Reduced IFNL1 and/or IFNL2, but not IFNL3 is associated with worse outcome in patients with COVID-19.

The recent pandemic was caused by the emergence of a new human pathogen, SARS-CoV-2. While the rapid development of many vaccines provided an end to the immediate crisis, there remains an urgent need to understand more about this new virus and what constitutes a beneficial immune response in terms of successful resolution of infection. Indeed, this is key for development of vaccines that provide long lasting protective immunity. The interferon lambda (IFNL) family of cytokines are produced early in response to infection and are generally considered anti-viral and beneficial. However, data regarding production of IFNL cytokines in COVID-19 patients is highly variable, and generally from underpowered studies. In this study, we measured all three IFNL1, IFNL2 and IFNL3 cytokines in plasma from a well characterised, large COVID-19 cohort (n=399) that included good representation from patients with a more indolent disease progression, and hence a beneficial immune response. While all three cytokines were produced, they differed in both the frequency of expression in patients, and the levels produced. IFNL3 was produced in almost all patients but neither protein level nor IFNL3/IFNL4 SNPs were associated with clinical outcome. In contrast, both IFNL1 and IFNL2 levels were significantly lower, or absent, in plasma of patients that had a more severe disease outcome. These data are consistent with the concept that early IFNL1 and IFNL2 cytokine production is protective against SARS-CoV-2 infection.

Kinetics of the reaction of OH with methyl nitrate (223-343 K).

Rate coefficients (k4) for the reaction of hydroxyl radicals (OH) with methyl nitrate (CH3ONO2) were measured over the temperature range 232-343 K using pulsed laser photolysis to generate OH and pulsed laser-induced fluorescence to detect it in real-time and under pseudo-first-order conditions. In order to optimize the accuracy of the rate coefficients obtained, the concentration of CH3ONO2 (the reactant in excess) was measured on-line by absorption spectroscopy at 213.86 nm for which the absorption cross-section was also measured (σ213.86 = 1.65 ± 0.09 × 10-18 cm2 molecule-1). The temperature-dependent rate coefficient is described by k4(T) = 7.5 × 10-13 exp[(-1034 ± 40)/T] cm3 molecule-1 s-1 with a room temperature rate coefficient of k4(296 ± 2 K) = (2.32 ± 0.12) × 10-14 cm3 molecule-1 s-1 where the uncertainty includes the statistical error of 2σ and an estimation of the potential systematic bias of 5%. This new dataset helps to consolidate the database for this rate coefficient and to reduce uncertainty in the atmospheric lifetime of CH3ONO2. As part of this study, an approximate rate coefficient for the reaction of H-atoms with CH3ONO2 (k9) was also derived at room temperature: k9(298 K) = (1.68 ± 0.45) × 10-13 cm3 molecule-1 s-1.

Television News Media Consumption and Misperceptions about COVID-19 among US Populations at High Risk for Severe Health Outcomes Early in the Pandemic.

Research indicates that misperceptions that become part of people's initial mental models about an issue tend to persist and influence their attitudes even after the misperception has been corrected. Recent work on evolving mental models suggests that communication efforts about the ongoing COVID-19 pandemic and its aftermath may be improved by crafting messages that acknowledge biases and misunderstandings about the virus and other infectious diseases that may remain among members of the target audience. This study was designed to provide insight into such biases by: (1) establishing salient categories of COVID-related misperceptions in the earliest months of the pandemic in the United States among (a) the general population, and (b) demographic sub-populations at high risk of severe health outcomes; (2) identifying demographic predictors of misperceptions; and (3) examining the relationship between consumption of different television news outlets and agreement with misperceptions about COVID-19. A national sample of 1,000 adults in the United States (48.1% male; M age = 47.32, SD = 18.01; 72.9% White/Caucasian, 14.3% Black/African American, 15.9% Hispanic/Latinx) completed a survey between March 19 and March 25, 2020. Results identify prevalent classes of salient early COVID-19 misperceptions. Adjusting for numerous covariates, data indicated individuals over the age of 60 held the fewest COVID-related misperceptions among various demographic sub-populations, misperceptions were most prevalent among Black respondents, and increased consumption of television network news was associated with lower levels of misperception. Consumption of some 24-hour news networks (FOX and MSNBC) were significant positive correlates of misperceptions.

