, with femoral-sided injuries, being more suitable for repair. We will discuss in details strategies for improving the mechanical and biological environment in order to allow primary healing to occur. In particular, we will explain mechanical supplementation such as Internal Brace Ligament Augmentation and Dynamic Intraligamentary Stabilisation techniques. These are novel techniques that aim to protect the primary repair by providing a stabilising construct that connects the femur and the tibia, thus bridging the repair., Bio Enhanced Repair: In addition, biological supplementation is being investigated as an adjunct and we will review the current literature with regards to bio-enhancement in the form platelet rich plasma, bio-scaffolds and stem cells. On the basis of current evidence, there appears to be a role for bio-enhancement, however, this is not yet translated into clinical practice., Conclusions: Several promising avenues of further research now exist in the form of mechanical and biological augmentation techniques. Further work is clearly needed but there is renewed interest and focus for primary ACL repair that may yet prove the new frontier in ligament repair.

AGS62P1 is an antibody drug conjugate (ADC) composed of a human IgG1κ monoclonal antibody against FLT3 (FMS-like tyrosine kinase 3) with a p-acetyl phenylalanine (pAF) residue inserted at position 124 of each heavy chain linked to the proprietary microtubule disrupting agent AGL-0182-30 via an alkoxyamine linker that forms an oxime upon conjugation to the antibody. AGS62P1 is currently in Phase I human clinical trials for acute myelogenous leukemia (AML). The identified primary metabolite of an oxime-linked ADC is presented for the first time. AGS62P1 metabolism was assessed in xenograft tumor-bearing mice and rats treated with the ADC using liquid chromatography and mass spectrometry-based methods described herein. In this study, we identified the metabolite of AGS62P1 as pAF-AGL-0185-30, which contains a fragment resulting from the catabolism of the antibody component of the ADC and hydrolysis of the terminal amide portion of the linker-payload. We demonstrated that the metabolite of AGS62P1 is tolerated in rats above 1.5 mg/kg and above 0.334 mg/kg in cynomolgus monkeys when given as a single dose. Furthermore, we established in vitro that pAF-AGL-0185-30 does not significantly inhibit hERG or cytochrome P450 family enzymes (CYPs).

Background: No general consensus has yet been established for the gold standard treatment of ankle syndesmotic complex injuries. Recent literature has documented the success of ankle tightrope fixation for heterogeneous ankle fracture patterns, resulting in syndesmotic complex injuries. We present a multicentre case series assessing the clinical, radiological and functional outcomes of patients with Weber C ankle fractures treated with the Arthrex TightRope ® fixation system., Method: We performed a retrospective analysis of all adult patients with Weber C ankle fractures who were treated with the Arthrex TightRope ® fixation system at four centres over a 3-year period. All patients were followed up for a mean of 14 months (range 12-26). Outcomes measures were assessed subjectively using functional scores (AOFAS and Olerud and Molander) and objectively using radiological measurements, complication rates and revision surgery rates., Results: Thirty-six patients met our eligibility criteria. The mean age at operation was 31 years (range 18-65). There were 20 males and 16 females. No patients were lost to follow-up. The ankle tightrope maintained satisfactory reduction in the ankle mortise in 97% of cases. Of these 35 successfully treated cases, no evidence of re-displacement on follow-up radiographs of the syndesmotic complex was observed at an average of 10.8 months (range 6-12). Post-operative mean medial clear space was 3.1 mm, and mean tibio-fibular overlap was 10.1 mm. The mean American Orthopaedic Foot and Ankle Society (AOFAS) score was 88.8 (range 67-98) at a mean follow-up of 14 months (range 12-26). The overall complication rate was 6% (one failure requiring revision surgery and one medial sided skin irritation requiring removal of suture button). No infections or wound complications occurred., Conclusion: Tightrope fixation is a safe alternative to screw fixation for syndesmotic complex injuries in Weber C ankle fractures. We have shown that it has low complication rates and a high patient satisfaction.

Background: As the era of interferon-alpha (IFN)-based therapy for hepatitis C ends, long-term treatment outcomes are now being evaluated., Aim: To more fully understand the natural history of hepatitis C infection by following a multisite cohort of patients., Methods: Patients with chronic HCV were prospectively enrolled in 1999-2000 from 11 VA medical centers and followed through retrospective medical record review., Results: A total of 2211 patients were followed for an average of 8.5 years after enrollment. Thirty-one percent of patients received HCV antiviral therapy, 15 % with standard IFN/ribavirin only, 16 % with pegylated IFN/ribavirin, and 26.7 % of treated patients achieved sustained virologic response (SVR). Cirrhosis developed in 25.8 % of patients. Treatment nonresponders had a greater than twofold increase in the hazard of cirrhosis and hepatocellular carcinoma, compared to untreated patients, whereas SVR patients were only marginally protected from cirrhosis. Nearly 6 % developed hepatocellular carcinoma, and 27.1 % died during the follow-up period. Treated patients, regardless of response, had a significant survival benefit compared to untreated patients (HR 0.58, CI 0.46-0.72). Improved survival was also associated with college education, younger age, lower levels of alcohol consumption, and longer duration of medical service follow-up-factors typically associated with treatment eligibility., Conclusions: As more hepatitis C patients are now being assessed for all-oral combination therapy, these results highlight that patient compliance and limiting harmful behaviors contribute a significant proportion of the survival benefit in treated patients and that the long-term clinical benefits of SVR may be less profound than previously reported., Competing Interests: All authors declare that they have no conflict of interest related to the data or interpretation of this study.

