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Objective To develop machine learning models that can predict post-transplantation major adverse cardiovascular events (MACE), all-cause mortality, and cardiovascular mortality in patients undergoing liver transplantation (LT). Design Retrospective cohort study. Setting High-volume tertiary care center. Participants The study comprised 1,459 consecutive patients undergoing LT between January 2008 and December 2019. Interventions None. Measurements and Main Results MACE, all-cause mortality, and cardiovascular mortality were modeled using logistic regression, least absolute shrinkage and selection surgery regression, random forests, support vector machine, and gradient-boosted modeling (GBM). All models were built by splitting data into training and testing cohorts, and performance was assessed using five-fold cross-validation based on the area under the receiver operating characteristic curve and Harrell's C statistic. A total of 1,459 patients were included in the final cohort; 1,425 (97.7%) underwent index transplantation, 963 (66.0%) were female, the median age at transplantation was 57 (11-70) years, and the median Model for End-Stage Liver Disease score was 20 (6-40). Across all outcomes, the GBM model XGBoost achieved the highest performance, with an area under the receiver operating curve of 0.71 (95% confidence interval [CI] 0.63-0.79) for MACE, a Harrell's C statistic of 0.64 (95% CI 0.57-0.73) for overall survival, and 0.72 (95% CI 0.59-0.85) for cardiovascular mortality over a mean follow-up of 4.4 years. Examination of Shapley values for the GBM model revealed that on the cohort-wide level, the top influential factors for postoperative MACE were age at transplantation, diabetes, serum creatinine, cirrhosis caused by nonalcoholic steatohepatitis, right ventricular systolic pressure, and left ventricular ejection fraction. Conclusion Machine learning models developed using data from a tertiary care transplantation center achieved good discriminant function in predicting post-LT MACE, all-cause mortality, and cardiovascular mortality. These models can support clinicians in recipient selection and help screen individuals who may be at elevated risk for post-transplantation MACE.

The Young’s modulus of polymer thin films was measured from bulk films that are micrometers in thickness down to films having a thickness of ∼6 nm, which is less than the radius of gyration, Rg. A simple, noninvasive technique in the same geometry, i.e., the wrinkling of a free-floating film on a water surface with a droplet of water on the surface of the film, was used to determine the modulus over this very large range of film thicknesses. Unlike a solid substrate, there are no in-plane stresses exerted on the film by the underlying liquid substrate except at the boundary of the film. Using recent theoretical developments in the treatment of wrinkling phenomena, we extracted the film modulus from measurements of the wrinkle length. The Young’s modulus does not show any systematic change with film thickness, from the thickest bulk films down to films with a thickness of ∼Rg for both PS and PMMA, although a slight increase of the Young’s modulus was found for the thinnest sub-Rg thick PS film.

BACKGROUND Dobutamine stress echocardiography (DSE) is commonly used for cardiovascular assessment before orthotopic liver transplantation (OLT). The coronary artery calcium score (CACS) is a useful screening tool for coronary artery disease (CAD). We aimed to compare the sensitivity and specificity of DSE and CACS for CAD in OLT candidates. MATERIAL AND METHODS A total of 265 of the 1589 patients who underwent OLT at our center between 2008 and 2019 had preoperative coronary angiography (CAG). Of these, 173 had DSE and 133 had a CT scan suitable for CACS calculation within 1 year of OLT. Patients with a nondiagnostic DSE were excluded (n=100). Two reviewers evaluated CACS on CT scans. The sensitivity/specificity of DSE and CACS for detection of angiographically significant CAD were calculated for patients with both tests (n=36). A separate analysis compared the sensitivity/specificity of a diagnostic DSE (n=73) and CACS (n=133) against CAG for all patients with either test. RESULTS Sensitivity and specificity were 57.1% and 89.7%, respectively, for DSE, compared with 71.4% and 62.1% for CACS at ≥100 Agatston score. For the analysis of all patients with either test, the sensitivity/specificity of DSE for detection of CAD and CACS were 30.8% and 85.0% and 80.0% and 62.8%, respectively. On ROC analysis, CACS was a satisfactory predictor of obstructive CAD (AUC, 0.76±0.06, 95% CI, 0.66-0.87; P0.001). CONCLUSIONS CACS may be an important tool for cardiovascular assessment in patients undergoing OLT. DSE was nondiagnostic in a large percentage of OLT candidates, limiting its use in this population.

