Multidrug-resistant bacterial infections after liver transplantation: Prevalence, impact, and risk factors.

BACKGROUND & AIMS: Infections by multidrug-resistant bacteria (MDRB) are an increasing healthcare problem worldwide. This study analyzes the incidence, burden, and risk factors associated with MDRB infections after liver transplant(ation) (LT). METHODS: This retrospective, multicenter cohort study included adult patients who underwent LT between January 2017 and January 2020. Risk factors related to pre-LT disease, surgical procedure, and postoperative stay were analyzed. Multivariate logistic regression analysis was performed to identify independent predictors of MDRB infections within the first 90 days after LT. RESULTS: We included 1,045 LT procedures (960 patients) performed at nine centers across Spain. The mean age of our cohort was 56.8 ± 9.3 years; 75.4% (n = 782) were male. Alcohol-related liver disease was the most prevalent underlying etiology (43.2.%, n = 451). Bacterial infections occurred in 432 patients (41.3%) who presented with a total of 679 episodes of infection (respiratory infections, 19.3%; urinary tract infections, 18.5%; bacteremia, 13.2% and cholangitis 11%, among others). MDRB were isolated in 227 LT cases (21.7%) (348 episodes). Enterococcus faecium (22.1%), Escherichia coli (18.4%), and Pseudomonas aeruginosa (15.2%) were the most frequently isolated microorganisms. In multivariate analysis, previous intensive care unit admission (0-3 months before LT), previous MDRB infections (0-3 months before LT), and an increasing number of packed red blood cell units transfused during surgery were identified as independent predictors of MDRB infections. Mortality at 30, 90, 180, and 365 days was significantly higher in patients with MDRB isolates. CONCLUSION: MDRB infections are highly prevalent after LT and have a significant impact on prognosis. Enterococcus faecium is the most frequently isolated multi-resistant microorganism. New pharmacological and surveillance strategies aimed at preventing MDRB infections after LT should be considered for patients with risk factors. IMPACT AND IMPLICATIONS: Multidrug-resistant bacterial infections have a deep impact on morbidity and mortality after liver transplantation. Strategies aimed at improving prophylaxis, early identification, and empirical treatment are paramount. Our study unveiled the prevalence and main risk factors associated with these infections, and demonstrated that gram-positive bacteria, particularly Enterococcus faecium, are frequent in this clinical scenario. These findings provide valuable insights for the development of prophylactic and empirical antibiotic treatment protocols after liver transplantation.

The role of HBIG in real life for patients undergoing liver transplantation due to HDV-related cirrhosis.

Recommended post-liver transplant (LT) prophylaxis in patients with hepatitis delta includes a nucleos(t)ide analogue (NA) and anti-hepatitis B immunoglobulin (HBIG) indefinitely. We analysed the use of HBIG in real-life clinical practice and its impact on HBV/HDV recurrence in 174 HDV-related LT patients from 10 Spanish liver transplant centres (1988-2018). Median post-LT follow-up was 7.8 (2.3-15.1) years and patient survival at 5 years was 90%. Most patients (97%) received HBIG in the immediate post-LT, but only 42% were on HBIG at the last control. Among those discontinuing HBIG, the median time on treatment was 18 (7-52) months. Post-LT HBsAg+ was detected in 16 (9%) patients and HBV-DNA in 12 (7%). Despite HBsAg positivity, HDV recurrence was reported only in three patients (1.7%), all of whom were not receiving NA and had discontinued HBIG. Our data suggest that a finite HBIG prophylaxis in HDV-LT is feasible, especially if high-barrier NAs are used.

Predictive models for hepatocellular carcinoma development after sustained virological response in advanced hepatitis C.