The identification of optimal target antigens on tumor cells is central to the advancement of new antibody-based cancer therapies. We performed suppression subtractive hybridization and identified nectin-4 (PVRL4), a type I transmembrane protein and member of a family of related immunoglobulin-like adhesion molecules, as a potential target in epithelial cancers. We conducted immunohistochemical analysis of 2,394 patient specimens from bladder, breast, lung, pancreatic, ovarian, head/neck, and esophageal tumors and found that 69% of all specimens stained positive for nectin-4. Moderate to strong staining was especially observed in 60% of bladder and 53% of breast tumor specimens, whereas the expression of nectin-4 in normal tissue was more limited. We generated a novel antibody-drug conjugate (ADC) enfortumab vedotin comprising the human anti-nectin-4 antibody conjugated to the highly potent microtubule-disrupting agent MMAE. Hybridoma (AGS-22M6E) and CHO (ASG-22CE) versions of enfortumab vedotin (also known as ASG-22ME) ADC were able to bind to cell surface-expressed nectin-4 with high affinity and induced cell death in vitro in a dose-dependent manner. Treatment of mouse xenograft models of human breast, bladder, pancreatic, and lung cancers with enfortumab vedotin significantly inhibited the growth of all four tumor types and resulted in tumor regression of breast and bladder xenografts. Overall, these findings validate nectin-4 as an attractive therapeutic target in multiple solid tumors and support further clinical development, investigation, and application of nectin-4-targeting ADCs. Cancer Res; 76(10); 3003-13. ©2016 AACR., (©2016 American Association for Cancer Research.)

Background: There are limited and inconsistent data regarding return-to-sport outcomes after revision anterior cruciate ligament reconstruction (ACLR)., Hypothesis: Return-to-sport rates will be lower after revision ACLR when compared with primary ACLR., Study Design: Case series; Level of evidence, 4., Methods: The study cohort consisted of 136 eligible patients who had undergone their first revision ACLR between March 2006 and March 2010. Of these, 109 patients (80%) completed a sports activity survey at a mean 5-year follow-up (range, 3-7 years). Follow-up also included the International Knee Documentation Committee (IKDC) subjective form, Marx Activity Scale, and Knee injury and Osteoarthritis Outcome Score-quality of life (KOOS-QOL) form. Operative details were obtained from the clinical record., Results: After revision ACLR, 46% (95% CI, 37%-55%) of patients returned to their preinjury level of sport, compared with 50% (95% CI, 41%-59%) after the primary reconstruction in the same patients. Of the patients who were not able to return to their preinjury level of sport after primary reconstruction, 33% improved to the point that they were able to do so after revision. Younger patients were more likely to have returned to their same level of sport (58% vs 38%, P < .05), while the rate of return was the same between male and female patients. Those who returned to their preinjury level of sport scored higher Marx (P < .01), KOOS-QOL (P < .001), and IKDC scores (P < .01) than those who did not. Patients with <50% thickness articular cartilage lesions at revision surgery were more likely to have returned to their preinjury level (52% vs 31%, P < .05) and had significantly better Marx (P < .01), KOOS-QOL (P < .01), and IKDC scores (P < .01) at follow-up. The status of the menisci at the time of revision surgery was not associated with rates of return to sport, but patients with an intact medial meniscus had significantly higher KOOS-QOL (P < .05) scores at follow-up., Conclusion: Return-to-sport rates of patients after revision ACLR were similar to those after their primary surgery but were still lower than the reported rates of ACLR patients who did not need revision surgery. Greater chondral pathologic abnormalities at revision surgery were associated with reduced function at follow-up., (© 2015 The Author(s).)

Purpose: Hepatocellular carcinoma (HCC), a common cause for cancer-related death, is increasing worldwide. Over the past decade, survival and quality of life of HCC patients have significantly improved due to better prevention strategies, early diagnosis, and improved treatment options. We performed this narrative review to synthesize current status on the HCC management., Methods: Literature search for publications especially over the last decade, which has changed the paradigm on the management of HCC., Results: Hepatitis B vaccination and treatment of chronic hepatitis B and C are important measures for HCC prevention. Screening and surveillance for HCC using ultrasonogram and alpha-fetoprotein estimation are directed toward cirrhotics and hepatitis B patients at high risk of HCC. If detected at an early stage, curative treatments for HCC can be used such as tumor resection, ablation and liver transplantation. HCC patients without curative options are managed by loco-regional therapies and systemic chemotherapy. Loco-regional treatments include trans-arterial chemoembolization, radioembolization and combinations of loco-regional plus systemic therapies. Currently, sorafenib is the only FDA-approved systemic therapy and newer better chemotherapeutic agents are being investigated. Palliative care for terminally ill patients with metastatic disease and/or poor functional status focusses on comfort care and symptom control., Conclusions: In spite of significant advancement in HCC management, its incidence continues to rise. There remains an urgent need to continue refining understanding of HCC and develop strategies to increase utilization of the available preventive measures and curative treatment modalities for HCC.