Patients with hepatocellular carcinoma (HCC) outside Milan criteria (MC) may be candidates for liver transplantation (LT) after successful downstaging. Factors that predict successful downstaging are unclear. We aimed to identify the predictors of successful downstaging of HCC in patients outside MC.We performed a retrospective cohort study on consecutive patients with HCC outside MC who received downstaging with locoregional therapy. Clinical and laboratory variables, tumor characteristics including total tumor volume (TTV) and up-to-7 criteria were recorded. We performed univariate and multivariate logistic regression analyses to identify variables associated with successful downstaging.Of 675 patients with HCC, 90 patients outside MC received downstaging. Fifty-three (59%) patients were successfully downstaged, 37 (41%) failed downstaging. University of California at San Francisco criteria, α-fetoprotein, up-to-7 criteria, TTV, and platelet count were predictors of successful downstaging on univariate analysis. Total tumor volume was an independent predictor of successful downstaging on multivariate logistic regression (P = 0.04, area under receiver operating characteristic curve 0.89 (95% confidence interval, 0.82-0.96). Fifty-two (76%) of 68 patients with TTV less than 200 cm were successfully downstaged, whereas only 1 (4.5%) of 22 patients with TTV greater than 200 cm were successfully downstaged. Forty-five (50%) patients underwent LT. Kaplan-Meier survival rates at 1 and 5 years post-LT were 95.3% and 79.4%, respectively. Patients who were successfully downstaged had better survival than patients who failed downstaging (P0.01).Total tumor volume is a good predictor of successful downstaging of HCC. Patients with TTV less than 200 cm may be considered good candidates for downstaging. Further studies with larger cohort of patients are needed to validate this approach in patients with HCC outside Milan.

Background & Aims There are no effective and safe treatments for chronic hepatitis C virus (HCV) infection of patients who have advanced liver disease. Methods In this phase 2, open-label study, we assessed treatment with the NS5A inhibitor ledipasvir, the nucleotide polymerase inhibitor sofosbuvir, and ribavirin in patients infected with HCV genotypes 1 or 4. Cohort A enrolled patients with cirrhosis and moderate or severe hepatic impairment who had not undergone liver transplantation. Cohort B enrolled patients who had undergone liver transplantation: those without cirrhosis; those with cirrhosis and mild, moderate, or severe hepatic impairment; and those with fibrosing cholestatic hepatitis. Patients were assigned randomly (1:1) to receive 12 or 24 weeks of a fixed-dose combination tablet containing ledipasvir and sofosbuvir, once daily, plus ribavirin. The primary end point was sustained virologic response at 12 weeks after the end of treatment (SVR12). Results We enrolled 337 patients, 332 (99%) with HCV genotype 1 infection and 5 (1%) with HCV genotype 4 infection. In cohort A (nontransplant), SVR12 was achieved by 86%–89% of patients. In cohort B (transplant recipients), SVR12 was achieved by 96%–98% of patients without cirrhosis or with compensated cirrhosis, by 85%−88% of patients with moderate hepatic impairment, by 60%–75% of patients with severe hepatic impairment, and by all 6 patients with fibrosing cholestatic hepatitis. Response rates in the 12- and 24-week groups were similar. Thirteen patients (4%) discontinued the ledipasvir and sofosbuvir combination prematurely because of adverse events; 10 patients died, mainly from complications related to hepatic decompensation. Conclusion The combination of ledipasvir, sofosbuvir, and ribavirin for 12 weeks produced high rates of SVR12 in patients with advanced liver disease, including those with decompensated cirrhosis before and after liver transplantation. ClinTrials.gov: NCT01938430.

