Developing deep learning-based strategies to predict the risk of hepatocellular carcinoma among patients with nonalcoholic fatty liver disease from electronic health records.

OBJECTIVE: The accuracy of deep learning models for many disease prediction problems is affected by time-varying covariates, rare incidence, covariate imbalance and delayed diagnosis when using structured electronic health records data. The situation is further exasperated when predicting the risk of one disease on condition of another disease, such as the hepatocellular carcinoma risk among patients with nonalcoholic fatty liver disease due to slow, chronic progression, the scarce of data with both disease conditions and the sex bias of the diseases. The goal of this study is to investigate the extent to which the aforementioned issues influence deep learning performance, and then devised strategies to tackle these challenges. These strategies were applied to improve hepatocellular carcinoma risk prediction among patients with nonalcoholic fatty liver disease. METHODS: We evaluated two representative deep learning models in the task of predicting the occurrence of hepatocellular carcinoma in a cohort of patients with nonalcoholic fatty liver disease (n = 220,838) from a national EHR database. The disease prediction task was carefully formulated as a classification problem while taking censorship and the length of follow-up into consideration. RESULTS: We developed a novel backward masking scheme to deal with the issue of delayed diagnosis which is very common in EHR data analysis and evaluate how the length of longitudinal information after the index date affects disease prediction. We observed that modeling time-varying covariates improved the performance of the algorithms and transfer learning mitigated reduced performance caused by the lack of data. In addition, covariate imbalance, such as sex bias in data impaired performance. Deep learning models trained on one sex and evaluated in the other sex showed reduced performance, indicating the importance of assessing covariate imbalance while preparing data for model training. CONCLUSIONS: The strategies developed in this work can significantly improve the performance of hepatocellular carcinoma risk prediction among patients with nonalcoholic fatty liver disease. Furthermore, our novel strategies can be generalized to apply to other disease risk predictions using structured electronic health records, especially for disease risks on condition of another disease.

Developing deep learning-based strategies to predict the risk of hepatocellular carcinoma among patients with nonalcoholic fatty liver disease from electronic health records.

Background: Deep learning models showed great success and potential when applied to many biomedical problems. However, the accuracy of deep learning models for many disease prediction problems is affected by time-varying covariates, rare incidence, and covariate imbalance when using structured electronic health records data. The situation is further exasperated when predicting the risk of one disease on condition of another disease, such as the hepatocellular carcinoma risk among patients with nonalcoholic fatty liver disease due to slow, chronic progression, the scarce of data with both disease conditions and the sex bias of the diseases. Objective: The goal of this study is to investigate the extent to which time-varying covariates, rare incidence, and covariate imbalance influence deep learning performance, and then devised strategies to tackle these challenges. These strategies were applied to improve hepatocellular carcinoma risk prediction among patients with nonalcoholic fatty liver disease. Methods: We evaluated two representative deep learning models in the task of predicting the occurrence of hepatocellular carcinoma in a cohort of patients with nonalcoholic fatty liver disease (n = 220,838) from a national EHR database. The disease prediction task was carefully formulated as a classification problem while taking censorship and the length of follow-up into consideration. Results: We developed a novel backward masking scheme to evaluate how the length of longitudinal information after the index date affects disease prediction. We observed that modeling time-varying covariates improved the performance of the algorithms and transfer learning mitigated reduced performance caused by the lack of data. In addition, covariate imbalance, such as sex bias in data impaired performance. Deep learning models trained on one sex and evaluated in the other sex showed reduced performance, indicating the importance of assessing covariate imbalance while preparing data for model training. Conclusions: Devising proper strategies to address challenges from time-varying covariates, lack of data, and covariate imbalance can be key to counteracting data bias and accurately predicting disease occurrence using deep learning models. The novel strategies developed in this work can significantly improve the performance of hepatocellular carcinoma risk prediction among patients with nonalcoholic fatty liver disease. Furthermore, our novel strategies can be generalized to apply to other disease risk predictions using structured electronic health records, especially for disease risks on condition of another disease.

Unsaturated or saturated dietary fat-mediated steatosis impairs hepatic regeneration following partial hepatectomy in mice.