BACKGROUND & AIMS: Life-long hepatocellular carcinoma (HCC) surveillance is recommended after sustained virological response (SVR) in patients with advanced hepatitis C. Since the identification of patients who could be safely discontinued for surveillance is essential, we aimed to identify subsets of patients with low-risk HCC. METHODS: 491 patients with advanced and compensated fibrosis (≥F3) were prospectively followed after achieving SVR with interferon-free therapies. Clinical-biological parameters and liver stiffness measurement (LSM) were performed before starting treatment (ST) and at SVR, and HCC surveillance was carried out. RESULTS: During a median follow-up of 49.8 months, 29 (5.9%) patients developed HCC [incidence rate: 1.6/100 patient-years (PYs)]. Two predictive models based on LSM (Model-A) or FIB-4 score (Model-B) were proposed. Only SVR parameters were included in the models, because they showed a higher accuracy for predicting HCC than ST measurements. Variables independently associated with HCC were LSM (HR, 1.03; 95% CI, 1.01-1.05), age (HR, 1.04; 95% CI, 1.01-1.08) and albumin levels (HR, 0.90; 95% CI, 0.84-0.97) in Model-A, and FIB-4 (HR, 1.22; 95% CI, 1.08-1.37) and albumin (HR, 0.90; 95% CI, 0.84-0.97) in model-B. Both models allow HCC risk stratification, identifying low-risk groups with an HCC incidence rate of 0.16/100 and 0.25/100 PYs, respectively. An overall increased hazard of HCC was observed over time. CONCLUSION: Simple models based on non-invasive markers of liver fibrosis, LSM or FIB-4, together with age and albumin levels at SVR permit to identify subsets of patients with HCC risk clearly <1%/year, for whom HCC surveillance might not be cost-effective.

Low applicability of the ''Six-and-twelve score" in hepatocellular carcinoma treated with Drug-Eluting Beads Transarterial Chemoembolization.

OBJECTIVE: The effectiveness of transarterial chemoembolization (TACE) in hepatocellular carcinoma (HCC) depends on the selection of suitable patients. The ''Six-and-twelve score" distinguishes three groups of ideal patients with different overall survival, based on the sum of the number and size of tumors. This may impact on clinical practice and trial design. The aim of this study was to assess the reproducibility and prognostic value of the model in western patients treated with Drug-Eluting Beads (DEB)-TACE. METHODS: Observational, retrospective, unicentric study with consecutive compensated patients treated with DEB-TACE from October 2008 to October 2017. Exclusion criteria were Child-Pugh ≥ 8 and DEB-TACE used as a bridge to liver transplantation. RESULTS: 225 HCC consecutive patients were included; BCLC-0/A n=131 (single nodules > 5, n=29) and BCLC-B n=94. The median overall survival (OS) was 27 months (95% CI 23.8-30.2). OS was different between BCLC-0/A vs BCLC-B: 30 vs 24 months (p= 0.03), Child-Pugh A5 vs A6-B7: 30 vs 27 months (p= 0.003). ''Six-and-twelve score" groups discriminated OS: group 1, n=123, 32 months (95% CI 27.5-63.5), group 2, n=101, 24 months (95% CI 19.6-28.4) and group 3, n=1, 27 months (p=0.024). When comparing the three scores, the ''Six-and-twelve score" showed the best discrimination power: C-index 0.603, Akaike's information criterion (AIC) 1.642, likelihood ratio test (LRT) 16.21. CONCLUSION: The ''Six-and-twelve score" is a prognostic tool for patients with HCC treated with DEB-TACE. However, few patients were included in the third group (score >12) and no differences were observed with BCLC, therefore its applicability is limited. .

Effects of everolimus plus minimized tacrolimus on kidney function in liver transplantation: REDUCE, a prospective, randomized controlled study.

BACKGROUND AND AIM: reduction in calcineurin inhibitor levels is considered crucial to decrease the incidence of kidney dysfunction in liver transplant (LT) recipients. The aim of this study was to evaluate the safety and impact of everolimus plus reduced tacrolimus (EVR + rTAC) vs. mycophenolate mofetil plus tacrolimus (MMF + TAC) on kidney function in LT recipients from Spain. METHODS: the REDUCE study was a 52-week, multicenter, randomized, controlled, open-label, phase 3b study in de novo LT recipients. Eligible patients were randomized (1:1) 28 days post-transplantation to receive EVR + rTAC (TAC levels ≤ 5 ng/mL) or to continue with MMF + TAC (TAC levels = 6-10 ng/mL). Mean estimated glomerular filtration rate (eGFR), clinical benefit in renal function, and safety were evaluated. RESULTS: in the EVR + rTAC group (n = 105), eGFR increased from randomization to week 52 (82.2 [28.5] mL/min/1.73 m2 to 86.1 [27.9] mL/min/1.73 m2) whereas it decreased in the MMF + TAC (n = 106) group (88.4 [34.3] mL/min/1.73 m2 to 83.2 [25.2] mL/min/1.73 m2), with significant (p < 0.05) differences in eGFR throughout the study. However, both groups had a similar clinical benefit regarding renal function (improvement in 18.6 % vs. 19.1 %, and stabilization in 81.4 % vs. 80.9 % of patients in the EVR + rTAC vs. MMF + TAC groups, respectively). There were no significant differences in the incidence of acute rejection (5.7 % vs. 3.8 %), deaths (5.7 % vs. 2.8 %), and serious adverse events (51.9 % vs. 44.0 %) between the 2 groups. CONCLUSION: EVR + rTAC allows a safe reduction in tacrolimus exposure in de novo liver transplant recipients, with a significant improvement in eGFR but without significant differences in renal clinical benefit 1 year after liver transplantation.