The STOP Program: a Hybrid Smoking Prevention and Cessation Training for Cancer Care Providers in Colombia and Peru.

We designed and tested the feasibility of the Smoking Cessation Training Program for Oncology Practice (STOP), a hybrid (face-to-face plus web-based) educational intervention to enhance Spanish-speaking cancer care professionals' (CCPs') ability to provide brief smoking prevention and cessation counseling to cancer patients and survivors. Changes in the CCPs' competencies (knowledge, attitude, self-efficacy, and practices toward smoking and smoking cessation services) were assessed post-training. Sixty CCPs from one major cancer center in Colombia (n = 30) and Peru (n = 30) were invited to participate in a 4-module hybrid training program on smoking prevention and cessation. Demographic and pre- and post-test evaluation data were collected. The training's acceptability was measured after each module. Bivariate analysis was conducted using Wilcoxon signed-rank test to compare the CCPs' competencies before and after the delivery of the STOP Program. Effect sizes were computed over time to assess the sustainability of the acquired competencies. Twenty-nine CCPs in Colombia and 24 CCPs in Peru completed the STOP Program (96.6% and 80.0% retention rates, respectively). In both countries, 98.2% of the CCPs reported that the overall structure and organization of the program provided an excellent learning experience. The pre-post-test evaluations indicated that the CCPs significantly improved their knowledge, attitude, self-efficacy, and practices toward smoking, smoking prevention, and cessation services. We found that the CCPs' self-efficacy and practices increased over time (1-, 3-, and 6-month assessments after completing the 4 educational modules). The STOP Program was effective and well-received, demonstrating remarkable changes in CCPs' competencies in providing smoking prevention and cessation services to cancer patients.

Psychosocial Determinants of COVID-19 Vaccination Intention Among White, Black, and Hispanic Adults in the US.

BACKGROUND: COVID-19 vaccine uptake is an urgent public health priority. PURPOSE: To identify psychosocial determinants (attitudes, normative pressure, and perceived behavioral control) of COVID-19 vaccination intentions for U.S. White, Black, and Hispanic adults, and how COVID-19 misperceptions, beliefs about the value of science, and perceived media bias relate to these determinants. METHODS: Longitudinal online survey using two national samples (18-49 years old/50 years and older), each stratified by racial/ethnic group (n = 3,190). Data were collected in October/November 2020 and were weighted by race group to be representative. RESULTS: Path analyses showed that more positive attitudes about getting vaccinated predict intention across age and racial/ethnic groups, but normative pressure is relevant among older adults only. Belief in the value of science was positively associated with most determinants across all groups, however the association of COVID-19 misperceptions and perceived media bias with the determinants varied by age group. CONCLUSIONS: Messages that emphasize attitudes toward vaccination can be targeted to all age and racial/ethnic groups, and positive attitudes are universally related to a belief in the value of science. The varying role of normative pressure poses messages design challenges to increase vaccination acceptance.

Rate Coefficients for OH + NO (+N2) in the Fall-off Regime and the Impact of Water Vapor.