Aim: To investigate the efficacy, safety, and cost of treatment of direct acting antivirals (DAAs) with and without peg interferon alfa2a (P), and/or ribavirin (R) in treating hepatitis C virus (HCV) genotype 1 patients., Methods: MEDLINE was searched for randomized controlled trials (RCT) using DAAs for HCV treatment. Phase 1 trials and studies with investigational drugs on genotype 2 or 3, and on human immunodeficiency virus patients were excluded. Data were pooled for sustained virologic response (SVR), serious adverse effects, and drug discontinuation rate on various treatment arms in trials: P + R; 1(st) generation DAA (telaprevir or boceprevir) + P + R; 2(nd) generation DAA (sofosbuvir or simeprevir) + P + R; 2(nd) generation DAA + R; two 2(nd) generation DAA + R; and two 2(nd) gen DAA. Data were analyzed separately for each arm for treatment naive and non-responders (NR) to previous treatment. The cost of treatment with each regimen for achieving one SVR was also compared., Results: Twenty three RCTs (n = 9354, 62% male, 11% cirrhosis) were analyzed. All oral (P free) regimens with combination of 2 DAA achieved SVR above 95%. The cost of treatment to achieve an SVR with DAA based regimens was lower for NR compared to P+R regimen. However, the cost per SVR remained higher for treatment naive patients., Conclusion: Second generation and emerging DAAs are promising agents in HCV treatment, with a very high level of safety and efficacy. An important drawback is their high cost. However, the present meta-analysis shows that the cost per SVR for non responders (but not for naive patients) was lower compared to P + R. This finding together with the superior safety profile and better compliance makes these drugs highly attractive. It is possible that further reduction in treatment duration may make them even more cost effective.

Hepatitis C virus (HCV) infection and alcohol abuse are two most important causes of chronic liver disease in the United States. Alcoholic hepatitis is a unique clinical syndrome among patients with chronic and active alcohol abuse with a potential for high short-term mortality. About 20% of patients presenting with alcoholic hepatitis have concomitant HCV infection. Mortality from alcoholic hepatitis is increased in the presence of concomitant hepatitis C due to synergistic interaction between HCV and alcohol in causing hepatocellular damage. Large prospective randomized studies are needed to develop guidelines on the use of corticosteroids among patients with alcoholic hepatitis and concomitant HCV infection. The impact of antiviral therapy on mortality and outcome in the setting of alcoholic hepatitis remains a novel area for future research.

Alcohol abuse and chronic hepatitis C virus (HCV) infection are two major causes of chronic liver disease in the United States. About 10%-15% of liver transplants performed in the United States are for patients with cirrhosis due to combined alcohol and HCV infection. Data on outcomes on graft and patient survival, HCV recurrence, and relapse of alcohol use comparing transplants in hepatitis C positive drinkers compared to alcohol abuse or hepatitis C alone are conflicting in the literature. Some studies report a slightly better overall outcome in patients who were transplanted for alcoholic cirrhosis vs those transplanted for HCV alone or for combined HCV and alcohol related cirrhosis. However, some other studies do not support these observations. However, most studies are limited to a retrospective design or small sample size. Larger prospective multicenter studies are needed to better define the outcomes in hepatitis C drinkers.

Alcoholic cirrhosis remains the second most common indication for liver transplantation. A comprehensive medical and psychosocial evaluation is needed when making a decision to place such patients on the transplant list. Most transplant centers worldwide need a minimum of 6 mo of alcohol abstinence for listing these patients. Patients with alcohol dependence are at high risk for relapse to alcohol use after transplantation (recidivism). These patients need to be identified and require alcohol rehabilitation treatment before transplantation. Recidivism to the level of harmful drinking is reported in about 15%-20% cases. Although, recurrent cirrhosis and graft loss from recidivism is rare, occurring in less than 5% of all alcoholic cirrhosis-related transplants, harmful drinking in the post-transplant period does impact the long-term outcome. The development of metabolic syndrome with cardiovascular events and de novo malignancy are important contributors to non liver-related mortality amongst transplants for alcoholic liver disease. Surveillance protocols for earlier detection of de novo malignancy are needed to improve the long-term outcome. The need for a minimum of 6 mo of abstinence before listing makes transplant a nonviable option for patients with severe alcoholic hepatitis who do not respond to corticosteroids. Emerging data from retrospective and prospective studies has challenged the 6 mo rule, and beneficial effects of liver transplantation have been reported in select patients with a first episode of severe alcoholic hepatitis who are unresponsive to steroids.