Epidemiological pattern, incidence, and outcomes of COVID-19 in liver transplant patients.

BACKGROUND & AIMS: The incidence and outcomes of coronavirus disease 2019 (COVID-19) in immunocompromised patients are a matter of debate. METHODS: We performed a prospective nationwide study including a consecutive cohort of liver transplant patients with COVID-19 recruited during the Spanish outbreak from 28 February to 7 April, 2020. The primary outcome was severe COVID-19, defined as the need for mechanical ventilation, intensive care, and/or death. Age- and gender-standardised incidence and mortality ratios (SIR and SMR) were calculated using data from the Ministry of Health and the Spanish liver transplant registry. Independent predictors of severe COVID-19 among hospitalised patients were analysed using multivariate Cox regression. RESULTS: A total of 111 liver transplant patients were diagnosed with COVID-19 (SIR = 191.2 [95% CI 190.3-192.2]). The epidemiological curve and geographic distribution overlapped widely between the liver transplant and general populations. After a median follow-up of 23 days, 96 patients (86.5%) were admitted to hospital and 22 patients (19.8%) required respiratory support. A total of 12 patients were admitted to the ICU (10.8%). The mortality rate was 18%, which was lower than in the matched general population (SMR = 95.5 [95% CI 94.2-96.8]). Overall, 35 patients (31.5%) met criteria of severe COVID-19. Baseline immunosuppression containing mycophenolate was an independent predictor of severe COVID-19 (relative risk = 3.94; 95% CI 1.59-9.74; p = 0.003), particularly at doses higher than 1,000 mg/day (p = 0.003). This deleterious effect was not observed with calcineurin inhibitors or everolimus and complete immunosuppression withdrawal showed no benefit. CONCLUSIONS: Being chronically immunosuppressed, liver transplant patients have an increased risk of acquiring COVID-19 but their mortality rates are lower than the matched general population. Upon hospital admission, mycophenolate dose reduction or withdrawal could help in preventing severe COVID-19. However, complete immunosuppression withdrawal should be discouraged. LAY SUMMARY: In liver transplant patients, chronic immunosuppression increases the risk of acquiring COVID-19 but it could reduce disease severity. Complete immunosuppression withdrawal may not be justified. However, mycophenolate withdrawal or temporary conversion to calcineurin inhibitors or everolimus until disease resolution could be beneficial in hospitalised patients.

Impact of Alcohol Abstinence on the Risk of Hepatocellular Carcinoma in Patients With Alcohol-Related Liver Cirrhosis.

INTRODUCTION: Although alcohol cessation is the only effective treatment for alcohol-related liver disease, few data exist concerning its influence on the risk of hepatocellular carcinoma (HCC). We aimed to evaluate the effect of alcohol abstinence on the incidence of HCC in patients with alcohol-related cirrhosis. METHODS: We studied 727 patients with alcohol-related cirrhosis (247 with compensated disease and 480 with previous decompensation) who were included in a surveillance program for the early detection of HCC and prospectively followed. Baseline clinical and biological parameters and alcohol consumption during follow-up were recorded. Abstinence was defined as the absence of any alcohol use. RESULTS: During follow-up (median 54 months), 354 patients (48.7%) remained abstinent and 104 developed HCC (2.3 per 100 person-years). Factors independently associated with the risk of HCC among patients with previous decompensation were age, male gender, and aspartate aminotransferase, whereas abstinence was not linked to a reduced risk (hazard ratio 0.95; 95% confidence interval 0.59-1.52). However, among patients without previous decompensation, prothrombin activity and abstinence were independently associated with the risk of HCC. Abstinent patients had a significant decrease in the risk of developing tumor (hazard ratio 0.35; 95% confidence interval 0.13-0.94). These results did not change after applying a competing risk analysis where death and liver transplantation were considered as competing events. DISCUSSION: Alcohol abstinence reduced the risk of HCC in patients with alcohol-related cirrhosis, but only in those without a history of decompensated disease. This finding emphasizes the need for an early diagnosis of alcohol-related liver disease and for implementing strategies leading to an increase in the rate of achieving and maintaining abstinence among this population.