BACKGROUND: Partial hepatectomy is a preferred treatment option for many patients with hepatocellular carcinoma however, pre-existing pathological abnormalities originating from hepatic steatosis can alter the decision to perform surgery or postoperative outcomes as a consequence of the impact steatosis has on liver regeneration. AIM: The aim of this study was to investigate the role of a saturated or unsaturated high fat diet-mediated steatosis on liver regeneration following partial hepatectomy. METHODS: Mice were fed a low-fat control diet (CD, 13% fat), lard-based unsaturated (LD, 60% fat) or milk-based saturated high fat diet (MD, 60% fat) for 16 weeks at which time partial hepatectomy (approx. 70% resection) was performed. At days-2 and 7 post hepatectomy, one hour prior to euthanization, mice were injected with 5-bromo-2'-deoxyuridine in order to monitor hepatic regeneration. Serum was collected and assessed for levels of ALT and AST. Resected and regenerated liver tissue were examined for inflammation-indicative markers employing RT-PCR, Western blots, and histological methods. RESULTS: Mice fed LD or MD exhibited higher NAFLD scores, increased expression of inflammatory cytokines, neutrophil infiltration, macrophage accumulation, increased apoptosis, and elevated levels of serum ALT and AST activities, a decrease in the number of BrdU-incorporated-hepatocytes in the regenerated livers compared to the mice fed CD. Mice fed MD showed significantly lower percent of BrdU-incorporated hepatocytes and a higher trend of inflammation compared to the mice fed LD. CONCLUSION: A diet rich in saturated or unsaturated fat results in NASH with decreased hepatic regeneration however unsaturated fat diet cause lower inflammation and higher regeneration than the saturated fat diet following partial hepatectomy in mice.

Medicaid expansion is associated with a higher likelihood of early diagnosis, resection, transplantation, and overall survival in patients with hepatocellular carcinoma.

BACKGROUND: We examined the association between Medicaid expansion (ME) and the diagnosis, treatment, and survival of patients with hepatocellular carcinoma (HCC). METHODS: We identified patients with HCC <65yrs with Medicaid or without insurance within the National Cancer Database before (2010-2013) or after (2015-2017) ME with early (cT1) or intermediate/advanced (cT2-T4 or M1) disease. RESULTS: We identified 4848 patients with HCC before and 4526 after ME. Prior to ME, there was no association between future ME status and diagnosis of early HCC (34.5% vs. 32.9%). There was no association between future ME status and treating early HCC with ablation, resection, or transplantation. Patients with early HCC in future ME states were less likely to die (HR = 0.81, 95% CI: 0.67-0.98). After ME, patients in ME states were more likely to be diagnosed with early HCC (39.2% vs. 32.1%). Patients with early disease in ME states were more likely to undergo resection (OR=1.78, 95% CI: 1.16-2.75) or transplantation (OR=3.20, 95% CI: 1.40-7.33). There was a further associated decrease in the hazard of death (HR=0.68, 95% CI: 0.54-0.86). CONCLUSION: ME was associated with early diagnosis of HCC. For early HCC, ME was associated with increased utilization of resection and transplantation and improvement in survival.

A nationwide analysis of clinical trial participation for common hepato-pancreato-biliary malignancies demonstrates survival advantages for subsets of trial patients but disparities in and infrequency of enrollment.

BACKGROUND: We describe factors associated with trial enrollment for patients with hepato-pancreato-biliary (HPB) malignancies. We analyzed the association and effect of trial enrollment on overall survival (OS). METHODS: The National Cancer Database (2004-2017) was queried for common HPB malignancies (pancreatic adenocarcinoma [PDAC] & neuroendocrine tumors, hepatocellular carcinoma [HCC], biliary tract cancers [BTC]). Multivariable logistic regression was used to identify factors associated with trial enrollment. OS was analyzed by multivariable Cox regression. Inverse-probability-weighted Cox regression was utilized to determine the effect of trial enrollment on OS. RESULTS: A total of 1573 (0.3%) of 511,639 patients were enrolled in trials; pancreatic malignancy: 1214 (0.4%); HCC: 217 (0.14%); BTC: 106 (0.15%). HCC and BTC were associated with lower likelihood of enrollment compared with pancreatic malignancy. Black and Hispanic patients were less likely to be enrolled compared to White patients. Treatment at academic facilities and metastatic disease were associated with higher likelihood of enrollment. Enrollment was associated with higher OS for PDAC, metastatic HCC, and metastatic BTC. Trial enrollment exhibited an OS advantage for PDAC and metastatic HCC. CONCLUSION: Nationally, fewer than 1% of patients with HPB malignancies were enrolled in clinical trials. There are racial, sociodemographic, and facility-based disparities in trial enrollment.