Elastic sheets offer a path to encapsulating a droplet of one fluid in another that is different from that of traditional molecular or particulate surfactants. In wrappings of fluids by sheets of moderate thickness with petals designed to curl into closed shapes, capillarity balances bending forces. Here, we show that, by using much thinner sheets, the constraints of this balance can be lifted to access a regime of high sheet bendability that brings three major advantages: ultrathin sheets automatically achieve optimally efficient shapes that maximize the enclosed volume of liquid for a fixed area of sheet; interfacial energies and mechanical properties of the sheet are irrelevant within this regime, thus allowing for further functionality; and complete coverage of the fluid can be achieved without special sheet designs. We propose and validate a general geometric model that captures the entire range of this new class of wrapped and partially wrapped shapes.

Bacterial and fungal infections are major causes of morbidity and mortality after liver transplantation (LT). The role of intestinal decontamination in the prevention of post-LT infections is controversial. Rifaximin is widely used for the treatment of hepatic encephalopathy. The effect of rifaximin on post-LT infections is unknown. The aim of our study was to determine the effect of rifaximin therapy in the pretransplant period on early bacterial infections (EBIs) and fungal infections within the first 30 days after LT. All adult patients who underwent LT at our institution (January 2009 to July 2011) were included in this retrospective cohort study. Patients receiving antibiotics other than pretransplant protocol antibiotics were excluded. Patients were stratified into 2 groups based on the presence or absence of rifaximin therapy for at least 2 days before LT. Infections were defined by the isolation of any bacterial or fungal organisms within 30 days of LT. Multivariate regression analysis, Student t tests, and Pearson's chi-square tests were used to compare the 2 groups. Two hundred sixty-eight patients were included, and 71 of these patients (26.5%) were on rifaximin at the time of LT. The 2 groups were comparable with respect to age, sex, race, and Model for End-Stage Liver Disease score. There were no significant differences in the rates of EBIs (30% for the non-rifaximin group and 25% for the rifaximin group, P = 0.48) or fungal infections between the 2 groups. There was no increase in antimicrobial resistance among the infecting organisms. There was no difference in survival between the rifaximin and non-rifaximin groups (98% versus 97%, P = 0.36). In conclusion, the use of rifaximin in the pre-LT period was not associated with an increased risk of bacterial or fungal infections in the early post-LT period. Liver Transpl 20:544–551, 2014. © 2014 AASLD.

Hepatocellular carcinoma (HCC) is an important cause of death in patients with liver disease, and its incidence appears to be rising in the United States. Because early diagnosis improves the chances of survival, it is important to identify patients who would benefit from surveillance. Once HCC is suspected on surveillance, noninvasive diagnostic tests are available to make an accurate diagnosis. Treatment should be individualized, based on the characteristics of the tumor and the degree of liver dysfunction.

Introduction Recurrent hepatocellular carcinoma (HCC) following liver transplantation (LT) carries a poor prognosis. The aim of our study was to assess the safety and efficacy of sorafenib in patients with recurrent HCC following LT. Methods A prospectively maintained LT database was retrospectively analyzed for patients with recurrent HCC following LT between 2001 and 2011–34 patients. Patients were divided into two groups based on whether they were prescribed sorafenib (n = 17) or not prescribed sorafenib (n = 17). The primary endpoint was overall survival. Results There were no significant differences between the two groups analyzed. Seventeen patients were on sorafenib for recurrent HCC, with a mean daily dose of ~444 mg. Mean duration of treatment was ~10 months. Side effects included: thrombocytopenia, diarrhea, rising transaminases, fatigue, hand–foot skin reaction, and nausea. Survival in the sorafenib vs. non-sorafenib group was greater at three-, six-, nine-, and 12-month intervals and overall survival. Conclusion Sorafenib can be well tolerated and safe in patients with recurrent HCC following LT and may be associated with a modest survival benefit. To our knowledge, this is the largest single-center retrospective analysis of patients prescribed sorafenib for recurrent HCC after LT.