Regorafenib Efficacy After Sorafenib in Patients With Recurrent Hepatocellular Carcinoma After Liver Transplantation: A Retrospective Study.

Safety of regorafenib in hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) has been recently demonstrated. We aimed to assess the survival benefit of regorafenib compared with best supportive care (BSC) in LT patients after sorafenib discontinuation. This observational multicenter retrospective study included LT patients with HCC recurrence who discontinued first-line sorafenib. Group 1 comprised regorafenib-treated patients, whereas the control group was selected among patients treated with BSC due to unavailability of second-line options at the time of sorafenib discontinuation and who were sorafenib-tolerant progressors (group 2). Primary endpoint was overall survival (OS) of group 1 compared with group 2. Secondary endpoints were safety and OS of sequential treatment with sorafenib + regorafenib/BSC. Among 132 LT patients who discontinued sorafenib included in the study, 81 were sorafenib tolerant: 36 received regorafenib (group 1) and 45 (group 2) received BSC. Overall, 24 (67%) patients died in group 1 and 40 (89%) in group 2: the median OS was significantly longer in group 1 than in group 2 (13.1 versus 5.5 months; P < 0.01). Regorafenib treatment was an independent predictor of reduced mortality (hazard ratio, 0.37; 95% confidence interval [CI], 0.16-0.89; P = 0.02). Median treatment duration with regorafenib was 7.0 (95% CI, 5.5-8.5) months; regorafenib dose was reduced in 22 (61%) patients for adverse events and discontinued for tumor progression in 93% (n = 28). The median OS calculated from sorafenib start was 28.8 months (95% CI, 17.6-40.1) in group 1 versus 15.3 months (95% CI, 8.8-21.7) in group 2 (P < 0.01). Regorafenib is an effective second-line treatment after sorafenib in patients with HCC recurrence after LT.

Evaluation of cardiovascular events in patients with hepatocellular carcinoma treated with sorafenib in the clinical practice. The CARDIO-SOR study.

BACKGROUND AND AIMS: The effectiveness of systemic treatment in advanced hepatocellular carcinoma (HCC) depends on the selection of patients, management of cirrhosis complications and expertise to treat adverse events. The aims of the study are to assess the frequency and management of cardiovascular events in HCC patients treated with sorafenib (SOR) and to create a scale to predict the onset of major adverse cardiovascular events (MACE). METHOD: Observational retrospective study with consecutive HCC patients treated with SOR between 2007 and 2019 in a western centre. In order to classify cardiovascular risk pre-SOR, we designed the CARDIOSOR scale with age, hypertension, diabetes, dyslipidaemia and peripheral vascular disease. Other adverse events, dosing and outcome data were collected during a homogeneous protocolled follow-up. RESULTS: Two hundred ninety-nine patients were included (219 BCLC-C). The median overall survival was 11.1 months (IQR 5.6-20.5), and duration of treatment was 7.4 months (IQR 3.3-14.7). Seventeen patients (6%) stopped SOR due to cardiovascular event. Thirty-three patients suffered MACE (7 heart failure, 11 acute coronary syndrome, 12 cerebrovascular accident and 8 peripheral vascular ischemia); 99 had a minor cardiovascular event, mainly hypertension (n = 81). Age was the only independent factor associated to MACE (HR 1.07; 95% CI 1.03-1.12; P = .002). The CARDIOSOR scale allows to identify the group of patients with higher risk of MACE (sHR 3.4; 95% CI 1.4-6.7; P = .04). CONCLUSION: The incidence of cardiovascular events in HCC patients treated with SOR is higher than expected. Multidisciplinary approach and clinical tools like CARDIOSOR scale could be helpful to manage these patients.

The development of early ascites is associated with shorter overall survival in patients with hepatocellular carcinoma treated with drug-eluting embolic chemoembolization.

