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Understanding the potential carcinogenic potency of nitrosamines is necessary to setting acceptable intake limits. Nitrosamines and the components that can form them are commonly present in food, water, cosmetics, and tobacco. The recent observation of nitrosamines in pharmaceuticals highlighted the need for effective methods to determine acceptable intake limits. Herein, we describe two computational models that utilize properties based upon quantum mechanical calculations in conjunction with mechanistic insights and established data to determine the carcinogenic potency of a variety of common nitrosamines. These models can be applied to experimentally untested nitrosamines to aid in the establishment of acceptable intake limits.

To explore clinical characteristics, risk profiles, and outcomes of patients with portopulmonary hypertension (PoPH) who have contraindications to liver transplant (LT).

Background: Although colorectal cancer screening by using a fecal occult blood test (FOBT), flexible sigmoidoscopy, colonoscopy, or barium enema x-ray reduces the incidence of and death from colorectal cancer, the rate of colorectal cancer screening in the general population is low. We conducted a randomized trial consisting of direct mailing of FOBT kits to increase colorectal cancer screening among residents of Wright County, Minnesota, a community in which colorectal cancer screening was promoted. Methods: At baseline, we mailed a questionnaire about colorectal cancer screening to a random sample of Wright County residents aged 50 years or older who were randomly selected from the Minnesota State Driver's License and Identification Card database (estimated N = 1451). The sample was randomly allocated into three equal subgroups: one group (control) received only the questionnaire, one group received FOBT kits by direct mail with reminders, and one group received FOBT kits by direct mail without reminders. Study participants were sent a follow-up questionnaire 1 year after baseline. We used the responses to the questionnaires to estimate the 1-year change in self-reported screening rates in each group and the differences in the changes among the groups, along with the associated bootstrap 95% confidence intervals (CIs). Results: At baseline, the estimated response rate was 86.5%, self-reported adherence to FOBT guidelines was 21.5%, and overall adherence to any colorectal cancer screening test guidelines was 55.8%. The 1-year rate changes in absolute percentage for self-reported adherence to FOBT use were 1.5% (95% CI = -2.9% to 5.9%) for the control group, 16.9% (95% CI = 11.5% to 22.3%) for the direct-mail-FOBT-with-no-reminders group, and 23.2% (95% CI = 17.2% to 29.3%) for the direct-mail-FOBT-with-reminders group. The 1-year rate changes for self-reported adherence to any colorectal cancer screening test were 7.8% (95% CI = 3.2% to 12.0%) for the control group, 13.2% (95% CI = 8.4% to 18.2%) for the direct-mail-FOBT-with-no-reminders group, and 14.1% (95% CI = 9.1% to 19.1%) for the direct-mail-FOBT-with-reminders group. Conclusion: Direct mailing of FOBT kits combined with follow-up reminders promotes more rapid increases in the use of FOBT and nearly doubles the increase in overall rate of adherence to colorectal cancer screening guidelines in a general population compared with a community-wide screening promotion and awareness campaign. [J Natl Cancer Inst 2004;96:770-80]

Supplemental Digital Content is available in the text.De novo malignancies (DNMs) following liver transplantation (LT) have been reported as 1 of the major causes of late mortality, being the most common cause of death in the second decade after LT. The overall incidence of DNMs is reported to be in the range of 3.1% to 14.4%, and the incidence is 2- to 3-fold higher in transplant recipients than in age- and sex-matched healthy controls. Long-term immunosuppressive therapy, which is the key in maintaining host tolerance and achieving good long-term outcomes, is known to contribute to a higher risk of DNMs. However, the incidence and type of DNM also depends on different risk factors, including patient demographics, cause of the underlying chronic liver disease, behavior (smoking and alcohol abuse), and pre-existing premalignant conditions. The estimated standardized incidence ratio for different DNMs is also variable. The International Liver Transplantation Society–Spanish Society of Liver Transplantation Consensus Conference working group on DNM has summarized and discussed the current available literature on epidemiology, risk factors, management, and survival after DNMs. Recommendations for screening and surveillance for specific tumors, as well as immunosuppression and cancer-specific management in patients with DNM, are summarized.