Black race is independently associated with underutilization of transplantation for clinical T1 hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality. Operative management of early disease includes ablation, resection, and transplantation. We compared the operative management of early-stage HCC in patients stratified by race. METHODS: We identified patients with cT1 HCC and Charlson-Deyo score 0-1 in the National Cancer Database (2004-2016). We compared operative/non-operative management by race, adjusting for clinicodemographic variables. We performed marginal standardization of logistic regression to ascertain adjusted probabilities of resection or transplantation in patients under 70 years of age with insurance. RESULTS: A total of 25,029 patients were included (White = 20,410; Black = 4619). After adjusting for clinico demographic variables, Black race was associated with a lower likelihood of undergoing operative intervention (OR 0.89,p = 0.009). Black patients were more likely to undergo resection (OR 1.23,p < 0.001) and less likely to undergo transplantation (OR 0.60,p < 0.001). Marginal standardization models demonstrated Black race was associated with increased probability of resection in patients >50yrs, with private insurance/Medicare, and lower probability of transplantation regardless of age or insurance payor. CONCLUSION: Black race is associated with lower rates of hepatic transplantation and higher rates of hepatic resection for early HCC regardless of age or insurance payor. The etiology of these disparities is multifactorial and correcting the root causes represents a critical area for improvement.

Outcomes of Surgical Mitral and Aortic Valve Replacements Among Kidney Transplant Candidates: Implications for Valve Selection.

Background Limited literature exists that evaluated outcomes of kidney transplant-eligible patients who are having dialysis and who are undergoing valve replacement. Our main objective in this study was to compare mortality, reoperation, and bleeding episodes between bioprosthetic and mechanical valve procedures among kidney transplant-eligible patients who are having dialysis. Methods and Results We studied 887 and 1925 dialysis patients from the United States Renal Data System, who underwent mitral valve replacement and aortic valve replacement (AVR) after being waitlisted for a kidney transplant (2000-2015), respectively. Time to death, time to reoperation, and time to bleeding requiring hospitalizations were compared separately for AVR and mitral valve replacement. Kaplan-Meier survival curves, Cox proportional hazards model for time to death, accelerated time to event model for time to reoperation, and counting process model for time to recurrent bleeding were used. There were no differences in mortality (hazard ratio [HR], 0.92; 95% CI, 0.77-1.09) or risk of reoperation or risk of significant bleeding events between bioprosthetic and mechanical mitral valve replacement. However, mechanical AVR was associated with a modestly significant less hazard of death (HR, 0.83; 95% CI, 0.74-0.94) compared with bioprosthetic AVR. There were no differences in time to reoperation, or time to significant bleeding events between bioprosthetic and mechanical AVR. Conclusions For kidney transplant waitlisted patients who are on dialysis and who are undergoing surgical valve replacement, bioprosthetic and mechanical valves have comparable survival, reoperation rates, and bleeding episodes requiring hospitalizations at both mitral and aortic locations. These findings emphasize that an individualized informed decision is recommended when choosing the type of valve for this special group of patients having dialysis.

A comparison of surgical resection and liver transplantation in the treatment of intrahepatic cholangiocarcinoma in the era of modern chemotherapy: An analysis of the National Cancer Database.