BACKGROUND: A single-centre cohort study was performed to identify the independent factors associated with the overall survival (OS) of hepatocellular carcinoma (HCC) patients treated with transarterial chemoembolization with drug-eluting beads (DEB-TACE). METHODS: A total of 216 HCC patients who underwent DEB-TACE from October 2008 to October 2015 at a tertiary hospital were consecutively recruited. The analysis of prognostic factors associated with overall survival after DEB-TACE, stressing the role of post-TACE events, was performed. RESULTS: The objective response (OR) rate (Modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria) to the first DEB-TACE (DEB-TACE-1) was 70.3%; the median OS from DEB-TACE-1 was 27 months (95% confidence interval (CI), 24-30). In the multivariate analysis, tumor size, AFP < 100 ng/mL and serum alkaline phosphatase were independent factors for survival following DEB-TACE-1. The most important clinical event associated with poor survival was the development of early ascites after DEB-TACE-1 (median OS, 17 months), which was closely related to the history of ascites, albumin and hemoglobin but not to tumour load or to response to therapy. CONCLUSIONS: Early ascites post-DEB-TACE is associated with the survival of patients despite adequate liver function and the use of a supra-selective technical approach. History of ascites, albumin and hemoglobin are major determinants of the development of early ascites post-DEB-TACE.

Changes in the characteristics of hospital admissions due to decompensated cirrhosis in the era of direct-acting antivirals against hepatitis C virus.

BACKGROUND: the development of interferon-free regimens, based on direct acting antivirals (DAAs) has revolutionized the treatment of hepatitis C virus (HCV) infection. AIMS: to determine if there have been changes in the characteristics of hospital admissions due to decompensated cirrhosis in a general hospital since the introduction of DAAs. PATIENTS AND METHODS: this was a prospective study of all hospital admissions due to decompensated cirrhosis during two periods: October 2012-October 2014 (P-I) and July 2016-July 2018 (P-II). Clinical and demographic variables were collected and standard statistical methods were used for the analysis. RESULTS: there were 746 hospital admissions; 347 in P-I and 399 in P-II. P-I patients were younger (59 vs 63 years; p = 0.034), while the proportion of admissions due to HCV-cirrhosis was lower in P-II (15.8 % vs 21.6 %; p = 0.041). There were no significant differences in the proportion of admissions due to other etiologies of cirrhosis between both periods. Patients in the P-II group presented an active viral infection (57.1 vs 97.3 %; p = 0.001) less frequently and had a higher rate of excessive alcohol consumption (55.5 vs 30.7 %; p = 0.003) when admitted, while HIV co-infection was less frequent (1.6 % vs 10.7 %; p = 0.039). CONCLUSION: the proportion of admissions due to decompensated HCV-related cirrhosis has decreased by almost 30 % since the introduction of the DAA. In addition, the characteristics of patients admitted have changed since the application of interferon-free regimens.

Preliminary experience on safety of regorafenib after sorafenib failure in recurrent hepatocellular carcinoma after liver transplantation.

Regorafenib is one option for second-line treatment of hepatocellular carcinoma (HCC), improving overall survival (OS) of sorafenib-tolerant patients who develop progression. We aim to evaluate the safety and outcomes of regorafenib as second-line treatment for HCC recurrence after liver transplantation (LT). This is a retrospective, multicenter, international study including regorafenib-treated LT patients (2015-2018), with analysis of baseline characteristics and evolutionary events during sorafenib/regorafenib treatment. Twenty-eight LT patients (57 years, 7% cirrhotics, 54% performance status 1) were included. Median time from LT to regorafenib initiation was 3.9 (1.1-18.5) years; median time on sorafenib was 11.3 (0.7-76.4) months and 14 (1-591) days from sorafenib discontinuation to regorafenib. During regorafenib (6.3 months), all patients had at least one adverse event (AE), the most common grade 3/4 AEs were fatigue (n = 7) and dermatological reaction (n = 5). While no liver rejection was observed, plasma levels of immunosuppressive drugs increased in five. Twenty-four patients developed progression (38% extrahepatic growth, 33% new extrahepatic lesions/vascular invasion). Median OS from regorafenib initiation was 12.9 (95% CI, 6.7-19.1) and 38.4 months (95% CI, 18.5-58.4) for the sorafenib initiation. This is the first study showing safety of regorafenib after LT, thus providing the rational of considering regorafenib in the clinical decision-making in sorafenib-tolerant patients with HCC recurrence after LT.