ABSTRACTDomestic minor sex trafficking is often thought of as a crime that happens somewhere else (outside of Australia), with most conceptualizations involving a child who is internationally trafficked. The lack of a clear definition of domestic minor trafficking is a challenge often cited in the literature. In response, the current research explored an operational definition of domestic minor sex trafficking, using a Delphi methodology. A commonly held view of Australians is that Australia is impervious to trafficking, despite numerous cases of exploitation appearing to fit the international and Australian legal definition of trafficking (identified in legal databases and media reports). The Delphi method is an iterative survey method developed by the Rand Corporation in the 1950s. In the current study, a panel of 14 experts participated in three rounds of online surveys to reach a consensus definition of domestic minor sex trafficking within Australia. Ten themes were identified and used to develop the operational definition. The results will be used as a basis to examine prevalence of domestic trafficking and the characteristics of those who domestically traffic children, in addition to examining clarity and effectiveness of the current legislation.

Survival of liver transplant recipients beyond 1 year since transplantation is compromised by an increased risk of cancer, cardiovascular events, infection, and graft failure. Few clinical tools are available to identify patients at risk of these complications, which would flag them for screening tests and potentially life-saving interventions. In this retrospective analysis, we aimed to assess the ability of deep learning algorithms of longitudinal data from two prospective cohorts to predict complications resulting in death after liver transplantation over multiple timeframes, compared with logistic regression models.

Patients undergoing evaluation for solid organ transplantation (SOT) often have a history of malignancy. Although the cancer has been treated in these patients, the benefits of transplantation need to be balanced against the risk of tumor recurrence, especially in the setting of immunosuppression. Prior guidelines of when to transplant patients with a prior treated malignancy do not take in to account current staging, disease biology, or advances in cancer treatments. To develop contemporary recommendations, the American Society of Transplantation held a consensus workshop to perform a comprehensive review of current literature regarding cancer therapies, cancer stage‐specific prognosis, the kinetics of cancer recurrence, and the limited data on the effects of immunosuppression on cancer‐specific outcomes. This document contains prognosis based on contemporary treatment and transplant recommendations for breast, colorectal, anal, urological, gynecological, and nonsmall cell lung cancers. This conference and consensus documents aim to provide recommendations to assist in the evaluation of patients for SOT given a history of a pretransplant malignancy. This article presents consensus expert opinion transplant recommendations for patients with a prior breast, colorectal, anal, urological, gynecological, or non‐small cell lung cancer. See the companion review on page 475and an editorial from Hart and Engels on page 447.

Patients undergoing evaluation for solid organ transplantation (SOT) frequently have a history of malignancy. Only patients with treated cancer are considered for SOT but the benefits of transplantation need to be balanced against the risk of tumor recurrence, taking into consideration the potential effects of immunosuppression. Prior guidelines on timing to transplant in patients with a prior treated malignancy do not account for current staging, disease biology, or advances in cancer treatments. To update these recommendations, the American Society of Transplantation (AST) facilitated a consensus workshop to comprehensively review contemporary literature regarding cancer therapies, cancer stage specific prognosis, the kinetics of cancer recurrence, as well as the limited data on the effects of immunosuppression on cancer‐specific outcomes. This document contains prognosis, treatment, and transplant recommendations for melanoma and hematological malignancies. Given the limited data regarding the risk of cancer recurrence in transplant recipients, the goal of the AST‐sponsored conference and the consensus documents produced are to provide expert opinion recommendations that help in the evaluation of patients with a history of a pretransplant malignancy for transplant candidacy. This article presents consensus expert opinion recommendations regarding the timing of transplantation for patients with a history of melanoma or hematological malignancies. The companion review is on page 460and an editorial from Hart and Engels is on page 447.