The termolecular, association reaction between OH and NO is a source of nitrous acid (HONO), an important atmospheric trace gas. Rate coefficients for the title reaction as recommended by evaluation panels differ substantially at the temperatures and pressures that prevail in the Earth's boundary layer where the reaction is in the fall-off regime between low- and high-pressure limiting rate coefficients. Using pulsed laser methods for generation and detection of OH, we have reinvestigated the kinetics of the title reaction at pressures of 22-743 Torr (1 Torr = 1.333 hPa) and temperatures (273, 298, and 333 K) in pure N2 and in N2-H2O bath gases. In situ optical absorption measurements were used to rule out any bias due to NO2 or HONO impurities. Our rate coefficients (k1) in N2 bath gas are parametrized in terms of low-pressure (k0) and high-pressure (k∞) rate coefficients and a fall-off parameter (FC) with k1,0N2 = 7.24 × 10-31 (T/300 K)-2.17 cm6 molecule-2 s-1, k1,∞ = 3.3 × 10-12 (T/300 K)-0.3 cm3 molecule-1 s-1, and FC = 0.53. Used with the "Troe" expression for termolecular reactions, these parameters accurately reproduce the current data in the fall-off regime and also capture literature rate coefficients at extrapolated temperatures. The presence of water vapor was found to enhance the rate coefficients of the title reaction significantly. The low-pressure limiting rate coefficient in H2O bath gas is a factor 5-6 larger than in N2, at room temperature (k1,0H2O = 4.55 × 10-30 (T/300 K)-4.85 cm6 molecule-2 s-1) indicating that H2O is much more efficient in quenching the association complex HONO* through collisional energy transfer. Based on measurements in N2-H2O mixtures, a parametrization of k1 including both N2 and H2O as third-body quenchers was derived. Neglecting the effect of H2O results, e.g., in an underestimation of k1 by >10% in the tropical boundary layer.

Evidence of the Associations between Individual and Partner Autonomy Support and Physiological Stress in the Context of Conversations about Weight among Couples Who are Overweight or Obese during a 6-Month Intervention.

The aim of the study was to examine the impact of supportive communication on acute physiological stress responses during weight-related conversations taking place throughout a couples' weight loss program. Participants were 47 married or cohabitating couples where each partner had a BMI of 25-40 kg/m2. Couples were randomized as a dyad into a traditional weight loss program or a program that also included training in providing support to one's partner throughout the weight loss process. Structured conversations between partners about weight management were videotaped at baseline and 6 months. Participants provided saliva samples before and after the conversations, which were assayed for cortisol and salivary alpha-amylase (sAA) to determine physiological stress and anxiety responses to conversations about weight. The results indicated that receiving support from one's partner when discussing weight-related issues was associated with greater physiological stress, as indicated by higher cortisol and sAA levels, whereas providing support to one's partner was associated with lower cortisol levels and higher sAA levels. The findings suggest that receiving support is not a universally positive experience, especially for populations facing health issues. The mixed findings for support provision align with previous studies identifying a negative association between affectionate communication and cortisol levels, as well as a positive association between sAA and anxiety and emotional arousal. The findings and their implications for understanding the physiological correlates of couples' conversations about weight are discussed.

Characterization of two photon excited fragment spectroscopy (TPEFS) for HNO3 detection in gas-phase kinetic experiments.

We have developed and tested two-photon excited fragment spectroscopy (TPEFS) for detecting HNO3 in pulsed laser photolysis kinetic experiments. Dispersed (220-330 nm) and time-dependent emission at (310 ± 5) nm following the 193 nm excitation of HNO3 in N2, air and He was recorded and analysed to characterise the OH(A2Σ) and NO(A2Σ+) electronic excited states involved. The limit of detection for HNO3 using TPEFS was ∼5 × 109 molecule cm-3 (at 60 torr N2 and 180 µs integration time). Detection of HNO3 using the emission at (310 ± 5 nm) was orders of magnitude more sensitive than detection of NO and NO2, especially in the presence of O2 which quenches NO(A2Σ+) more efficiently than OH(A2Σ). While H2O2 (and possibly HO2) could also be detected by 193 nm TPEFS, the relative sensitivity (compared to HNO3) was very low. The viability of real-time TPEFS detection of HNO3 using emission at (310 ± 5) nm was demonstrated by monitoring HNO3 formation in the reaction of OH + NO2 and deriving the rate coefficient, k2. The value of k2 obtained at 293 K and pressures of 50-200 torr is entirely consistent with that obtained by simultaneously measuring the OH decay and is in very good agreement with the most recent literature values.