BACKGROUND: The main surgical approach to patients with localized intrahepatic cholangiocarcinoma (ICC) is hepatectomy, but transplantation has been described. A comparison of outcomes between these surgical approaches is necessary to determine if one is preferable. METHODS: Patients with ICC were identified using the National Cancer Database (2010-2016). Patients were grouped based on operation and matched 1:1 by propensity score. Pathologic and postoperative outcomes, as well as overall survival were analyzed. RESULTS: There were 1879 hepatectomy and 74 liver transplantation patients. Before matching, transplantation patients were younger and more often treated at academic centers. More patients who underwent a transplantation received neoadjuvant chemotherapy (70.3% vs. 12.8%). Patients who underwent transplantation had more pathologic T0 (7.7% vs. 0.4%) and T1 (47.7% vs. 42.1%) tumors (p < .001). There were no differences in length of stay, unplanned readmissions, 30/90-day mortality, or median survival between groups (36.1 vs. 36.1 months, p = .34). After matching (n = 57/group), there were no differences in postoperative outcomes or survival between transplantation or hepatectomy (36.1 vs. 33.6 months, p = .57). CONCLUSION: Among patients with ICC, hepatectomy and liver transplantation were associated with similar postoperative outcomes and survival. In light of the resources and chronic immunosuppression required for transplantation, hepatectomy seems preferable for localized ICC.

Predictors of Outcomes of COVID-19 in Patients With Chronic Liver Disease: US Multi-center Study.

BACKGROUND & AIMS: Chronic liver disease (CLD) represents a major global health burden. We undertook this study to identify the factors associated with adverse outcomes in patients with CLD who acquire the novel coronavirus-2019 (COVID-19). METHODS: We conducted a multi-center, observational cohort study across 21 institutions in the United States (US) of adult patients with CLD and laboratory-confirmed diagnosis of COVID-19 between March 1, 2020 and May 30, 2020. We performed survival analysis to identify independent predictors of all-cause mortality and COVID-19 related mortality, and multivariate logistic regression to determine the risk of severe COVID-19 in patients with CLD. RESULTS: Of the 978 patients in our cohort, 867 patients (mean age 56.9 ± 14.5 years, 55% male) met inclusion criteria. The overall all-cause mortality was 14.0% (n = 121), and 61.7% (n = 535) had severe COVID-19. Patients presenting with diarrhea or nausea/vomiting were more likely to have severe COVID-19. The liver-specific factors associated with independent risk of higher overall mortality were alcohol-related liver disease (ALD) (hazard ratio [HR] 2.42, 95% confidence interval [CI] 1.29-4.55), decompensated cirrhosis (HR 2.91 [1.70-5.00]) and hepatocellular carcinoma (HCC) (HR 3.31 [1.53-7.16]). Other factors were increasing age, diabetes, hypertension, chronic obstructive pulmonary disease and current smoker. Hispanic ethnicity (odds ratio [OR] 2.33 [1.47-3.70]) and decompensated cirrhosis (OR 2.50 [1.20-5.21]) were independently associated with risk for severe COVID-19. CONCLUSIONS: The risk factors which predict higher overall mortality among patients with CLD and COVID-19 are ALD, decompensated cirrhosis and HCC. Hispanic ethnicity and decompensated cirrhosis are associated with severe COVID-19. Our results will enable risk stratification and personalization of the management of patients with CLD and COVID-19. Clinicaltrials.gov number NCT04439084.

Management of disappearing colorectal liver metastases: an international survey.

BACKGROUND: Improved chemotherapy response rates have lead to "disappearing" colorectal liver metastases (dCRLM). We aim to assess management patterns of dCRLM from an international body of hepatobiliary surgeons. METHODS: A survey was designed, tested for item relevance, readability and content validity, and distributed to the AHPBA, IHPBA and ANZHPBA. RESULTS: The majority of 226 respondents were <15 years from training (69%), practiced in academia (82%) and devoted >50% of their practice to hepatobiliary (75%). Surgeons utilize CT(45%) or MRI(47%) for preoperative planning with a preferred imaging interval of <6 weeks. Nearly all have experienced dCRLM (99%) and 63% of surgeons have waited a few months to assess for durability of response prior to definitive surgical/ablative therapy. Only 24% place fiducial markers for lesions <1-cm prior to neoadjuvant chemotherapy. Intra-operatively, 97% of surgeons perform ultrasound, and 71% ablation. When a tumor has "disappeared," 49% elect for observation and 31% resect if the dCRLM is superficial. Of those electing observation, 87% believe there is effective treatment with progression on surveillance imaging. CONCLUSIONS: Nearly all surgeons have experienced dCRLM with half choosing observation over intervention due to the belief that these lesions may be re-addressed in the future.