Supplemental Digital Content is available in the text.

Adverse Childhood Experiences (ACE) are associated with the development of negative health behaviors and medical illness. ACE’s association with poor health outcomes has been well documented in the general population; however, this relationship remains less clear in liver transplant (LT) recipients. The aims of this study therefore were to determine the prevalence of ACE and the influence of ACE on LT outcomes.

This study describes the analytical performance of the QuantideX qPCR BCR-ABL IS Kit, the first Food and Drug Administration–cleared assay designed to monitor breakpoint cluster region–Abelson tyrosine-protein kinase 1 (BCR-ABL1) fusion transcripts isolated from peripheral blood specimens from patients with chronic myeloid leukemia. This multiplex real-time quantitative RT-PCR assay amplifies both e13a2 and e14a2 Major BCR-ABL1 transcripts and the reference target ABL1. The test results are provided in international scale (IS) values by incorporating armored RNA-based calibrators that have defined IS values tied directly to the World Health Organization BCR-ABL1 Primary Reference Materials, without the necessity of determining and maintaining conversion factors. For each batch run, the integrated interpretive software evaluates run and specimen quality control metrics (including a sufficient amount of ABL1 control transcripts to ensure a minimal limit of detection) and calculates both molecular response (MR) and %IS values for each specimen. The test has a limit of detection of MR4.7 (0.002%IS) and a linear range from MR0.3 (50%IS) to MR4.7 (0.002%IS) for both Major transcripts. Single-site and multisite precision studies demonstrated a maximum SD of 0.13 MR (30% CV within the assay range between MR0.7 and MR3.7). The performance of this BCR-ABL1 monitoring test meets all of the clinical guideline recommendations for sensitivity and IS reporting for the management of chronic myeloid leukemia patients.

Supplemental digital content is available in the text.

Nonalcoholic steatohepatitis (NASH) is a growing indication for liver transplant whether the primary or secondary cause of liver disease, and it is expected to be the leading indication in the years to come. Nonalcoholic steatohepatitis recurs after transplant but the impact of the recurrence on allograft and patient outcomes is unclear. A group of multidisciplinary transplant practice providers convened at the International Liver Transplantation Society NASH consensus conference with the purpose of determining the current knowledge and future directions for understanding the recurrence rates, risk and management of NASH in the transplant allograft. Specific questions relating to posttransplant NASH were proposed and reviewed in detail with recommendations on future actions to fill the knowledge gaps.

Liver transplant candidates undergo psychosocial assessment as a component of their pretransplant evaluation. Global psychosocial assessment scales, including the Psychosocial Assessment of Candidates for Transplantation (PACT), capture and quantify these psychiatric and social variables.