Smooth wrinkles and sharply crumpled regions are familiar motifs in biological or synthetic sheets, such as rapidly growing plant leaves and crushed foils. Previous studies have addressed both morphological types, but the generic route whereby a featureless sheet develops a complex shape remains elusive. Here we show that this route proceeds through an unusual sequence of distinct symmetry-breaking instabilities. The object of our study is an ultrathin circular sheet stretched over a liquid drop. As the curvature is gradually increased, the surface tension stretching the sheet over the drop causes compression along circles of latitude. The compression is relieved first by a transition into a wrinkle pattern, and then into a crumpled state via a continuous transition. Our data provide conclusive evidence that wrinkle patterns in highly bendable sheets are not described by classical buckling methods, but rather by a theory which assumes that wrinkles completely relax the compressive stress. With this understanding we recognize the observed sequence of transitions as distinct symmetry breakings of the shape and the stress field. The axial symmetry of the shape is broken upon wrinkling but the underlying stress field preserves this symmetry. Thus, the wrinkle-to-crumple transition marks symmetry-breaking of the stress in highly bendable sheets. By contrast, other instabilities of sheets, such as blistering and cracking, break the homogeneity of shape and stress simultaneously. The onset of crumpling occurs when the wrinkle pattern grows to half the sheet’s radius, suggesting a geometric, material-independent origin for this transition.

ObjectivesLiver transplantation (LT) in Milan Criteria (MC) hepatocellular carcinoma (HCC) has excellent outcomes. Pre-transplant loco-regional therapy (LRT) has been used to downstage HCC to meet the MC. However, its benefit in patients with a brief waiting time to transplant remains unclear. This study evaluated outcomes in patients with short waitlist times to LT for MC-compliant HCC.MethodsPatients undergoing LT for MC HCC at either of two transplant centres between 2002 and 2009 were retrospectively evaluated for outcome. Patients for whom post-transplant follow-up amounted to

Background The pattern and severity of postoperative complications after colectomy and total proctocolectomy with ileoanal pouch for patients with IBD with liver cirrhosis from primary sclerosing cholangitis have not been well characterized. Objective This study aimed to evaluate the immediate and long-term outcomes for patients with cirrhosis from primary sclerosing cholangitis undergoing colectomy for IBD. Design This is a retrospective study. Setting This study was conducted at Cleveland Clinic, a tertiary medical center. Patients From 1989 to 2009, 23 patients (22 ulcerative colitis and 1 Crohn's disease) who underwent colectomy were included. Results The mean duration of primary sclerosing cholangitis before surgery was 6.8 ± 4.9 years, and the mean duration of IBD was 18 ± 10.7 years. All patients had cirrhosis; the mean Model for Endstage Liver Disease score was 9.3 ± 1.6, and most patients were Child Pugh class A or early B. Eight patients were on the orthotopic liver transplantation list. Indications for colectomy were dysplasia (n = 13), failure or complications of medical therapy (n = 7), cancer (n = 2), and colonic perforation at colonoscopy (n = 1). Nineteen patients (82.6%) developed postoperative complications including bleeding (43.5%), ileus (17.4%), wound infection (8.7%), worsening liver function (34.8%), pelvic abscess (13%), and deep vein thrombosis (8.7%). Two patients, both after total proctocolectomy/IPAA, died of septic shock after pelvic abscess in the postoperative period. Two patients underwent transjugular intrahepatic portosystemic shunt procedure before total proctocolectomy/IPAA; none developed pelvic abscess or mortality. There were no differences in mortality or morbidity between patients who underwent an ileoanal pouch procedure or colectomy with ileostomy. Conclusions Colectomy in patients with IBD complicated with cirrhotic primary sclerosing cholangitis is associated with a high early postoperative morbidity rate. Due consideration needs to be given to strategies to reduce pelvic sepsis, especially after ileoanal pouch, because this is associated with mortality.