Background: Hepatitis C virus (HCV) infection and alcohol abuse are common causes of cirrhosis in the USA. There are limited data on HCV prevalence and mortality trends in patients with alcoholic hepatitis (AH)., Aim: The present study was carried out to assess HCV prevalence and mortality in AH patients., Methods: Patients with a primary or a secondary discharge diagnosis of AH obtained from the Nationwide Inpatient Sample dataset (1998-2007) were stratified based on the presence of HCV. Factors associated with HCV positivity and in-hospital mortality were examined using multivariable logistic regression., Results: Of 76 957 719 admissions, 111 726 had AH (7240 were HCV positive). The prevalence of HCV in AH patients was 3.6% in 1998 and 7.7% in 2007. In-hospital mortality was 3.2% (6.3% in 1998 and 2.7% in 2007), with an ~7% annual decrease between 1998 and 2007. HCV was an independent predictor of in-hospital mortality after controlling for calendar year [odds ratio 1.29; 95% CI (1.12-1.49); P=0.0005]., Conclusion: Patients with AH have a higher prevalence of HCV compared with the general population. Although in-hospital mortality in AH patients has improved, HCV infection predicts a higher mortality. Further studies are required to determine the mechanisms of interaction of HCV and AH and develop treatment strategies to improve outcome of HCV-infected AH patients.

Unlabelled: Data on liver transplantation for patients with alcoholic hepatitis are limited. Using the United Network for Organ Sharing database (2004-2010), adults undergoing liver transplantation for a listing diagnosis of alcoholic hepatitis were matched for age, gender, ethnicity, and model for endstage disease (MELD) score, donor risk index, and year of transplantation with three patients transplanted for a listing diagnosis of alcoholic cirrhosis. Study outcomes of graft and patient survival on follow-up were also analyzed for cohorts based on the diagnosis of the explant (46 alcoholic hepatitis and 138 alcoholic cirrhosis) and diagnosis at both listing as well as of the explant (11 alcoholic hepatitis and 33 alcoholic cirrhosis). Five-year graft and patient survival of alcoholic hepatitis and alcoholic cirrhosis patients were 75% and 73% (P = 0.97) and 80% and 78% (P = 0.90), respectively. Five-year graft and patient survival rates were also similar for cohorts based on diagnosis of the explant and diagnosis at listing as well as explant. Cox proportional regression analysis adjusting for other variables showed no impact of the etiology of liver disease (alcoholic hepatitis versus alcoholic cirrhosis) on the graft and patient survival. The causes of graft loss and patient mortality were similar in the two groups, and were not alcohol-related in any patient., Conclusion: Compared with alcoholic cirrhosis, patients with alcoholic hepatitis have similar posttransplantation graft and patient survival. Based on these preliminary findings, liver transplantation may be considered in a select group of patients with alcoholic hepatitis who fail to improve with medical therapy. Prospective studies are needed to assess the long-term outcome after liver transplantation in patients with alcoholic hepatitis., (Copyright © 2011 American Association for the Study of Liver Diseases.)

Background: Pegylated interferon (PEGIFN) and ribavirin combination is the standard of care for the treatment of chronic hepatitis C virus (HCV) infection. Studies comparing the efficacy and safety of PEGIFN alfa-2a and PEGIFN alfa-2b in treatment-naïve HCV-infected patients have shown conflicting results., Aim: We performed a systematic review and meta-analysis of studies comparing the efficacy and safety of PEGIFN alfa-2a and PEGIFN alfa-2b in HCV-infected patients naïve to treatment., Methods: Nine studies (five abstracts) with 3,546 patients (1,771 treated with PEGIFN alfa-2a) comparing PEGIFN alfa-2a and PEGIFN alfa-2b in treatment-naïve HCV patients were analyzed. Efficacy outcomes were sustained virologic response (SVR) and treatment discontinuation rates due to serious adverse effects (SAE)., Results: Pooled data on outcomes (reported as odds ratios [ORs] with 95% confidence intervals [CIs]: [OR (95% CI)]) showed higher SVR in patients treated with PEGIFN alfa-2a as compared to treatment with PEGIFN alfa-2b [1.36 (1.07-1.73); P=0.01]. Subgroup analysis of good quality studies on SVR in genotypes 2 and 3 also favored PEGIFN alfa-2a over PEGIFN alfa-2b (1.91 [1.09-3.37]; P=0.02). SVR results obtained with the two types of IFN showed no impact of viral load and the presence or absence of cirrhosis. Treatment discontinuation rates due to SAE, reported in six studies (two abstracts) on 3,211 patients (1,604 treated with PEGIFN alfa-2a), were similar in the two types of PEGIFN [0.66 (0.37-1.16); P=0.15]., Conclusions: PEGIFN alfa-2a has superior efficacy with higher SVR as compared to PEGIFN alfa-2b in treatment-naïve HCV-infected patients. The safety profile of the two types of PEGIFN was similar.

Alcoholic liver disease (ALD) is a major cause of alcohol-related morbidity and mortality. Its presentation ranges from fatty liver to alcoholic hepatitis (AH), cirrhosis, and hepatocellular carcinoma. Although the amount and pattern of alcohol consumption is a well recognized predisposing factor for the development of serious liver pathology, environmental factors and the host's genetic make-up may also play significant roles that have not yet been entirely explored. Continuing alcohol consumption is a major factor that influences the survival of patients with AH. The presence of cirrhosis at presentation or its development on follow up is a major factor determining the outcome in the long run. This chapter deals with the epidemiology and magnitude of ALD in general and AH in particular.

General measures for treating patients with alcoholic hepatitis (AH) are similar irrespective of the disease severity. Alcohol abstinence is the cornerstone of treatment and can be achieved with appropriate social support, Alcoholics Anonymous and sometimes pharmacological therapy. Alcohol withdrawal should be anticipated and treatment initiated to prevent this complication. Treatment for complications of cirrhosis should be as for any other patient with cirrhosis. AH patients are particularly prone to infections and malnutrition. These should be identified and treated appropriately using broad spectrum antibiotics and nutritional support respectively.