The CD200 is a cell membrane protein expressed by tumor cells, and its receptor CD200 receptor (CD200R) is expressed by immune cells including macrophages and dendritic cells. The formation of CD200-CD200R inhibits the cellular functions of the targeted immune cells, so CD200 is one type of the immune checkpoint and blockade CD200-CD200R formation is a potential cancer treatment. However, the CD200 blockade has opposite treatment outcomes in different types of cancers. For instance, the CD200R deficient mice have a higher tumor load than the wild type (WT) mice in melanoma suggesting that CD200-CD200R inhibits melanoma. On the other hand, the antibody anti-CD200 treatment in pancreatic ductal adenocarcinoma (PDAC) and head and neck squamous cell carcinoma (HNSCC) significantly reduces the tumor load indicating that CD200-CD200R promotes PDAC and HNSCC. In this work, we hypothesize that different mechanisms of CD200-CD200R in tumor microenvironment could be one of the reasons for the diverse treatment outcomes of CD200 blockade in different types of cancers. We create one Ordinary Differential Equations (ODEs) model for melanoma including the inhibition of CCL8 and regulatory T cells and the switching from M2 to M1 macrophages by CD200-CD200R to capture the tumor inhibition by CD200-CD200R. We also create another ODEs model for PDAC and HNSCC including the promotion of the polarization and suppressive activities of M2 macrophages by CD200-CD200R to generate the tumor promotion by CD200-CD200R. Furthermore, we use these two models to investigate the treatment efficacy of the combination treatment between the CD200-CD200R blockade and the other immune checkpoint inhibitor, anti-PD-1. Our result shows that different mechanisms of CD200-CD200R can induce different treatment outcomes in combination treatments, namely, only the CD200-CD200R blockade reduces tumor load in melanoma and only the anti-PD-1 and CD200 knockout decrease tumor load in PDAC and HNSCC. Moreover, in melanoma, the CD200-CD200R mainly utilizes the inhibitions on M1 macrophages and dendritic cells to inhibit tumor growth, instead of M2 macrophages. • ODE models for CD200-CD200R and PD-1-PD-L1. • Different mechanisms of CD200-CD200R lead to diverse treatment outcomes. • Mechanism of CD200-CD200R also affects the functions of PD-1-PD-L1. [ABSTRACT FROM AUTHOR]

I enjoyed the article by my buddy Bob Wieman ['Aviators,' November]. We could write a book about our days at Atsugi Air Base in Japan. With old-timers leaving, we second [...]

ABSTRACT:Recent research indicates that paid employment is an important recovery goal for many people living with psychosis; however, employment rates among this group remain very low compared to the general population and people with physical disabilities. This study explored the perceived benefits and costs of paid employment and unemployment for people living with psychosis. The study draws on findings from a qualitative study of 137 people living in South East Queensland, Australia. Fourteen focus groups and 31 individual interviews were conducted with a purposive sample drawn from six stakeholder groups: clients living with psychosis, caregivers, health practitioners, employers, employment consultants, and community members. The most frequently perceived benefits of employment related to self-concept, personal satisfaction, and mental health benefits, while the most commonly perceived costs of employment were work-related stress, workrelated financial expenses, and the physical demands of work. The main perceived benefits of unemployment were freedom to pursue preferred activities, relief from work-related pressure, and improved access to entitlements. The most frequently referenced costs of unemployment were poor mental health, deskilling, and deconditioning. The findings provide insight into factors that may affect motivation and influence work-related decisions among people living with psychosis.

ABSTRACT:Clinicians generally recognize that psychotic disorders have a primary impact on motivation, including to engage in employment. However, secondary impacts of psychotic disorder as well as broader psychosocial factors may also be important determinants of work motivation (Hampson, Hicks, & Watt, 2016). This article explores determinants of job motivation among people living with psychotic disorders, drawing on the results of a qualitative study of 137 participants from 6 different stakeholder groups (clients, caregivers, employers, health professionals, community members, and employment service providers). NVivo 10 was used to explore participant responses relating to work motivation. In addition to primary impacts of the psychotic condition on work motivation, this study found that systemic factors, individual differences in personal attributes, and interpersonal factors influenced motivation to work. Findings indicate that the determinants of employment motivation among people living with psychosis are complex and dynamic, and suggest that appropriate individual and systemic interventions may increase their work motivation.

In underwater photography, as with mast pastimes, certain fads come and go. The one that has turned the corner from a fad to an accepted photo technique is split image […]

This study examined the relationship between coping style and long-term posttraumatic stress symptoms in an Australian sample of volunteer firefighters 84 months following a bushfire disaster. A total of 277 firefighters completed 4 questionnaires to assess patterns of psychiatric morbidity. A 2-way repeated-measures analysis of variance was conducted to investigate the effect of time and disorder on coping. Firefighters evidencing distress were more likely to use both problem- and emotion-focused methods of coping. Based on previous research, it was hypothesized that problem-focused coping strategies would be used after 84 months. The use of both problem- and emotion-focused coping may be due to the length of time following this disaster or unique characteristics of firefighters. These data suggest that present coping theories are not sufficient to account for the onset and pattern of psychiatric morbidity within a firefighter sample. The authors declare no conflicts of interest including financial, consultant, institutional, and other relationships that might lead to bias.