Surgical Duct-to-Duct Reconstruction: an Alternative Approach to Late Biliary Anastomotic Stricture After Deceased Donor Liver Transplantation.

BACKGROUND: Bilio-enteric diversion is the current surgical standard in patients after deceased donor liver transplantation (DDLT) with a biliary anastomotic stricture failing interventional treatment and requiring surgical repair. In contrast to this routine, the aim of this study was to show the feasibility and safety of a duct-to-duct biliary reconstruction. PATIENTS: Between 2012 and 2019, we performed a total of 308 DDLT in 292 adult patients. The overall biliary complication rate was 20.5%. Patients with non-anastomotic or combined strictures were excluded from this analysis. Out of 273 patients after a primary duct-to-duct reconstruction, 20 (7.3%) developed late isolated AS. Seven of these patients failed interventional biliary treatment and required a surgical repair. RESULTS: Duct-to-duct reconstruction was feasible and successful in all patients. Liver function tests fully normalized and no patient required any form of biliary intervention after surgery. One patient with intraoperative cholangiosepsis was ICU bound for 5 days, and another patient with a subhepatic abscess required percutaneous drainage. There was no perioperative death. The median length of hospital stay was 8 (5-17) days. The median time of follow-up after relaparotomy was 1593 (434-2495) days. CONCLUSION: Duct-to-duct reconstruction is a feasible and safe option in selected patients requiring surgical repair for isolated AS after DDLT. This approach preserves the biliary anatomy and avoids the potential side effects of a bilio-enteric diversion.

Liver Injury in Liver Transplant Recipients With Coronavirus Disease 2019 (COVID-19): U.S. Multicenter Experience.

BACKGROUND AND AIMS: Coronavirus disease 2019 (COVID-19) is associated with liver injury, but the prevalence and patterns of liver injury in liver transplantation (LT) recipients with COVID-19 are open for study. APPROACH AND RESULTS: We conducted a multicenter study in the United States of 112 adult LT recipients with COVID-19. Median age was 61 years (interquartile range, 20), 54.5% (n = 61) were male, and 39.3% (n = 44) Hispanic. Mortality rate was 22.3% (n = 25); 72.3% (n = 81) were hospitalized and 26.8% (n = 30) admitted to the intensive care unit (ICU). Analysis of peak values of alanine aminotransferase (ALT) during COVID-19 showed moderate liver injury (ALT 2-5× upper limit of normal [ULN]) in 22.2% (n = 18) and severe liver injury (ALT > 5× ULN) in 12.3% (n = 10). Compared to age- and sex-matched nontransplant patients with chronic liver disease and COVID-19 (n = 375), incidence of acute liver injury was lower in LT recipients (47.5% vs. 34.6%; P = 0.037). Variables associated with liver injury in LT recipients were younger age (P = 0.009; odds ratio [OR], 2.06; 95% confidence interval [CI], 1.20-3.54), Hispanic ethnicity (P = 0.011; OR, 6.01; 95% CI, 1.51-23.9), metabolic syndrome (P = 0.016; OR, 5.87; 95% CI, 1.38-24.99), vasopressor use (P = 0.018; OR, 7.34; 95% CI, 1.39-38.52), and antibiotic use (P = 0.046; OR, 6.93; 95% CI, 1.04-46.26). Reduction in immunosuppression (49.4%) was not associated with liver injury (P = 0.156) or mortality (P = 0.084). Liver injury during COVID-19 was significantly associated with mortality (P = 0.007; OR, 6.91; 95% CI, 1.68-28.48) and ICU admission (P = 0.007; OR, 7.93; 95% CI, 1.75-35.69) in LT recipients. CONCLUSIONS: Liver injury is associated with higher mortality and ICU admission in LT recipients with COVID-19. Hence, monitoring liver enzymes closely can help in early identification of patients at risk for adverse outcomes. Reduction of immunosuppression during COVID-19 did not increase risk for mortality or graft failure.

Peroxisomal footprint in the pathogenesis of nonalcoholic steatohepatitis.