Uncertainty Management and Curve Flattening Behaviors in the Wake of COVID-19's First Wave.

The coronavirus (COVID-19) outbreak poses a substantial threat to public health. Individual efforts to engage in COVID-19 precautionary behaviors are necessary to flatten the pandemic's curve in the waiting period before a vaccine is developed. This study sought to apply the Theory of Motivated Information Management to investigate the relationships among COVID-19 illness uncertainty, information management, and actual precautionary behaviors, both preparatory and preventative. The results of a national opt-in online panel demonstrate that uncertainty discrepancy, anxiety, and information management strategies are key predictors of the adoption of COVID-19 preparation and prevention behaviors. The results further identify diverging associations across age groups with respect to associations between information management and precautionary behaviors. Implications for theory and practice are discussed.

Estimation of economic value for efficiency and animal health and welfare traits, teat and udder structure, in Canadian Angus cattle.

The Canadian Angus Association recently developed genetic evaluations for teat and udder structure, which impact efficiencies, and animal health and welfare. Genetic selection tools are most effective incorporated into economic selection indexes. An important factor in the development of economic indexes is the estimation of the economic value and discounted gene expression coefficients, and thereby the economic weight, of each trait. Traditional estimation methods, interrogation of previous studies quantifying the impact of the traits and bioeconomic modelling, were reinforced using producer surveys that employed pairwise ranking methods. Estimates of discounted genetic expression coefficients, economic value and economic weight for teat and udder score in Canadian Angus cattle were 0.31 per sire, $52.47, and $16.91 per score change on a per calf born basis, respectively, indicating that functional traits such as teat and udder structure have a significant impact on profitability and should be included in genetic selection programmes. Limitations in previous studies illustrate the need for longitudinal studies on traits that impact efficiencies and animal health and welfare.

Beyond heuristics: CFD-based novel multiparameter scale-up for geometrically disparate bioreactors demonstrated at industrial 2kL-10kL scales.

The timely delivery of the most up-to-date medicines and drug products is essential for patients throughout the world. Successful scaling of the bioreactors used within the biopharmaceutical industry plays a large part in the quality and time to market of these products. Scale and topology differences between vessels add a large degree of complication and uncertainty within the scaling process. Currently, this approach is primarily achieved through extensive experimentation and facile empirical correlations, which can be costly and time consuming while providing limited information. The work undertaken in the current study demonstrates a more robust and complete approach using computational fluid dynamics (CFD) to provide potent multiparameter scalability, which only requires geometric and material properties before a comprehensive and detailed solution can be generated. The CFD model output parameters that can be applied in the scale-up include mass transfer rates, mixing times, shear rates, gas hold-up values, and bubble residence times. The authors examined three bioreactors with variable geometries and were able to validate them based on single-phase and multiphase experiments. Furthermore, leveraging the resulting CFD output information enabled the authors to successfully scale-up from a known 2kL to a novel and disparate 5kL single-use bioreactor in the first attempted cell culture. This multiparameter scaling approach promises to ultimately lead to a reduction in the time to market providing patients with earlier access to the most groundbreaking medicines.

Percutaneous thermal ablation for treatment of osteoid osteoma: a systematic review and analysis.