In biomedical optical spectroscopy tissue-mimicking phantoms have been widely used for imitating optical properties of biological tissues. As tissue is a turbid medium involving scatterers, absorbing and fluorescing molecules, modelling a tissue in the form of a phantom should have the same realistic complexity comparable to that of tissues. In optical spectroscopy, fluorescence phenomena have been extensively investigated as an optical technique for disease diagnosis. The fluorescence signal is distorted by optical properties of a biological tissue. The purpose of this study is to investigate whether the use of Intralipid as a scattering agent in a turbid medium containing fluorophores can affect fluorescent intensity by the phenomena of scattering and collisional quenching. The results indicate that phantom sets with different concentrations of Tyrosine and Intralipid have their emission peaks distorted at 300 nm and also show secondary peaks when used for fluorescence studies in UV region., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Hepatocellular carcinoma (HCC) is third most common cause of tumour-related death in the US with hepatitis C virus (HCV) the most common aetiology. Surgical resection and tumour ablation are curative in patients who cannot be transplanted. With native liver having cirrhosis, HCC recurrence is a potential problem., Aim: To perform a systematic review and meta-analysis of studies evaluating efficacy of IFN to prevent HCC recurrence after its curative treatment in HCV-related cirrhosis., Methods: Ten studies (n = 645, 301 treated with IFN) on the use of IFN after resection or ablation of HCV-associated HCC were analysed., Results: Pooled data showed benefit of IFN for HCC prevention with OR (95% CI) of 0.26 (0.15-0.45); P < 0.00001. The proportion of patients surviving at 5 years (n = 505 in 6 studies) was in favour of IFN with OR of 0.31 [(95% CI 0.21-0.46); P < 0.00001]. Data were homogeneous for HCC recurrence (chi(2) 12.05, P = 0.21) and survival (chi(2) 6.93, P = 0.44). The benefit of IFN was stronger with sustained virological response compared with nonresponders for HCC recurrence [0.19 (0.06-0.60); P = 0.005] and survival [0.31 (0.11-0.90); P = 0.03]., Conclusion: Interferon treatment after curative resection or ablation of HCC in HCV-related cirrhotics prevents HCC recurrence and improves survival., (© 2010 Blackwell Publishing Ltd.)

Background: Chronic use of NSAIDs is associated with gastrointestinal (GI) toxicity that increases with age., Aim: To evaluate the GI safety and therapeutic efficacy of ibuprofen chemically associated with phosphatidylcholine (PC) in osteoarthritic (OA) patients., Methods: A randomized, double-blind trial of 125 patients was performed. A dose of 2400 mg/day of ibuprofen or an equivalent dose of ibuprofen-PC was administered for 6 weeks. GI safety was assessed by endoscopy. Efficacy was assessed by scores of analgesia and anti-inflammatory activity. Bioavailability of ibuprofen was pharmacokinetically assessed., Results: Ibuprofen-PC and ibuprofen provided similar bioavailability/therapeutic efficacy. In the evaluable subjects, a trend for improved GI safety in the ibuprofen-PC group compared with ibuprofen that did not reach statistical significance was observed. However, in patients aged >55 years, a statistically significant advantage for ibuprofen-PC treatment vs. ibuprofen in the prevention of NSAID-induced gut injury was observed with increases in both mean Lanza scores and the risk of developing >2 erosions or an ulcer. Ibuprofen-PC was well tolerated with no major adverse events observed., Conclusion: Ibuprofen-PC is an effective osteoarthritic agent with an improved GI safety profile compared with ibuprofen in older OA patients, who are most susceptible to NSAID-induced gastroduodenal injury.

Background: Since the discovery of the hepatitis C virus (HCV), extensive literature has emerged on alcohol and HCV interaction., Goal: To understand the impact of alcohol and HCV infection on the severity of liver disease and the mechanisms of interaction between the two., Study: Of 1269 articles (1991 to 2006) searched through MEDLINE and cited cross references, 133 were thoroughly reviewed to assess: (a) prevalence of combined alcohol use and HCV, (b) severity of liver disease (c) treatment response, and (d) mechanisms of interaction between HCV and alcohol. Data on study design, patient demographics, diagnostic tests used, and study outcomes were extracted for critical analysis., Results: Prevalence of HCV is 3-fold to 30-fold higher in alcoholics compared with the general population. Patients with HCV infection and alcohol abuse develop more severe fibrosis with higher rate of cirrhosis and hepatocellular cancer compared with nondrinkers. Increased oxidative stress seems to be the dominant mechanism for this synergism between alcohol and the HCV. Abstinence is the key to the management of liver disease due to HCV and alcohol. Data have shown that lower response rates to interferon in alcoholics with HCV infection are likely due to noncompliance., Conclusions: Alcoholics with HCV infection have more severe liver disease compared with nondrinkers. Patients should be encouraged to enroll in rehabilitation programs so as to improve treatment adherence and response.