Direct-acting antivirals are effective and safe in HCV/HIV-coinfected liver transplant recipients who experience recurrence of hepatitis C: A prospective nationwide cohort study.

Direct-acting antivirals have proved to be highly efficacious and safe in monoinfected liver transplant (LT) recipients who experience recurrence of hepatitis C virus (HCV) infection. However, there is a lack of data on effectiveness and tolerability of these regimens in HCV/HIV-coinfected patients who experience recurrence of HCV infection after LT. In this prospective, multicenter cohort study, the outcomes of 47 HCV/HIV-coinfected LT patients who received DAA therapy (with or without ribavirin [RBV]) were compared with those of a matched cohort of 148 HCV-monoinfected LT recipients who received similar treatment. Baseline characteristics were similar in both groups. HCV/HIV-coinfected patients had a median (IQR) CD4 T-cell count of 366 (256-467) cells/µL. HIV-RNA was <50 copies/mL in 96% of patients. The DAA regimens administered were SOF + LDV ± RBV (34%), SOF + SMV ± RBV (31%), SOF + DCV ± RBV (27%), SMV + DCV ± RBV (5%), and 3D (3%), with no differences between the groups. Treatment was well tolerated in both groups. Rates of SVR (negative serum HCV-RNA at 12 weeks after the end of treatment) were high and similar for coinfected and monoinfected patients (95% and 94%, respectively; P = .239). Albeit not significant, a trend toward lower SVR rates among patients with advanced fibrosis (P = .093) and genotype 4 (P = .088) was observed. In conclusion, interferon-free regimens with DAAs for post-LT recurrence of HCV infection in HIV-infected individuals were highly effective and well tolerated, with results comparable to those of HCV-monoinfected patients.

Characterization and comparative analysis of the genome of Puccinia sorghi Schwein, the causal agent of maize common rust.

Rust fungi are one of the most devastating pathogens of crop plants. The biotrophic fungus Puccinia sorghi Schwein (Ps) is responsible for maize common rust, an endemic disease of maize (Zea mays L.) in Argentina that causes significant yield losses in corn production. In spite of this, the Ps genomic sequence was not available. We used Illumina sequencing to rapidly produce the 99.6Mbdraft genome sequence of Ps race RO10H11247, derived from a single-uredinial isolate from infected maize leaves collected in the Argentine Corn Belt Region during 2010. High quality reads were obtained from 200bppaired-end and 5000bpmate-paired libraries and assembled in 15,722 scaffolds. A pipeline which combined an ab initio program with homology-based models and homology to in planta enriched ESTs from four cereal pathogenic fungus (the three sequenced wheat rusts and Ustilago maydis) was used to identify 21,087 putative coding sequences, of which 1599 might be part of the Ps RO10H11247 secretome. Among the 458 highly conserved protein families from the euKaryotic Orthologous Groups (KOG) that occur in a wide range of eukaryotic organisms, 97.5% have at least one member with high homology in the Ps assembly (TBlastN, E-value⩽e-10) covering more than 50% of the length of the KOG protein. Comparative studies with the three sequenced wheat rust fungus, and microsynteny analysis involving Puccinia striiformis f. sp. tritici (Pst, wheat stripe rust fungus), support the quality achieved. The results presented here show the effectiveness of the Illumina strategy for sequencing dikaryotic genomes of non-model organisms and provides reliable DNA sequence information for genomic studies, including pathogenic mechanisms of this maize fungus and molecular marker design.

Boiling and Pressure Cooking Impact on IgE Reactivity of Soybean Allergens.

BACKGROUND: Soybean is one of the 8 foods that causes the most significant rate of food allergies in the USA and Europe. Thermal processing may impact on the allergenic potential of certain foods. We aimed to investigate modifications of the IgE-binding properties of soybean proteins due to processing methods that have been previously found to impact on the allergenicity of legumes such as peanut. METHODS: Soybean seeds were subjected to different thermal processing treatments. To evaluate their impact on the IgE-binding capacity of soybean proteins, individual sera from 25 patients sensitized to soybean were used in in vitro immunoassays. Detection of specific soybean allergens in untreated and treated samples was carried out with specific monoclonal and polyclonal antibodies. In vivo studies of skin prick testing (SPT) were also performed. RESULTS: The IgE reactivity of soybean was resistant to boiling up to 30 min, and this treatment had a higher impact when applied for 60 min. Treatment that combined heat and pressure produced a fragmentation of proteins in both soluble and insoluble fractions that went along with a decreased capacity to bind IgE and reduced the SPT wheal size. However, allergens such as 7S globulins survived this treatment. CONCLUSIONS: Thermal-processing methods able to attenuate the capacity of soybean proteins to bind IgE may contribute to the improvement of food safety and could constitute a potential strategy for the induction of tolerance to soybean.

