Right vs left portal branch puncture in TIPS creation with controlled expansion covered stent: comparison of hemodynamic and clinical outcomes.

PURPOSE: To retrospectively compare outcomes of TIPS performed by puncturing left portal vein (LPV) vs right portal vein (RPV) to access the portal system. MATERIALS AND METHODS: One hundred ninety-three consecutive patients underwent TIPS with controlled expansion covered stent by using the LPV (37 patients) or the RPV (156 patients). Patients were followed until the last clinical evaluation, liver transplantation, or death. RESULTS: Demographics and clinical characteristics of the two groups were comparable. The median follow-up was 9.6 months (range 0.1-50.6). Portosystemic pressure gradient (PSG) before TIPS 15.7 mmHg ± 4.7 in RPV group (RPVG) vs 15.4 mmHg ± 4.5 in LPV group (LPVG) (p = 0.725). After TIPS, PSG 6.3 mmHg ± 2.8 in RPVG vs 6.2 mmHg ± 2.2 (p = 0.839). In LPVG, the stent was dilated to 8-mm in 95% of patients vs 77% of RPVG (p = 0.015). Two (5.4%) and 22 (14%) patients underwent TIPS revision in LPVG and RPVG (p = 0.15). The incidence of overt HE was 13% in LPVG and 24% in RPVG (p = 0.177). Rebleeding occurred in 3 of 49 patients (6%) with variceal bleeding as an indication: 2/41 patients (4.9%) in RPVG vs 1/8 patients (12.5%) in LPVG (p = 0.417). Among 126 patients with refractory ascites 20 patients (15.9%) needed paracentesis 3 months after the procedure: 18/101 patients (17.8%) in RPVG vs 2/25 patients (8%) in LPVG (p = 0.231). Thirty-seven patients (19%) died: 32 (21%) in RPVG and 5 (14%) in LPVG (p = 0.337). CONCLUSION: Compared with RPV puncture, in TIPS created through the LPV, the targeted PSG was reached with a smaller stent diameter. However, no significant difference in clinical outcomes was observed. KEY POINTS: • A LPV approach for TIPS creation does not lead to better control of complications of portal hypertension as compared to a RPV approach.

Clinical outcomes of transjugular intrahepatic portosystemic shunt with PTFE-covered stents after liver transplantation and technical results in split and whole liver graft recipients.

OBJECTIVES: To assess the outcomes of transjugular intrahepatic portosystemic shunt (TIPS) creation using PTFE-covered stents in liver transplant (LT) recipients and to analyze the technical result of TIPS creation in split grafts (SG) compared with whole liver grafts (WG). METHODS AND MATERIALS: Single-center, retrospective study, analyzing LT patients who underwent TIPS using PTFE-covered stents. Clinical and technical variables were analyzed. RESULTS: Between 2005 and 2021, TIPS was created using PTFE-covered stents in 48 LT patients at a median of 43 months (range, 0.5-192) after LT. TIPS indications were refractory ascites (RA) in 33 patients (69%), variceal bleeding (VB) in 9 patients (19%), others in 6 (12%). Ten patients (21%) received a SG. Technical success rate was 100% in both groups: in two WG recipients, (5%) a second attempt was required. An unconventional approach (combined transhepatic or transplenic access) was needed in 2 WG (5%) and 2 SG recipients (20%). Two procedure-related death occurred in the WG group. After a median follow-up of 22 months (range, 0,1-144), 16 patients (48%) in the RA group did not require post-TIPS paracentesis, in the VB group rebleeding occurred in 3 patients (33%). Fifteen patients (31%) underwent TIPS revision. Overt hepatic encephalopathy occurred in 14 patients (29%). Patient survival at 6 months, 1 year, and 3 years was 77%, 66%, and 43%, respectively. CONCLUSIONS: The feasibility and safety of TIPS creation in SG are comparable to that of WG. TIPS creation using PTFE-covered stents represents a viable option to treat portal hypertensive complications in LT recipients. KEY POINTS: • TIPS creation using PTFE-covered stents represents a viable option to treat complications of PH in LT recipients. • TIPS creation in LT SG recipients appears to be safe and feasible as in WG. • Results from this study may help to refine the management of LT patients with recurrent portal hypertensive complications encouraging physicians to consider TIPS creation as a treatment option in both SG and WG recipients.