Background/goals: Many patients with a history of injection drug use (IDU) are excluded from hepatitis C virus (HCV) treatment. This prospective multicenter study aimed to determine the impact of IDU history on HCV treatment candidacy and outcomes., Study: Between 1999 and 2001, 4318 HCV-infected patients seen at 24 VA Medical Centers were evaluated for HCV treatment candidacy and followed prospectively. Univariate and multivariate logistic regression analyses were used to determine whether an IDU history was associated with HCV treatment candidacy, HCV treatment acceptance, early treatment discontinuation, and virologic response., Results: Of 4318 participants, 2611 (61%) reported an IDU history. IDU history was not significantly associated with HCV treatment candidacy, acceptance, early discontinuation of therapy, or virologic response (all P values nonsignificant). Instead, reduced HCV treatment candidacy was independently associated with low-income [odds ratio (OR)=1.46, 95% confidence interval (CI)=1.22-1.74), education < or = 12 years (OR=1.23, 95% CI=1.03-1.46), and alcohol consumption > or = 3 drinks/d (OR=2.08, 95% CI=1.68-2.57), whereas early discontinuation of HCV therapy was independently associated with low-income and consuming > or = 3 alcoholic drinks/d., Conclusions: A history of IDU was not associated with HCV treatment candidacy or outcomes, supporting national guidelines to evaluate former IDUs on a case-by-case basis for HCV treatment.

Background: Although HIV testing is recommended for persons with hepatitis C virus (HCV) infection who are at risk for HIV, little is known about HIV testing in this population., Methods: Data were prospectively collected in 4364 HCV-infected patients at 24 Veterans Affairs medical centers across the United States, including demographics, risk factors for HIV infection, and self-reported information on HIV testing., Results: Overall, 76.8% had been tested for HIV at least once, 14.8% were never tested, 6.6% did not know if they were tested, and 1.8% declined to answer. Multivariable analysis identified injection drug use, needlestick injury, sex with a same-sex partner, a greater number of lifetime sexual partners, and sex with an injection drug user as factors that were independently associated with HIV testing. At least one risk factor for HIV infection was present in 84.5% of the 646 patients who were never HIV tested. Among the 3350 subjects who were tested for HIV, 8.4% were positive, 88.3% were negative, 2.4% did not know the results of their test, and 0.9% declined to answer. Multivariable analysis identified African American and Hispanic race/ethnicity, income < or = 10,000 dollars, sex with a same-sex partner, and sex with an injection drug user as the only variables that were independently associated with HIV seropositivity., Conclusions: Although a substantial proportion of HCV-infected patients have been tested for HIV, missed opportunities for early diagnosis of HIV infection exist. Public health strategies to improve HIV testing among patients with chronic HCV infection are needed.

In vivo corneal absorption of the dipeptide prodrugs of acyclovir (ACV) was evaluated using microdialysis in rabbits. A corneal well was placed on the cornea of the anesthetized New Zealand White rabbits with implanted linear probes into the aqueous humor. Two hundred microliters of a 1% solution of L-valine-ACV (VACV), glycine-valine-ACV (GVACV), valine-valine-ACV (VVACV), and valine-tyrosine-ACV (VYACV) was placed in the corneal well and was allowed to diffuse for a period of 2 h, following which the drug solution was aspirated and well removed. Samples were collected every 20 min throughout the infusion and postinfusion phases and were analyzed by HPLC to obtain the aqueous humor concentrations. Absorption rate constants of all the compounds were found to be lower than the elimination rate constants. GVACV exhibited highest absorption rate (ka) compared with other prodrugs, but all the prodrugs showed similar terminal elimination rate (lambda(z)). The time of maximum absorption (Tmax) of ACV after administration of VACV and the dipeptide prodrugs did not vary significantly (p < 0.05). GVACV exhibited the highest concentration (Cmax) and area under curve (AUC) upon absorption (p < 0.05) compared to VACV, VVACV, and VYACV. Dipeptide prodrugs of ACV were absorbed through the cornea at similar rates but to varying extents. The dipeptide prodrug GVACV owing to its enhanced absorption of ACV seems to be a promising candidate for the treatment of ocular HSV infections.

Background & Aims: Patients with hepatitis C virus (HCV) infection who use alcohol have been excluded from clinical trials; therefore, outcomes with antiviral therapy are unknown. The aim of the study was to determine the impact of alcohol use on HCV treatment outcomes., Methods: Subjects using alcohol were categorized as follows: no alcohol versus regular alcohol use, quantity consumed (none, <6 drinks/day, >/=6 drinks/day), CAGE score <2 or >/=2, and recent alcohol use (past 12 months). Patients were treated with interferon plus ribavirin., Results: A total of 4061 subjects were enrolled, and 726 (18%) received treatment. Alcohol use (past and within 12 months) reduced treatment candidacy. Past alcohol use did not affect the end-of-treatment response, sustained virologic response (SVR), and treatment discontinuation rates. However, recent alcohol use resulted in higher treatment discontinuation (40% vs 26%; P = .0002) and tended to reduce the SVR (14% vs 20%; P = .06), but when patients who discontinued treatment were excluded from analysis, the trend in favor of nondrinkers for SVR disappeared (25% vs 23%). These findings were also consistent in subgroup analyses on race and genotype., Conclusions: Eligibility for anti-HCV treatment was reduced in past and recent drinkers. Recent alcohol use was associated with increased treatment discontinuation and lower SVR. However, patients who use alcohol and completed the treatment had a response comparable to that of nondrinkers. Patients with a history of alcohol use should not be excluded from HCV therapy. Instead, additional support should be provided to these patients to ensure their ability to complete treatment.