Mapping a gene on wheat chromosome 4BL involved in a complementary interaction with adult plant leaf rust resistance gene LrSV2.

KEY MESSAGE: A complementary gene to LrSV2 for specific adult plant leaf rust resistance in wheat was mapped on chromosome 4BL, tightly linked to Lr12 / 31. LrSV2 is a race-specific adult plant leaf rust (Puccinia triticina) resistance gene on subdistal chromosome 3BS detected in the cross of the traditional Argentinean wheat (Triticum aestivum) variety Sinvalocho MA and the experimental line Gama6. The analysis of the cross of R46 [recombinant inbred line (RIL) derived from Sinvalocho MA carrying LrSV2 gene and the complementary gene Lrc-SV2 identified in the current paper] and the commercial variety Relmo Siriri (not carrying neither of these two genes) allowed the detection of the unlinked complementary gene Lrc-SV2 because the presence of one dominant allele of both is necessary to express the LrSV2-specific adult plant resistance. Lrc-SV2 was mapped within a 1-cM interval on chromosome 4BL using 100 RILs from the cross Sinvalocho MA × Purple Straw. This genetic system resembles the Lr27+31 seedling resistance reported in the Australian varieties Gatcher and Timgalen where interacting genes map at similar chromosomal positions. However, in high-resolution maps, Lr27 and LrSV2 were already mapped to adjacent intervals on 3BS and Lrc-SV2 map position on 4BL is distal to the reported Lr12/31-flanking microsatellites.

Incidence and risk factors associated with hepatocellular carcinoma surveillance failure.

BACKGROUND AND AIM: Surveillance for hepatocellular carcinoma (HCC) intends to detect tumors at an early stage to improve survival. The study aims were to assess the frequency and risk factors associated with HCC surveillance failure. METHODS: The study analyzed data from 188 consecutive patients diagnosed with HCC within a surveillance program conducted among 1,242 cirrhotic patients and based on ultrasonography and alpha-fetoprotein (AFP) testing every 3 or 6 months. Program failure was defined as the detection of HCC exceeding the Milan criteria. Variables recorded at entry into the program, during follow-up and at HCC diagnosis, were analyzed. RESULTS: At diagnosis, 50 (26.6%) HCC tumors were beyond the Milan criteria. In univariate analysis, Child-Pugh B at entry (P = 0.03), development of complications of portal hypertension before tumor diagnosis (P = 0.03), and failure to complete the prior screening round (P = 0.02), Child-Pugh B/C (P = 0.001) and AFP ≥ 100 ng/mL (P = 0.03) at diagnosis, were associated with failure. In multivariate analysis, only Child-Pugh B/C (hazard ratio, 3.18; 95% confidence interval, 1.66-6.10, P < 0.001) and AFP ≥ 100 ng/mL, both at diagnosis (hazard ratio, 2.80; 95% confidence interval, 1.37-5.71, P = 0.005), were independently associated with failure. Survival was higher among patients with tumors within the Milan criteria than those with program failure (33.9 vs 7.6 months, P < 0.001). CONCLUSIONS: Approximately 25% of HCC cases diagnosed among patients included in a surveillance program were beyond the Milan criteria. Child-Pugh B/C and AFP ≥ 100 ng/mL at diagnosis were associated with program failure. However, Child-Pugh B at entry and development of liver-related complications during follow-up can be early predictors of failure.

Prevalence and progression of chronic kidney disease after liver transplant: a prospective, real-life, observational, two-year multicenter study.