Purpose To compare retrospectively the safety and efficacy of yttrium-90 ( 90 Y) radioembolization with the safety and efficacy of chemoembolization in patients with unresectable hepatocellular carcinoma (HCC). Materials and Methods Survival and complication rates were evaluated for patients with HCC who underwent chemoembolization or radioembolization at a single institution between August 2007 and April 2010. Complications were graded according to a standardized grading system for embolization procedures. Survival was determined via the Kaplan-Meier method, and multivariable analysis for factors affecting survival was performed. Results This study included 73 patients with HCC who underwent index embolization with radioembolization (n = 38; 52.1%) or chemoembolization (n = 35; 47.9%). The two patient populations were similar in terms of demographics, etiology of cirrhosis, functional status, tumor characteristics, Child-Pugh class, previous liver-directed therapy, and number of patients with bilirubin > 2.0 mg/dL. There was no significant difference in survival between the radioembolization (median 8.0 months) and chemoembolization (median 10.3 months) cohorts ( P = .33). Postembolization syndrome was significantly more severe in patients who underwent chemoembolization, which led to increased total hospitalization rates in these patients. The rates of other complications and rehospitalization were similar between groups. Increased age, Child-Pugh class B, hepatitis seropositivity, bilobar tumor distribution, tumor vascular invasion, and presence of extrahepatic metastases were associated with reduced patient survival. Conclusions Patients treated with radioembolization did not show a survival advantage over patients treated with chemoembolization. However, patients who underwent chemoembolization had significantly higher rates of hospitalization as a result of postembolization syndrome.

We have made measurements of force and velocity fluctuations in a variety of dense, gravity-driven granular flows under flow conditions close to the threshold of jamming. The measurements reveal a microscopic state that evolves rapidly from entirely collisional to largely frictional, as the system is taken close to jamming. On coarse-grained time scales, some descriptors of the dynamics—such as the probability distribution of force fluctuations, or the mean friction angle—do not reflect this profound change in the micromechanics of the flow. Other quantities, such as the frequency spectrum of force fluctuations, change significantly, developing low-frequency structure in the fluctuations as jamming is approached. We also show evidence of spatial structure, with force fluctuations being organized into local collision chains. These local structures propagate rapidly in the flow, with consequences far away from their origin, leading to long-range correlations in velocity fluctuations.

Introduction. The progression of chronic liver disease to cirrhosis involves both innate and adaptive immune system dysfunction resulting in increased risk of infectious complications. Vaccinations against pneumococcus, hepatitis A virus (HAV), and hepatitis B virus (HBV) are well tolerated and effective in disease prevention and reduction in morbidity and mortality. Prior studies assessing vaccination rates in patients with cirrhosis have specific limitations and to date no study has provided a comprehensive evaluation of vaccination rates in patients with cirrhosis in the United States.Aim. This study assessed vaccination rates for pneumococcus, HAV, and HBV in patients with cirrhosis.Results. Overall 59.7% of patients with cirrhosis received at least 1 vaccination during the study period. Vaccination rates within the same or following year of cirrhosis diagnosis were 19.9%, 7.7%, and 11.0% against pneumococcus, HAV, and HBV, respectively. Trend analysis revealed significant increases in vaccination rates for pneumococcus in all patients with cirrhosis and within subgroups based on age, gender, and presence of concomitant diabetes.Conclusion. The study demonstrated that vaccination rates in patients with cirrhosis remain suboptimal. Ultimately, the use of electronic medical record (EMR) reminders improved communication between healthcare professionals and public health programs to increase awareness are fundamental to reducing morbidity, mortality, and health-care related costs of vaccine preventable diseases in patients with cirrhosis.