OBJECTIVE: Although radiofrequency ablation is well validated for treatment of osteoid osteoma, newer technologies, namely cryoablation, have been less thoroughly studied. The purpose is to perform a systematic review and pooled analysis of percutaneous ablation technologies for treatment of osteoid osteoma with subset analysis of intra-articular and spinal tumors. MATERIAL AND METHODS: A total of 36 of 79 identified manuscripts met inclusion criteria, comprising 1863 ablations in 1798 patients. Inclusion criteria were (1) retrospective or prospective analysis of thermal ablation of osteoid osteomas in any location, (2) at least 6 months of clinical follow-up, (3) 10 or more patients, (4) patients not included in a second study included in this review, and (5) English language or English translation available. Success rate was defined as all ablations minus technical failures, clinical failures, and recurrences. Subset analysis of intra-articular and spinal tumors was performed. RESULTS: Overall success rate was 91.9% (95% CI 91-93%). Technical failure, clinical failure, and recurrence rates were 0.3%, 2.1%, and 5.6% respectively. Complications were seen in 2.5% (95% CI 1.9-3.3%) patients. There was no significant difference when comparing radiofrequency ablation and cryoablation (p = 0.92). Success rates for intra-articular (radiofrequency ablation) and spinal tumors (radiofrequency and cryoablation) were 97% and 91.6% respectively. CONCLUSION: Percutaneous ablation of osteoid osteomas was highly successful with low complication rates. Efficacy of radiofrequency ablation and cryoablation is similar, which is consequential because cryoablation is associated with decreased pain, predictable nerve regeneration, and theoretical immunotherapy benefits. Treatment of more challenging intra-articular and spinal lesions demonstrated similarly high success and low complication rates.

A novel technique for removing a fibrin sheath from a mediport catheter in the pediatric population.

Mediport (also known as port, portacath or Infusaport) is a commonly placed central venous access in pediatric patients. Fibrin sheath formation around the central venous catheter is a common biological response leading to port malfunction in the form of inability to aspirate but preserved capacity for infusion of fluids. If fibrinolytic therapy fails, percutaneous fibrin sheath stripping via transfemoral route or replacement with a new mediport are routine/conventional treatments for a fibrin sheath. We describe a novel technique for removing a fibrin sheath by exteriorizing the catheter through the neck entry site, stripping the fibrin sheath from the catheter manually under sterile conditions and replacing the catheter via a peel-away sheath introduced through the same skin incision as an alternative to complete port replacement or attempted catheter stripping.

The Longitudinal Effects of Expressive Writing on Victims of Relational Transgressions.

This study investigated the longitudinal effects of written disclosure on physiological and communicative health outcomes for victims of severe relational transgressions in dating relationships. Participants were assigned to a two-step writing condition, a benefit-finding condition, or a control condition to write once a day for three consecutive days on the same topic. Testosterone and forgiveness communication were assessed twice over the course of one-month. The results demonstrate that conditional forgiveness levels were higher for participants in both experimental conditions than in the control condition, whereas neither of the experimental conditions reduced testosterone levels. Across the writing conditions, testosterone levels were negatively associated with conditional forgiveness and positively associated with direct forgiveness. Finally, the results revealed that linguistic features in the writing predicted levels of testosterone and conditional forgiveness.

Multi-subgroup gene screening using semi-parametric hierarchical mixture models and the optimal discovery procedure: Application to a randomized clinical trial in multiple myeloma.

This article proposes an efficient approach to screening genes associated with a phenotypic variable of interest in genomic studies with subgroups. In order to capture and detect various association profiles across subgroups, we flexibly estimate the underlying effect size distribution across subgroups using a semi-parametric hierarchical mixture model for subgroup-specific summary statistics from independent subgroups. We then perform gene ranking and selection using an optimal discovery procedure based on the fitted model with control of false discovery rate. Efficiency of the proposed approach, compared with that based on standard regression models with covariates representing subgroups, is demonstrated through application to a randomized clinical trial with microarray gene expression data in multiple myeloma, and through a simulation experiment.

Genome-wide association scan for heterotic quantitative trait loci in multi-breed and crossbred beef cattle.