Nonalcoholic steatohepatitis (NASH) is a form of fatty liver disease where benign hepatic steatosis leads to chronic inflammation in the steatotic liver of a patient without any history of alcohol abuse. Mechanisms underlying the progression of hepatic steatosis to NASH have long been investigated. This review outlines the potential role of peroxisomal dysfunctions in exacerbating the disease in NASH. Loss of peroxisomes as well as impaired peroxisomal functions have been demonstrated to occur in inflammatory conditions including NASH. Because peroxisomes and mitochondria co-operatively perform many metabolic functions including O2 and lipid metabolisms, a compromised peroxisomal biogenesis and function can potentially contribute to defective lipid and reactive oxygen species metabolism which in turn can lead the progression of disease in NASH. Impaired peroxisomal biogenesis and function may be due to the decreased expression of peroxisomal proliferator-activated receptor-α (PPAR-α), the major transcription factor of peroxisomal biogenesis. Recent studies indicate that the reduced expression of PPAR-α in NASH is correlated with the activation of the toll-like receptor-4 pathway (TLR-4). Further investigations are required to establish the mechanistic connection between the TLR-4 pathway and PPAR-α-dependent impaired biogenesis/function of peroxisomes in NASH.

Post-Reperfusion Syndrome in Liver Transplantation: Does a Caval Blood Flush Vent Help?

BACKGROUND Post-reperfusion syndrome (PRS) during liver transplantation can range from a benign event to a profound hemodynamic excursion from baseline with significant morbidity. Multiple variables can be responsible for the diverse presentations. Over time, our group noticed that a blood flush of the liver graft via a caval vent (in addition to a standard chilled flush via the portal vein) appeared to result in a milder reperfusion effect. Attenuation of PRS via caval vent seemed to minimize hemodynamic instability and reduce metabolic derangements associated with reperfusion. MATERIAL AND METHODS This was a prospective observational pilot study of standard practice with the addition of lab values and hemodynamic evaluations. We methodically observed normal clinical flow in 20 adult orthotopic liver transplant recipients. We analyzed blood and fluid samples at set time intervals during the peri-reperfusion phase. RESULTS Sixteen out of 20 patients received a blood flush via caval venting. Mean arterial pressure (MAP) and heart rate were better preserved in the patient population that received a caval blood flush vent. Elevations in central venous pressure (CVP) were similar between the 2 groups. Lab values (blood gas, electrolyte, and hemoglobin) of the patients' blood were similar, with no notable differences. Analysis of the initial blood flushed through the liver graft proved to be hypothermic, acidotic, and hyperkalemic. CONCLUSIONS Pre-reperfusion caval venting in liver transplantation (in addition to a portal vent and a chilled LR/albumin portal flush solution) appears to have favorable hemodynamic effects. The literature on this technique is sparse and larger studies are needed.

Safety and benefits of new techniques and technologies in less invasive mitral valve repair.

OBJECTIVE: To assess the safety and benefits of new techniques and technologies such as single-dose (del Nido) cardioplegia and suture fasteners (COR-KNOT) in patients undergoing mini-thoracotomy for degenerative mitral valve repair (MVR). METHODS: From 2009 to 2016, 252 patients underwent primary isolated degenerative MVR by mini-thoracotomy by a single surgeon. Del Nido cardioplegia was used in 153 patients (61%) and COR-KNOT in 168 (67%). Patient outcomes were compared using propensity-matching separately for del Nido versus Buckberg cardioplegia and COR-KNOT versus knot-pusher. RESULTS: There were no operative deaths and 99.2% of the patients had none/trivial mitral regurgitation at discharge. In patients receiving del Nido or Buckberg cardioplegia, occurrence of adverse events was similar. However, aortic cross clamp (AoCC; 54.2 ± 15.7 vs 64 ± 15.8 min; P < 0.0001) and operative room (OR; 308 ± 42.1 vs 336 ± 63 min; P < 0.001) times were shorter with del Nido cardioplegia. In patients receiving COR-KNOT versus knot-pusher, occurrence of adverse events was similar. However, AoCC (54.1 ± 15.2 vs 66.1 ± 15.9 min; P < 0.0001) and OR (311 ± 43.6 vs 336 ± 65.4 min; P < 0.0001) times were shorter with COR-KNOT. Results were similar after matching for both, del Nido versus Buckberg cardioplegia and COR-KNOT versus knot-pusher. CONCLUSION: New techniques and technologies, such as del Nido cardioplegia and COR-KNOT, decrease AoCC and OR times without compromising patient safety.