Brain magnetic resonance imaging radiomics features associated with hepatic encephalopathy in adult cirrhotic patients.

PURPOSE: Hepatic encephalopathy (HE) is a potential complication of cirrhosis. Magnetic resonance imaging (MRI) may demonstrate hyperintense T1 signal in the globi pallidi. The purpose of this study was to evaluate the performance of MRI-based radiomic features for diagnosing and grading chronic HE in adult patients affected by cirrhosis. METHODS: Adult patients with and without cirrhosis underwent brain MRI with identical imaging protocol on a 3T scanner. Patients without history of chronic liver disease were the control population. HE grading was based on underlying liver disease, severity of clinical manifestation, and number of encephalopathic episodes. Texture analysis was performed on axial T1-weighted images on bilateral lentiform nuclei at the level of the foramina of Monro. Diagnostic performance of texture analysis for the diagnosis and grading of HE was assessed by calculating the area under the receiver operating characteristics (AUROC) with 95% confidence interval (CI). RESULTS: The final study population consisted of 124 patients, 70 cirrhotic patients, and 54 non-cirrhotic controls. Thirty-eight patients had history of HE with 22 having an HE grade > 1. The radiomic features predicted the presence of HE with an AUROC of 0.82 (95% CI: 0.73, 0.90; P < .0001; 82% sensitivity, 66% specificity). Radiomic features predicted grade 1 HE (AUROC 0.75; 95% CI: 0.61, 0.89; P < .0001; 94% sensitivity, 60% specificity) and grade ≥ 2 HE (AUROC 0.82; 95% CI: 0.71, 0.93; P < .0001, 95% sensitivity, 57% specificity). CONCLUSION: In cirrhotic patients, MR radiomic is effective in predicting the presence of chronic HE and in grading its severity.

Recurrent graft failure secondary to portal vein steal syndrome: a case report with an unusual indication for a third liver transplant.

BACKGROUND: Portal vein shunt is common in chronic hepatic diseases and after a liver transplant. Ensuring a satisfactory portal flow is essential to support a rapid liver recovery, of paramount importance to meet the recipient's metabolic needs. CASE PRESENTATION: We report the case of a 32-year-old female undergoing a third liver transplant due to recurrence of graft failure secondary to portosystemic shunting. The patient, affected with biliary atresia, was first transplanted in 2009 with a right split liver graft. The clinical course was complicated by biliary stenosis of the Roux-en-Y anastomosis and multiple episodes of acute rejection treated with steroid boluses, plastic dilation of the biliary anastomosis, and biliary catheter placement. Unfortunately, in 2017 a liver biopsy showed an autoimmunity with histological evidence of ANA 1:80 (granular and nucleolar pattern). This was a contributing factor of liver function impairment, leading to the need to perform a second liver transplant, complicated by an acute rejection, with only a partial response to steroid therapy. Due to the further worsening of the liver function (MELD: 40, Child-Pugh: C11), the patient was relisted for a liver transplant. After five days, she received her third liver transplant, with an entire graft of an AB0 identical group. Intraoperative exploration revealed multiple collaterals and large splenocaval shunts, with a significant alteration of the portal flow and hypertension, isolated and closed with a vascular stapler to restore the graft's regular portal vein flow. CONCLUSIONS: In patients listed for a liver transplant, portal steal syndrome should be identified prior to the transplant. Our recommendation is to consider intraoperative or perioperative closure of the portal collateral varices.

Performance of the model for end-stage liver disease score for mortality prediction and the potential role of etiology.