INTRODUCTION: chronic kidney disease is a frequent complication after liver transplantation. The use of calcineurin inhibitors is one of the causes of this complication. Current immunsuppression regimens that reduce the use of calcineurin inhibitors may be associated with an improved preservation of renal function. OBJECTIVE: the study aimed to assess the evolution of renal function after liver transplantation in the current routine clinical practice. METHODS: an observational, prospective, multicenter study in adult liver transplant recipients was performed. Two hundred and thirty patients with a good renal function before transplantation were assessed six months post-transplantation (baseline) and every six months until month 30. RESULTS: at baseline, 32% of the patients had a reduction in the glomerular filtration rate below < 60 ml/min/1.73 m2. The mean glomerular filtration rate increased from 72.3 to 75.6 ml/min/1.73 m2 at baseline and month 30 respectively (p < 0.01). The mean serum creatinine levels (mg/dl) decreased from 1.13 to 1.09 (p < 0.01). The percentage of patients with stage 3 chronic kidney disease decreased from 31.7% to 26.4%, whereas the percentage of patients with stage 4 remained unchanged (0.4% at baseline and 0.5% at month 30). No patients progressed to end-stage kidney disease that required dialysis or renal transplantation. CONCLUSION: in the routine clinical practice, a moderate deterioration of renal function is frequent after liver transplantation. However, advanced chronic kidney disease is infrequent in patients with a good pre-transplant renal function.

Cyclosporine A in addition to standard ART during primary HIV-1 infection: pilot randomized clinical trial.

Background: Initiating ART during acute/recent HIV-1 infection reduces viral reservoir formation. It has been proposed that, during this phase, the size of the viral reservoir could be further reduced by the association of immunomodulatory therapy with ART. Contradictory results have emerged, however, from two trials evaluating the impact on immune recovery and the viral reservoir of adding cyclosporine A to ART during primary HIV-1 infection. Patients and methods: Twenty patients with acute/recent HIV-1 infection were randomized to receive ART alone (tenofovir, emtricitabine and lopinavir/ritonavir) or associated with 8 weeks of cyclosporine A (0.3-0.6 mg/kg twice daily). The impact on viral load, immune response and integrated and non-integrated DNA viral reservoir at 0, 8 and 36 weeks of treatment was evaluated. Results: The estimated median time from HIV-1 infection to ART onset was 63 days (IQR 53; 79.5) with 90% of patients at Fiebig V stage. No significant differences were observed in viral load decay, CD4 T cell recovery, immune response markers or the evolution of integrated DNA at week 8 (end of cyclosporine A) and week 36 between groups. However, non-integrated DNA significantly increased in the cyclosporine A arm between weeks 0 and 36. Cyclosporine A was well tolerated. Conclusions: Adding cyclosporine A to ART during acute/recent infection did not improve immune recovery. However, unintegrated DNA increased in the cyclosporine A group, suggesting an anti-integration effect, a point warranting further research (ClinicalTrials.gov Identifier: NCT00979706).

Adherence to a Semiannual Surveillance Program for Hepatocellular Carcinoma in Patients With Liver Cirrhosis.

BACKGROUND: Patient adherence to screening for hepatocellular carcinoma (HCC) is not well known. Our aims were to analyze the adherence to a surveillance program in a prospective cohort of cirrhotic patients and to examine its association with HCC stage at diagnosis. MATERIALS AND METHODS: A total of 770 patients with cirrhosis were examined semiannually by ultrasound and alpha-fetoprotein at a tertiary center. We collected data on 17 variables at baseline. Suboptimal adherence was defined as failure to complete 2 consecutive screening rounds. RESULTS: Over a median follow-up period of 42.0 months (interquartile range: 60.0), 125 patients (16.2%) had suboptimal adherence. Active or previous intravenous drug use [hazard ratio (HR), 5.33; 95% confidence interval (CI), 3.07-9.23], active alcohol consumption (HR, 3.03; 95% CI, 2.03-4.51), absence of liver decompensation before the inclusion in the program (HR, 1.65; 95% CI, 1.07-2.55) and aspartate transaminase/alanine transaminase ratio ≥1.6 (HR, 1.82; 95% CI, 1.23-2.70) were independent predictors of suboptimal adherence. Compared with those with optimal adherence, patients with suboptimal adherence had a more advanced HCC stage at diagnosis (P=0.015), they were less frequently treated with curative intention (P=0.078) and survived less (median: 14.2 mo; IQR: 36.0 vs. 22.7 mo; IQR: 47.4; P=0.160), although these differences were not significant. CONCLUSIONS: The adherence to the process of HCC surveillance can be considered as adequate among cirrhotic patients. Active alcohol consumption and a history of intravenous drug use are the strongest predictors of suboptimal adherence. These patients have a more advanced HCC stage at diagnosis and tend to be less frequently treated with curative intention.