De novo malignancies are one of the leading causes of late mortality after liver and kidney transplantation. Nonmelanoma skin cancer is the most common malignancy, followed by posttransplant lymphoproliferative disorder and solid organ tumors. Immunosuppression is a key factor for cancer development, although many other transplant-related and traditional risk factors also play a role. In this review, the authors summarize risk factors and outcomes of frequently encountered de novo malignancies after liver and kidney transplantation to stratify recipients at highest risk. Future efforts in prospectively validated, cost-effective surveillance strategies that improve survival of these complex patients are greatly needed.

The intestinal microbiome and immune system are in close symbiotic relationship in health. Gut microbiota plays a role in many chronic liver diseases and cirrhosis. However, alterations in the gut microbiome after liver transplantation and the implications for liver transplant recipients are not well understood and rely mainly on experimental animal studies. Recent advances in molecular techniques have identified that increased intestinal permeability, decreased beneficial bacteria, and increased pathogenic species may play important roles in the early posttransplant period. The associations between microbiota perturbation and postliver transplant infections and acute rejection are evolving. The link with metabolic syndrome, obesity, and cardiac disease in the general population require translation into the transplant recipient. This review focuses on our current knowledge of the known and potential interaction of the microbiome in the liver transplant recipient. Future human studies focused on microbiota changes in liver transplant patients are warranted and expected.The role of the microbiome in several human diseases is just beginning to be unraveled. In this review, the authors highlight the current evidence and potential mechanisms implicated in the association between microbiota perturbation and liver transplant complications, including rejection, infections, or posttransplant metabolic complications.

The International Liver Transplantation Society and the Spanish Society of Liver Transplantation consensus conference on extrahepatic cancer and liver transplantation (LT) was held on January 28–30, 2021. Working groups were organized to focus on one topic and develop evidence-based recommendations specifically addressing (a) nonhepatic cancer in LT candidates, (b) de novo malignancies after LT, (c) prevention and management of donor-derived malignancies after LT, and (d) nonhepatic cancer in the pediatric population. All consensus conference attendees voted on the recommendations proposed as well as the quality of evidence according to the Grading of Recommendations, Assessment, Development and Evaluation system.

When the immune-checkpoint programmed death-1 (PD-1) binds to its ligand programmed death ligand 1 (PD-L1) to form the complex PD-1-PD-L1, this complex inactivates immune cells resulting in cell apoptosis, downregulation of immune reaction, and tumor evasion. The antibody, anti-PD-1 or anti-PD-L1, blocks the PD-1-PD-L1 complex formation to restore the functions of T cells. Combination of anti-PD-1 with other treatment shows promising in different types of cancer treatments. Interferon-gamma (IFN- γ) plays an important role in immune responses. It is mainly regarded as a pro-inflammatory cytokine that promotes the proliferation of CD8 + T cell and cytotoxic T cell, enhances the activation of Th1 cells and CD8 + T cells, and enhances tumor elimination. However, recent studies have been discovering many anti-inflammatory functions of IFN- γ , such as promotion of the PD-L1 expression, T cell apoptosis, and tumor metastasis, as well as inhibition of the immune recognition and the killing rates by T cells. In this work, we construct a mathematical model incorporating pro-inflammatory and anti-inflammatory functions of IFN- γ to capture tumor growth under anti-PD-1 treatment in the wild type and IFN- γ null mutant melanoma. Our simulation results qualitatively fit experimental data that IFN- γ null mutant with anti-PD-1 obtains the highest tumor reduction comparing to IFN- γ null mutant without anti-PD-1 and wild type tumor with anti-PD-1 therapy. Moreover, our synergy analysis indicates that, in the combination treatment, the tumor volume decreases as either the dosage of anti-PD-1 increases or the IFN- γ production efficiency decreases. Thus, the combination of anti-PD-1 and IFN- γ blockade improves the tumor reduction comparing to the monotherapy of anti-PD-1 or the monotherapy of IFN- γ blockade. We also find a threshold curve of the minimal dosage of anti-PD-1 corresponding to the IFN- γ production efficiency to ensure the tumor reduction under the presence of IFN- γ. • Free boundary PDE model of anti-PD-1 and IFN- γ. • IFN- γ has pro-tumor and anti-tumor functions in melanoma. • Anti-PD-1 and IFN- γ have antagonistic effect in melanoma treatment. [ABSTRACT FROM AUTHOR]