Assessment of risk factors for increased resource utilization in kidney transplantation.

BACKGROUND: There are only a limited number of studies that have sought to identify patients at high risk for medication errors and subsequent adverse clinical outcomes. This study sought to identify risk factors for increased health care resource utilization in kidney transplant recipients based on drug-related problems and self-administered surveys. METHODS: In this prospective observational study, adult kidney transplant recipients seen in the transplant clinic between September and November 2015 were surveyed for self-reported demographics, medication adherence, and health status/outlook. Subsequently, patients were assessed for associations between survey results, pharmacist-derived drug-related problems, and health resource utilization over a minimum 6-mo follow-up period. Based on univariate associations, two risk cohorts were identified and compared for health care utilization using multivariable Poisson regression. RESULTS: A total of 237 patients were included, with a mean follow-up of 8 mo. From the patient survey data, Medicaid insured or self-rated poor health status were identified as a significant risk cohort. From pharmacist assessments, those who received incorrect medication or lacked appropriate follow-up medication monitoring were identified as a significant risk cohort (pharmacy errors). The Medicaid insured or self-rated poor health status cohort experienced 43% more total health care encounters (incident rate ratios [IRR] 1.43, 1.01-2.02) and 35% more transplant clinic visits (IRR 1.35, 1.03-1.77). The pharmacy errors cohort experienced 4.2 times the rate of total health care encounters (IRR 4.17, 1.55-11.2), 4.1 times the rate of hospital readmissions (IRR 4.09, 1.58-10.6), and 2.3 times the rate of transplant clinic visits (IRR 2.31, 1.04-5.11). CONCLUSIONS: Medicaid insurance, self-rated poor health status, and errors in the medication regimen or monitoring were significant risk factors for increased health care utilization in kidney transplant recipients. Further research is warranted to validate these potential risk factors, determine the long-term impact on graft/patient survival, and assess the mutability of these risks through prospective identification and intervention.

Natural immunoglobulin M initiates an inflammatory response important for both hepatic ischemia reperfusion injury and regeneration in mice.

Complement plays a role in both hepatic ischemia reperfusion (IR) injury (IRI) and liver regeneration, but it is not clear how complement is activated in either process. We investigated the role of self-reactive immunoglobulin M (IgM) antibodies in activating complement after hepatic IR and liver resection. Natural IgM antibodies that recognize danger-associated molecular patterns (neoepitopes) activate complement following both hepatic IR and liver resection. Antibody-deficient Rag1-/- mice were protected from hepatic IRI, but had increased hepatic injury and an impaired regenerative response after 70% partial hepatectomy (PHx). We identified two IgM monoclonal antibodies (mAbs) that specifically reversed the effect of Rag1 deficiency in both models; B4 (recognizes Annexin IV) and C2 (recognizes subset of phospholipids). Focusing on the B4-specific response, we demonstrated sinusoidal colocalization of IgM and C3d in Rag1-/- mice that were reconstituted with B4 mAb, and furthermore that the Annexin IV neoepitope is specifically and similarly expressed after both hepatic IR and PHx in wild-type (WT) mice. A single-chain antibody construct (scFv) derived from B4 mAb blocked IgM binding and reduced injury post-IR in WT mice, although, interestingly, B4scFv did not alter regeneration post-PHx, indicating that anti-Annexin IV antibodies are sufficient, but not necessary, for the regenerative response in the context of an entire natural antibody repertoire. We also demonstrated expression of the B4 neoepitope in postischemic human liver samples obtained posttransplantation and a corollary depletion in IgM recognizing the B4 and C2 neoepitopes in patient sera following liver transplantation. Conclusion: These data indicate an important role for IgM in hepatic IRI and regeneration, with a similar cross-species injury-specific recognition system that has implications for the design of neoepitope targeted therapeutics. (Hepatology 2018;67:721-735).

Morbid obesity and functional status as predictors of surgical complication after renal transplantation.