BACKGROUND: Heterosis has been suggested to be caused by dominance effects. We performed a joint genome-wide association analysis (GWAS) using data from multi-breed and crossbred beef cattle to identify single nucleotide polymorphisms (SNPs) with significant dominance effects associated with variation in growth and carcass traits and to understand the mode of action of these associations. METHODS: Illumina BovineSNP50 genotypes and phenotypes for 11 growth and carcass traits were available for 6796 multi-breed and crossbred beef cattle. After performing quality control, 42,610 SNPs and 6794 animals were used for further analyses. A single-SNP GWAS for the joint association of additive and dominance effects was conducted in purebred, crossbred, and combined datasets using the ASReml software. Genomic breed composition predicted from admixture analyses was included in the mixed effect model to account for possible population stratification and breed effects. A threshold of 10% genome-wide false discovery rate was applied to declare associations as significant. The significant SNPs with dominance association were mapped to their corresponding genes at 100 kb. RESULTS: Seven SNPs with significant dominance associations were detected for birth weight, weaning weight, pre-weaning daily gain, yearling weight and marbling score across the three datasets at a false discovery rate of 10%. These SNPs were located on bovine chromosomes 1, 3, 4, 6 and 21 and mapped to six putative candidate genes: U6atac, AGBL4, bta-mir-2888-1, REPIN1, ICA1 and NXPH1. These genes have interesting biological functions related to the regulation of gene expression, glucose and lipid metabolism and body fat mass. For most of the identified loci, we observed over-dominance association with the studied traits, such that the heterozygous individuals at any of these loci had greater genotypic values for the trait than either of the homozygous individuals. CONCLUSIONS: Our results revealed very few regions with significant dominance genetic effects across all the traits studied in the three datasets used. Regarding the SNPs that were detected with dominance associations, further investigation is needed to determine their relevance in crossbreeding programs assuming that dominance effects are the main cause of (or contribute usefully to) heterosis.

The Critical Role of Supply Chains in Preventing Human Immunodeficiency Virus Drug Resistance in Low- and Middle-Income Settings.

The functioning of the supply chain may be a driving factor behind the development of human immunodeficiency virus (HIV) drug resistance (HIVDR) in many low- and middle-income countries (LMICs). Additionally, the effectiveness of supply chains will likely impact the scale-up of both viral-load monitoring and HIVDR testing. This article describes the complexities of global supply chains relevant for LMICs and presents early data on stock-outs and drug substitutions in several countries supported by the US President's Emergency Plan for AIDS Relief. Supply chain systems will need to be strengthened to minimize interruptions as new antiretroviral therapy regimens are introduced and to facilitate adoption of new laboratory technologies.

Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial.

BACKGROUND: Patients with advanced sarcomas have a poor prognosis and few treatment options that improve overall survival. Chemotherapy and targeted therapies offer short-lived disease control. We assessed pembrolizumab, an anti-PD-1 antibody, for safety and activity in patients with advanced soft-tissue sarcoma or bone sarcoma. METHODS: In this two-cohort, single-arm, open-label, phase 2 study, we enrolled patients with soft-tissue sarcoma or bone sarcoma from 12 academic centres in the USA that were members of the Sarcoma Alliance for Research through Collaboration (SARC). Patients with soft-tissue sarcoma had to be aged 18 years or older to enrol; patients with bone sarcoma could enrol if they were aged 12 years or older. Patients had histological evidence of metastatic or surgically unresectable locally advanced sarcoma, had received up to three previous lines of systemic anticancer therapy, had at least one measurable lesion according to the Response Evaluation Criteria In Solid Tumors version 1.1, and had at least one lesion accessible for biopsy. All patients were treated with 200 mg intravenous pembrolizumab every 3 weeks. The primary endpoint was investigator-assessed objective response. Patients who received at least one dose of pembrolizumab were included in the safety analysis and patients who progressed or reached at least one scan assessment were included in the activity analysis. Accrual is ongoing in some disease cohorts. This trial is registered with ClinicalTrials.gov, number NCT02301039. FINDINGS: Between March 13, 2015, and Feb 18, 2016, we enrolled 86 patients, 84 of whom received pembrolizumab (42 in each disease cohort) and 80 of whom were evaluable for response (40 in each disease cohort). Median follow-up was 17·8 months (IQR 12·3-19·3). Seven (18%) of 40 patients with soft-tissue sarcoma had an objective response, including four (40%) of ten patients with undifferentiated pleomorphic sarcoma, two (20%) of ten patients with liposarcoma, and one (10%) of ten patients with synovial sarcoma. No patients with leiomyosarcoma (n=10) had an objective response. Two (5%) of 40 patients with bone sarcoma had an objective response, including one (5%) of 22 patients with osteosarcoma and one (20%) of five patients with chondrosarcoma. None of the 13 patients with Ewing's sarcoma had an objective response. The most frequent grade 3 or worse adverse events were anaemia (six [14%]), decreased lymphocyte count (five [12%]), prolonged activated partial thromboplastin time (four [10%]), and decreased platelet count (three [7%]) in the bone sarcoma group, and anaemia, decreased lymphocyte count, and prolonged activated partial thromboplastin time in the soft-tissue sarcoma group (three [7%] each). Nine (11%) patients (five [12%] in the bone sarcoma group and four [10%] in the soft-tissue sarcoma group) had treatment-emergent serious adverse events (SAEs), five of whom had immune-related SAEs, including two with adrenal insufficiency, two with pneumonitis, and one with nephritis. INTERPRETATION: The primary endpoint of overall response was not met for either cohort. However, pembrolizumab showed encouraging activity in patients with undifferentiated pleomorphic sarcoma or dedifferentiated liposarcoma. Enrolment to expanded cohorts of those subtypes is ongoing to confirm and characterise the activity of pembrolizumab. FUNDING: Merck, SARC, Sarcoma Foundation of America, QuadW Foundation, Pittsburgh Cure Sarcoma, and Ewan McGregor.