Improvements in overall survival early after liver transplantation result in a growing number of patients with the potential for long-term survival. Data available on long-term survival, to date, reflect the situation of patients who received their liver transplant during a very different health-care era. Translating these data into the current medical era of liver transplantation is an important task, as a better understanding of aspects associated with morbidity and mortality is fundamental in improving the long-term outcome of liver transplant recipients. Malignancy screening, optimal treatment of recurrent disease and adequate management of metabolic disease are crucial contributions to advance patient care. In this Review, data specific to the liver transplant recipient will be evaluated and, in the absence of sufficient evidence at this time, recommendations and guidelines for the general population on management of long-term concerns will be assessed for their applicability after liver transplantation. In addition, other preventive strategies relating to pregnancy, contraception and vaccination are reviewed in detail.

To assess safety and outcomes (metabolic and liver) of bariatric surgery in patients with cirrhosis with or without portal hypertension.

The Great White Shark has always been one of diving's holy grail experiences, and South Africa is the place. No question, the area within 100 miles of Cape Town has […]

There is increased concern regarding circulating levels of lidocaine immediately after the use of a needle-free device with buffered lidocaine. As a result, we conducted a prospective study to assess lidocaine circulation after the use of a needle-free device for the delivery of a local anesthetic in 10 healthy adult subjects. After informed consent, 2 peripheral intravenous catheters were placed in the antecubital fossa of each arm. Two milligrams of 1 buffered lidocaine was administered by the study physician via the needle-free device on the dorsum of the subject’s hand. Within 2 minutes, a third intravenous catheter was placed in the location of the lidocaine administration and 5 mL of blood was collected from all 3 sites. If blood samples returned positive for lidocaine, they were also collected 1 hour and 2 hours after administration. Toxic levels of lidocaine were found in blood drawn from 2 subjects immediately after lidocaine administration. Results also showed that certain subjects had increasing levels of lidocaine over time. Other subjects also had increasing lidocaine serum levels from blood drawn on the arm opposite the administration site. We concluded that there may be systemic lidocaine levels with the administration of the needle-free device and that these levels may reach the toxic range in adults. Further investigation will be required to determine whether this finding has clinical significance, especially considering the smaller body mass of children.

Several letters to the editor are presented in response to articles in previous issues including "A symbol solution" in the February 15, 2014 issue, "Just one more" by Mark Broatch in the February 8, 2014 issue, and "Health" by Margo White in the February 15, 2014 issue.

Analysis of donor and recipient genetic risk factors for obesity and diabetes after transplant finds that recipient, but not donor, PNPLA‐3 G allele is independently associated with obesity after liver transplantation, pointing to a peripheral rather than central mechanism of action and explaining some of the risk for posttransplant obesity.