Autoimmune hepatitis commonly relapses after corticosteroid therapy, and long-term management strategies have been proposed based on the premise that repeated relapses after drug withdrawal are inevitable. Our goal was to determine the frequency that remission can be sustained after its induction and termination of therapy. A total of 107 patients who had entered remission on conventional regimens were assessed for sustained remission after initial treatment and after relapse and re-treatment. Re-treatment strategies included conventional regimens and long-term maintenance schedules. Twenty-two patients (21%) achieved a sustained remission after initial treatment, and 24 of 85 patients who relapsed and were re-treated (28%) had a similar outcome. The probability of a sustained remission was 47% after 10 years of follow-up. Patients who sustained remission after initial therapy were distinguished only by a lower serum gamma-globulin level at entry. Conventional re-treatment schedules after relapse were able to induce a sustained remission more commonly then long-term maintenance schedules (59% vs. 12%, P =.00002). In conclusion, patients who respond to initial corticosteroid therapy can achieve a sustained remission after treatment withdrawal or after relapse and re-treatment. All patients are candidates for this outcome, and withdrawal of medication, even during maintenance schedules, is necessary to assess its likelihood.

We have performed neutron diffraction experiments on deuterated propylene glycol, an organic glass former, at temperatures ranging from where its dynamical response approaches that of normal liquids to below the point where relaxation times appear to diverge. Our studies extend over a very broad range of scattering wave vector (0.01

The dynamic specific heat Cp(ν) and thermal conductivity, κ, of the simple glass‐forming liquid di‐n‐butylphthalate are measured over a wide frequency range (4 mHz–8 kHz) by a nonadiabatic ac technique due to Birge and Nagel. The relaxation frequency obtained from the specific heat is found to be non‐Arrhenius down to the lowest temperatures attained in this measurement. The temperature dependence of the relaxation frequency is in close agreement with that obtained from shear modulus and dielectric susceptibility measurements indicating that all motions in the supercooled liquid are strongly coupled to one another. The shape of the relaxation spectrum changes with temperature. The width of the relaxation is similar to that of the dynamic specific heat of other supercooled liquids. The thermal conductivity is frequency independent through the calorimetric glass transition. The static specific heat is reported over a wide range in temperature extending up to 100 K above the melting point. No evidence is fou...

Autoimmune hepatitis commonly relapses after corticosteroid therapy, and long-term management strategies have been proposed based on the premise that repeated relapses after drug withdrawal are inevitable. Our goal was to determine the frequency that remission can be sustained after its induction and termination of therapy. A total of 107 patients who had entered remission on conventional regimens were assessed for sustained remission after initial treatment and after relapse and re-treatment. Re-treatment strategies included conventional regimens and long-term maintenance schedules. Twenty-two patients (21%) achieved a sustained remission after initial treatment, and 24 of 85 patients who relapsed and were re-treated (28%) had a similar outcome. The probability of a sustained remission was 47% after 10 years of follow-up. Patients who sustained remission after initial therapy were distinguished only by a lower serum gamma-globulin level at entry. Conventional re-treatment schedules after relapse were able to induce a sustained remission more commonly then long-term maintenance schedules (59% vs. 12%, P =.00002). In conclusion, patients who respond to initial corticosteroid therapy can achieve a sustained remission after treatment withdrawal or after relapse and re-treatment. All patients are candidates for this outcome, and withdrawal of medication, even during maintenance schedules, is necessary to assess its likelihood.

The radial wrinkle pattern generated by a liquid drop on a floating elastic sheet has stimulated a number of advances in the understanding of wrinkle patterns in ultrathin sheets. A puzzle associated with the spatial extent of this simple, highly symmetric pattern has only recently been resolved, but several other basic aspects of the pattern remain unexplained. Our previous experiments have studied the extent and wavenumber of the pattern via 2-dimensional images. In the current study we report a full 3-dimensional topographical characterization of this archetypical problem, and of its counterpart, a bubble beneath a sheet. In addition to measurements of the wrinkle amplitude, these studies reveal the elastic deformation and the resulting wrinkle pattern beneath the drop. We also show that the flat boundary condition at the contact line of the drop is achieved by a cascade of wrinkles on both sides of the boundary. Finally, we report studies by high-speed video imaging of the propagation of the wrinkle pattern, with the unexpected result that the wavenumber is established early in the development of the pattern, before it has reached its full spatial extent.