In previous hepatitis C virus (HCV) treatment studies, Black patients not only had a lower sustained viral response (SVR) rate to interferon and ribavirin (RBV) than non-Black patients but also a higher frequency of HCV genotype 1 (GT-1) infection. The aim of this community-based study was to determine whether Black patients have a lower SVR rate independent of genotype. We prospectively enrolled 785 patients (24.8% Black, 71.5% White, 3.7% others) who received interferon alpha-2b 3 MU three times weekly + RBV 1000-1200 mg/day for 24 weeks (GT-2/3) or 48 weeks (GT-1). Black patients were more commonly infected with GT-1 (86.8%vs 64.8%, P < 0.001) and less frequently had an SVR compared with non-Black patients (8.4%vs 21.6%, P < 0.001). Within GT-1, Black patients had a lower SVR rate than non-Black patients (6.1%vs 14.1%, P = 0.004) but not within GT-2/3 (50.0%vs 36.5%, P = 0.47). Black patients had lower baseline haemoglobin levels (14.8 vs 15.3 g/dL, P < 0.001) and neutrophil counts (2900 vs 4100/mm(3), P < 0.001) and required more frequent dose reductions of RBV (29.8%vs 18.5%, P < 0.001) and interferon (4.7%vs 1.6%, P = 0.012). However, dose reductions were not associated with lower SVR rates while early treatment discontinuations were (2.9%vs 25.7%, P < 0.001). Independent predictors of SVR were GT-1 [odds ratio (OR) 0.33; 95% confidence interval (CI) 0.20-0.55; P < 0.001], Black race (OR 0.45; 95% CI 0.22-0.93; P = 0.030), and advanced fibrosis, stages 3 + 4 (OR 0.53; 95% CI 0.31-0.92; P = 0.023). In conclusion, Black patients infected with HCV GT-1 (but not GT-2/3) have a lower SVR rate than non-Black patients. This is not explained by their lower baseline haemoglobin levels and neutrophil counts that lead to higher rates of ribavirin and interferon dose reductions.

Tumors arising from the anal canal are usually of epithelial origin and are mostly squamous cell carcinoma or basal cell carcinoma. We present a case of benign anal adenomas arising from the anus, an extremely rare diagnosis. A 78-year-old white man presented with rectal bleeding of several months duration. Examination revealed a 4 cm friable mass attached to the anus by a stalk. At surgery, the mass was grasped with a Babcock forceps and was resected using electrocautery. Microscopic examination revealed a tubulovillus adenoma with no areas of high grade dysplasia or malignant transformation. The squamocolumnar junction was visible at the edges of the lesion confirming the anal origin of the tumor. We believe the tubulovillus adenoma arose from either an anal gland or its duct that opens into the anus. Although seen rarely, it is important to recognize and treat these tumors at an early stage because of their potential to transform into adenocarcinoma.

Purpose: TRX1 is a nondepleting anti-CD4 monoclonal IgG1 antibody being developed to induce tolerance by blocking CD4-mediated functions. The purpose of this study is to describe the pharmacokinetics (PK) and pharmacodynamics (PD) of TRX1 and to develop a receptor-mediated PK/PD model that characterizes the relationships between serum TRX1 concentration and total and free CD4 expression in healthy male volunteers., Methods: Nine subjects from three dosing cohorts in double-blinded, placebo-controlled phase I clinical study was included in the analysis. Serum TRX1 levels were determined using enzyme-linked immunosorbent assay. Blood total and free CD4 receptor levels were determined by using flow cytometric analyses. The receptor-mediated PK/PD model was developed to describe the dynamic interaction of TRX1 binding with CD4 receptors., Results and Conclusions: TRX1 displayed nonlinear pharmacokinetic behavior and the CD4 receptors on T cells were saturated and down-modulated following treatment with TRX1. Results from in vitro studies using purified human T cells suggested that CD4-mediated internalization may constitute one pathway by which CD4 is down-modulated and TRX1 is cleared in vivo. The developed receptor-mediated PK/PD model adequately described the data. This PK/PD model was used to simulate PK/PD time profiles after different dosing regimens to help guide the dose selection in future clinical studies.

Background: Patients with chronic hepatitis C virus (HCV) infection who consume large quantities of alcohol have more severe liver disease compared with HCV patients without a history of alcohol consumption. The mechanism by which alcohol worsens HCV related liver disease is not properly understood. One possibility is that alcohol stimulates HCV replication, and the present meta-analysis was performed to examine this issue., Methods: The effect of alcohol on viral titres was assessed in three ways: comparison of the heaviest drinkers with non-drinkers; effect of graded doses of alcohol; and effect of abstinence in the same individual., Results: A total of 14 studies were identified. Comparison of patients with the highest alcohol use with the abstinent group showed a significant association with viral load in three studies, five studies had a positive direction, while the remaining four studies found a negative relationship. Analysis of the combined results showed no association between alcohol consumption and virus levels (p = 0.29). Assessment of graded doses of alcohol also showed no significant difference between non-drinkers and moderate drinkers (p = 0.50), between non-drinkers and heavy drinkers (p = 0.35), or between moderate drinkers and heavy drinkers (p = 0.32). Five studies examined the influence of abstinence on viral titres but none provided sufficient data for statistical analysis., Conclusions: The present study has failed to show an association between alcohol use and HCV viral titres. These observations raise the possibility that the hepatic damage caused by alcohol and HCV may be purely additive, involving different mechanisms and pathways.