Host conditioning and rejection monitoring in hepatocyte transplantation in humans.

BACKGROUND & AIMS: Hepatocyte transplantation partially corrects genetic disorders and has been associated anecdotally with reversal of acute liver failure. Monitoring for graft function and rejection has been difficult, and has contributed to limited graft survival. Here we aimed to use preparative liver-directed radiation therapy, and continuous monitoring for possible rejection in an attempt to overcome these limitations. METHODS: Preparative hepatic irradiation was examined in non-human primates as a strategy to improve engraftment of donor hepatocytes, and was then applied in human subjects. T cell immune monitoring was also examined in human subjects to assess adequacy of immunosuppression. RESULTS: Porcine hepatocyte transplants engrafted and expanded to comprise up to 15% of irradiated segments in immunosuppressed monkeys preconditioned with 10Gy liver-directed irradiation. Two patients with urea cycle deficiencies had early graft loss following hepatocyte transplantation; retrospective immune monitoring suggested the need for additional immunosuppression. Preparative radiation, anti-lymphocyte induction, and frequent immune monitoring were instituted for hepatocyte transplantation in a 27year old female with classical phenylketonuria. Post-transplant liver biopsies demonstrated multiple small clusters of transplanted cells, multiple mitoses, and Ki67+ hepatocytes. Mean peripheral blood phenylalanine (PHE) level fell from pre-transplant levels of 1343±48µM (normal 30-119µM) to 854±25µM (treatment goal ≤360µM) after transplant (36% decrease; p<0.0001), despite transplantation of only half the target number of donor hepatocytes. PHE levels remained below 900µM during supervised follow-up, but graft loss occurred after follow-up became inconsistent. CONCLUSIONS: Radiation preconditioning and serial rejection risk assessment may produce better engraftment and long-term survival of transplanted hepatocytes. Hepatocyte xenografts engraft for a period of months in non-human primates and may provide effective therapy for patients with acute liver failure. LAY SUMMARY: Hepatocyte transplantation can potentially be used to treat genetic liver disorders but its application in clinical practice has been impeded by inefficient hepatocyte engraftment and the inability to monitor rejection of transplanted liver cells. In this study, we first show in non-human primates that pretreatment of the host liver with radiation improves the engraftment of transplanted liver cells. We then used this knowledge in a series of clinical hepatocyte transplants in patients with genetic liver disorders to show that radiation pretreatment and rejection risk monitoring are safe and, if optimized, could improve engraftment and long-term survival of transplanted hepatocytes in patients.