BACKGROUND: This study evaluated the impact of body mass index (BMI) and patient functional status on the risk for surgical complications after kidney transplant. METHODS: This retrospective cohort study of adult kidney transplant recipients grouped patients by baseline Karnofsky status (low function ≤ 70%) and further stratified by morbid obesity (BMI ≥ 35 kg/m2) to assess surgical complication risk. RESULTS: 736 patients were included with surgical complications occurring in 25%. Logistic regression analysis with interaction terms demonstrated that morbid obesity and low functional status conditionally impact risk with an OR of 2.8 [95% CI (1.1-7.3)]. Within the functional status cohort, BMI ≥35 kg/m2 was associated with increased risk of surgical complication, superficial wound infection, and DGF. Independent predictors for surgical complications included diabetes and morbid obesity with low functional status. There was no significant difference in graft loss or death across the cohorts. CONCLUSIONS: While neither morbid obesity nor poor functional status alone predicts increased complications, the combined presence is associated with significant increase in risk for surgical complications after renal transplantation.

Valganciclovir (VGCV) followed by cytomegalovirus (CMV) hyperimmune globulin compared to VGCV for 200 days in abdominal organ transplant recipients at high risk for CMV infection: A prospective, randomized pilot study.

BACKGROUND: With the advent of effective antivirals against cytomegalovirus (CMV), use of CMV hyperimmune globulin (HIG) has decreased. Although antiviral prophylaxis in patients at high risk for CMV is effective, many patients still have late infection, never developing antibodies sufficient to achieve immunity. Utilizing a combination of antiviral and CMV HIG may allow patients to achieve immunity and decrease late CMV infections. METHODS: This was a prospective randomized, open-label, pilot study comparing valganciclovir (VGCV) prophylaxis for 200 days vs VGCV for 100 days followed by CMV HIG in abdominal transplant recipients at high risk for CMV. The primary outcome was a comparison of late CMV disease. RESULTS: Forty patients were randomized to VGCV for 200 days (n = 20) or VGCV for 100 days followed by 3 doses of monthly CMV HIG (n = 20). Numerically, more overall CMV infections occurred in the CMV HIG group (45 vs 20%, P = .09). No differences in overall CMV infections or late CMV disease were seen between groups (20% vs 15%, P = 1.00 and 0 vs 0, P = 1.00). All CMV disease occurred within 200 days, with 63% occurring while patients were on VGCV. No differences were found in toxicities, graft function, or rejection between groups. Patients with CMV infection at any time had a higher body weight than those who did not have an infection (82 vs 95 kg, P = .049). CONCLUSION: Use of CMV HIG sequentially with prophylaxis may be an effective and affordable prophylactic regimen in abdominal transplant recipients at high risk for CMV, and warrants larger prospective study. Increased monitoring for patients with obesity may be warranted.

Design and approach of the Living Organ Video Educated Donors (LOVED) program to promote living kidney donation in African Americans.

PURPOSE: To describe the rationale, methodology, design, and interventional approach of a mobile health education program designed for African Americans with end stage renal disease (ESRD) to increase knowledge and self-efficacy to approach others about their need for a living donor kidney transplant (LDKT). METHODS: The Living Organ Video Educated Donors (LOVED) program is a theory-guided iterative designed, mixed methods study incorporating three phases: 1) a formative evaluation using focus groups to develop program content and approach; 2) a 2-month proof of concept trial (n=27) to primarily investigate acceptability, tolerability and investigate increases of LDKT knowledge and self-efficacy; and 3) a 6-month, 2-arm, 60-person feasibility randomized control trial (RCT) to primarily investigate increases in LDKT knowledge and self-efficacy, and secondarily, to increase the number of living donor inquiries, medical evaluations, and LDKTs. The 8-week LOVED program includes an interactive web-based app delivered on 10″ tablet computer incorporating weekly interactive video education modules, weekly group video chat sessions with an African American navigator who has had LDKT and other group interactions for support and improve strategies to promote their need for a kidney. RESULTS: Phase 1 and 2 have been completed and the program is currently enrolling for the feasibility RCT. Phase 2 experienced 100% retention rates with 91% adherence completing the video modules and 88% minimum adherence to the video chat sessions. CONCLUSIONS: We are in the early stages of an RCT to evaluate the LOVED program; to date, we have found high tolerability reported from Phase 2.