Objectives: The natural history of chronic hepatitis C and treatment response are different between blacks and Caucasians, but little comparable data is available about Latinos., Methods: A cross-sectional secondary analysis to investigate differences between 421 anti-HCV-positive, treatment-naïve, HCV-viremic Latinos and 2,510 Caucasians in 24 VA medical centers enrolled in a prospective study., Results: Latinos were infected at a younger age and were less likely to have blood contact during combat, surgery, and needle stick injury, but were more frequently HIV coinfected (20.4%vs 3.9%, p < 0.0001) and prior HAV infection (39.9%vs 26.4%, p= 0.0001). Latinos were more likely to be treatment candidates, but less likely to actually initiate treatment. Liver histology (123 Latinos, 743 Caucasians) showed no difference in fibrosis or fibrosis rate, but steatosis (54.7%vs 43.2%, p= 0.038) was more common in Latinos. Eighty-eight Latinos and 481 Caucasians were subsequently treated with interferon-ribavirin: body mass index (BMI), duration of infection, baseline tests, liver histology and genotype distribution were similar. Compared with Caucasians, Latinos discontinued treatment prematurely more often (39.8%vs 28.9%, p= 0.043) and tended to have lower sustained virological response (SVR) rates (14.8%vs 22.5%, p= 0.10). Multivariate analysis found Latino race and history of recent alcohol use to be associated with early treatment discontinuation, whereas genotype and viral load but not ethnicity to be associated with SVR., Conclusions: Latinos were infected younger, more frequently HIV coinfected, more likely to meet criteria for antiviral therapy yet less likely to initiate treatment and had a trend toward lower SVR rates than Caucasians, but not in severity of liver disease. Latino ethnicity was associated with early discontinuation but not as an independent predictor of SVR.

Background: Many veterans may not be candidates for hepatitis C virus (HCV) treatment due to contraindications to therapy. The aims of this study were to determine the proportion of HCV-infected veterans who were eligible for interferon alfa and ribavirin therapy and to evaluate barriers to HCV treatment., Methods: We prospectively enrolled 4,084 veterans who were referred for HCV treatment over a 1-yr period at 24 Veterans Affairs (VA) Medical Centers. Treatment candidacy was assessed using standardized criteria and the opinion of the treating clinician., Results: Overall, 32.2% (95% CI, 30.8-33.7%) were candidates for HCV treatment according to standardized criteria, whereas 40.7% (95% CI, 39.2-42.3%) were candidates in the opinion of the treating clinician. Multivariable analysis identified ongoing substance abuse (OR = 17.68; 95% CI, 12.24-25.53), comorbid medical disease (OR = 9.62; 95% CI, 6.85-13.50), psychiatric disease (OR = 9.45; 95% CI, 6.70-13.32), and advanced liver disease (OR = 8.43; 95% CI, 4.42-16.06) as the strongest predictors of not being a treatment candidate. Among patients who were considered treatment candidates, 76.2% (95% CI, 74.0-78.3%) agreed to be treated and multivariable analysis showed that persons >/=50 yr of age (OR = 1.37; 95% CI, 1.07-1.76) and those with >50 lifetime sexual partners (OR = 1.44; 95% CI, 1.08-1.93) were more likely to decline treatment., Conclusions: The majority of veteran patients are not suitable candidates for HCV treatment because of substance abuse, psychiatric disease, and comorbid medical disease, and many who are candidates decline therapy. Multidisciplinary collaboration is needed to overcome barriers to HCV therapy in this population.

The impact of efflux pumps and metabolic enzymes on the therapeutic activity of various drugs has been well established. The presence of efflux pumps on various tissues and tumours has been shown to regulate the intracellular concentration needed to achieve therapeutic activity. The notable members of efflux proteins include P-glycoprotein, multi-drug resistance protein and breast cancer resistance protein. These efflux pumps play a pivotal role not only in extruding xenobiotics but also in maintaining the body's homeostasis by their ubiquitous presence and ability to coordinate among themselves. In this review, the role of efflux pumps in drug delivery and the importance of their tissue distribution is discussed in detail. To improve pharmacokinetic parameters of substrates, various strategies that modulate the activity of efflux proteins are also described. Drug metabolising enzymes mainly include the cytochrome P450 family of enzymes. Extensive drug metabolism due to the this family of enzymes is the leading cause of therapeutic inactivity. Therefore, the role of metabolising enzymes in drug delivery and disposition is extensively discussed in this review. The synergistic relationship between metabolising enzymes and efflux proteins is also described in detail. In summary, this review emphasises the urgent need to make changes in drug discovery and drug delivery as efflux pumps and metabolising enzymes play an important role in drug delivery and disposition.