The effect of nitrogen content, the secondary compounds (tannin and proanthocyanidin) content, the dry matter content of 4 clones, and the different developmental stages of macadamia nuts, on the abundance of Gymnandrosoma aurantianum, was studied. Nitrogen content differed between clones and the stages of development of the nuts, being highest in the most tolerant clones 508>660>344>246. Highest dry matter contents were found in the tolerant clones, 508 and 660, and in the outer layer, than in the susceptible clones 246 and 344 and in the inner layers (2 and 3). Proanthocyanidin content was highest in layer 2 of clones 508 and 660 than in clones 246 and 344. Results show that food quality affects the performance of nutborer larvae, where the larvae have to overcome first a physical barrier, followed by a chemical barrier, to be able to feed on macadamia nuts. [ABSTRACT FROM AUTHOR]

Obesity is increasingly common before and after liver transplantation (LT), yet optimal management remains unclear. Our aim was to analyze the effectiveness of a multidisciplinary protocol for obese patients requiring LT, including a noninvasive pretransplant weight loss program, and a combined LT plus sleeve gastrectomy (SG) for obese patients who failed to lose weight prior to LT. Since 2006, all patients referred LT with a BMI > 35 were enrolled. There were 37 patients who achieved weight loss and underwent LT alone, and 7 who underwent LT combined with SG. In those who received LT alone, weight gain to BMI > 35 was seen in 21/34, post‐LT diabetes (DM) in 12/34, steatosis in 7/34, with 3 deaths plus 3 grafts losses. In patients undergoing the combined procedure, there were no deaths or graft losses. One patient developed a leak from the gastric staple line, and one had excess weight loss. No patients developed post‐LT DM or steatosis, and all had substantial weight loss (mean BMI = 29). Noninvasive pretransplant weight loss was achieved by a majority, though weight gain post‐LT was common. Combined LT plus SG resulted in effective weight loss and was associated with fewer post‐LT metabolic complications. Long‐term follow‐up is needed.

AbstractConsumers with co-occuring mental health, substance use and physical impairments present with a wide array of needs that cannot be addressed by one sole agency. The Complex Needs Assessment Panel and Integrated Support (CNAPIS) was developed to coordinate care and service delivery for young adults with co-occuring disorders. Utilising a multi-method evaluation approach, consumer interviews and file reviews were completed appraising the service’s effectiveness. Results from the initial evaluation are encouraging regarding meeting the programme’s objectives, including improving the quality and availability of support, coordinating care, service integration, flexibility in service delivery and responding to consumer’s needs. Further evaluation is required to determine the longer term benefits of such programmes.

Recognition, management, and prevention of medical complications and comorbidities after liver transplant is the key to improved long-term outcomes. Beyond allograft-related complications, metabolic syndrome, cardiovascular disease, renal dysfunction, and malignancies are leading causes of morbidity and mortality in this patient population. Primary care physicians have an important role in improving outcomes of liver transplant recipients and are increasingly relied on for managing these complex patients. This review serves to assist the primary care physician in the long-term management issues of liver transplant recipients.

The IL28Bgenotype has been linked to sustained virological response (SVR) in hepatitis C virus (HCV). Its role on disease biology and progression is less clear. We characterized the effects of IL28Bgenotype on HCV recurrence, allograft histology, rate of SVR, and survival after liver transplantation (LT) in HCV.

IL28Bpolymorphisms are strongly associated with response to treatment for HCV infection. IL28Bacts on interferon‐stimulated genes via the JAK‐STAT pathway, which has been implicated in development of insulin resistance. We investigated whether IL28Bpolymorphisms are associated with posttransplant diabetes mellitus (DM). Consecutive HCV patients who underwent liver transplantation between 1–1995 and 1–2011 were studied. Genotyping of the polymorphism rs12979860 was performed on DNA collected from donors and recipients. Posttransplant DM was screened for by fasting blood glucoses every 1–3 months. Of 221 included patients, 69 developed posttransplant DM (31%). Twenty‐two patients with recipient IL28Bgenotype TT (48%), 25 with IL28Bgenotype CT (25%) and 22 with IL28Bgenotype CC (29%) developed posttransplant DM. TT genotype was statistically significantly associated with posttransplant DM over time (log rank p = 0.012 for TT vs. CT and p = 0.045 for TT vs. CC). Multivariate Cox regression analysis correcting for donor age, body mass index, baseline serum glucose, baseline serum cholesterol, recipient age and treated rejection, showed that recipient IL28Bgenotype TT was independently associated with posttransplant DM (hazard ratio 2.51; 95% confidence interval 1.17–5.40; p = 0.011). We conclude that the risk of developing posttransplant DM is significantly increased in recipients carrying the TT polymorphism of the IL28Bgene.

Rate-limiting millisecond motions in wild-type (WT) Ribonuclease A (RNase A) are modulated by histidine 48. Here, we incorporate an unnatural amino acid, thia-methylimidazole, at this site (H48C-4MI) to investigate the effects of a single residue on protein motions over multiple timescales and on enzyme catalytic turnover. Molecular dynamics simulations reveal that H48C-4MI retains some crucial WT-like hydrogen bonding interactions but the extent of protein-wide correlated motions in the nanosecond regime is decreased relative to WT. NMR Carr-Purcell-Meiboom-Gill relaxation dispersion experiments demonstrate that millisecond conformational motions in H48C-4MI are present over a similar pH range compared to WT. Furthermore, incorporation of this nonnatural amino acid allows retention of WT-like catalytic activity over the full pH range. These studies demonstrate that the complexity of the protein energy landscape during the catalytic cycle can be maintained using unnatural amino acids, which may prove useful in enzyme design efforts.

Although mortality rates following liver transplantation (LT) are well described, there is a lack of detailed, prospective studies determining patterns of and risk factors for long-term mortality. We analyzed the multicenter, prospectively obtained The National Institute of Diabetes and Digestive and Kidney Diseases LT Database of 798 transplant recipients from 1990 to 1994 (follow-up 2003). Overall, 327 recipients died. Causes of death >1 year: 28 hepatic, 22 malignancy, 11 cardiovascular, 9 infection, 6 renal failure. Renal-related death increased dramatically over time. Risk factors for death >1 year (univariate): male gender, agedecade, pre-LT diabetes, post-LT diabetes, post-LT hypertension, post-LT renal insufficiency, retransplantation >1 year, pre-LT malignancy, alcoholic disease (ALD) and metabolic liver disease, with similar risks noted for death >5 years. Hepatitis C, retransplantation, post-LT diabetes, hypertension and renal insufficiency were significant risk factors for liver-related death. Cardiac deaths associated with age, male gender, ALD, cryptogenic disease, pre-LT hypertension and post-LT renal insufficiency. In summary, the leading causes of late deaths after transplant were graft failure, malignancy, cardiovascular disease and renal failure. Older age, diabetes and renal insufficiency identified patients at highest risk of poor survival overall. Diligent management of modifiable post-LT factors including diabetes, hypertension and renal insufficiency may impact long-term mortality.

Deriving electrical energy from glucose and other carbohydrates under mild conditions is an important research objective because these biomolecules are abundant, renewable, have high energy density, and are convenient as fuels. This rich promise has not been realized because stable, inexpensive, and efficient catalysts are not available to oxidize carbohydrates and transfer all or nearly all of their electrons to fuel cell anodes. We report here that viologen catalysts meet these demanding criteria by catalytically oxidizing glucose and other carbohydrates in a mildly alkaline solution, making possible a direct carbohydrate fuel cell. Formate and carbonate are major products of carbohydrate oxidation, demonstrating that extensive carbon-carbon bond breaking has occurred. A rudimentary fuel cell utilizing viologen catalysts and glucose or dihydroxyacetone as fuels demonstrated electrical power production at up to superficial current density. Improved catalyst function and cell design should significantly advance the efficiency and viability of direct carbohydrate fuel cell technology as a means of generating electrical energy from renewable biomass.