BACKGROUND & AIMS: Although the discriminative ability of the model for end-stage liver disease (MELD) score is generally considered acceptable, its calibration is still unclear. In a validation study, we assessed the discriminative performance and calibration of 3 versions of the model: original MELD-TIPS, used to predict survival after transjugular intrahepatic portosystemic shunt (TIPS); classic MELD-Mayo; and MELD-UNOS, used by the United Network for Organ Sharing (UNOS). We also explored recalibrating and updating the model. METHODS: In total, 776 patients who underwent elective TIPS (TIPS cohort) and 445 unselected patients (non-TIPS cohort) were included. Three, 6 and 12-month mortality predictions were calculated by the 3 MELD versions: discrimination was assessed by c-statistics and calibration by comparing deciles of predicted and observed risks. Cox and Fine and Grey models were used for recalibration and prognostic analyses. RESULTS: In the TIPS/non-TIPS cohorts, the etiology of liver disease was viral in 402/188, alcoholic in 185/130, and non-alcoholic steatohepatitis in 65/33; mean follow-up±SD was 25±9/19±21 months; and the number of deaths at 3-6-12 months was 57-102-142/31-47-99, respectively. C-statistics ranged from 0.66 to 0.72 in TIPS and 0.66 to 0.76 in non-TIPS cohorts across prediction times and scores. A post hoc analysis revealed worse c-statistics in non-viral cirrhosis with more pronounced and significant worsening in the non-TIPS cohort. Calibration was acceptable with MELD-TIPS but largely unsatisfactory with MELD-Mayo and -UNOS whose performance improved much after recalibration. A prognostic analysis showed that age, albumin, and TIPS indication might be used to update the MELD. CONCLUSIONS: In this validation study, the performance of the MELD score was largely unsatisfactory, particularly in non-viral cirrhosis. MELD recalibration and candidate variables for an update to the MELD score are proposed. LAY SUMMARY: While the discriminative performance of the model for end-stage liver disease (MELD) score is credited to be fair to good, its calibration, the correspondence of observed to predicted mortality, is still unsettled. We found that application of 3 different versions of the MELD in 2 independent cirrhosis cohorts yielded largely imprecise mortality predictions particularly in non-viral cirrhosis. Thus, we propose a recalibration and suggest candidate variables for an update to the model.

Adult to Adult Living Donor Liver Transplantation in Recipients with Low MELD: A Strategy Intended to Overcome Donor Shortage.

Recent series have demonstrated advantages of living donor over deceased donor liver transplantation, with particular benefit for those with low model for end-stage liver disease score. The logic underlying the transplantation of patients before they become too sick is intuitive. It reduces mortality and drop outs from the waiting list and makes transplant surgery less demanding. Those principles have to be balanced with donor safety and transplant benefit for the recipient avoiding early, futile transplantation. The authors report a case of adult to adult right lobe living donor liver transplantation performed for a recipient affected by primary biliary cirrhosis with MELD score of 15, in a transplant center located in an area of Europe characterized by chronic organ shortage.

Radiation exposure during transjugular intrahepatic portosystemic shunt creation in patients with complete portal vein thrombosis or portal cavernoma.

BACKGROUND: This study aims to evaluate radiation exposure in patients with complete portal vein thrombosis (CPVT) or portal cavernoma (PC) undergoing transjugular intrahepatic portosystemic shunt (TIPS) creation using real-time ultrasound guidance for portal vein targeting. MATERIALS AND METHODS: This is a single institution retrospective analysis. Between August 2009 and September 2018, TIPS was attempted in 49 patients with CPVT or PC. Radiation exposure (dose area product [DAP], air KERMA (AK) and fluoroscopy time [FT]), technical success, clinical success, complications and survival were analyzed. RESULTS: In total, 29 patients had CPVT and 20 patients had PC. 41/49 patients had cirrhosis. TIPS indications were refractory ascites (n = 25), variceal bleeding (n = 16) and other (n = 8). TIPS was successfully placed in 94% (46/49) of patients via a transjugular approach alone (n = 40), a transjugular/transhepatic approach (n = 5) and a transjugular/transsplenic approach (n = 1). Median DAP was 261 Gy * cm2 (range 29-950), median AK was 0.2 Gy (range 0.05-0.5), and median FT was 28.2 min (range 7.7-93.7). Mean portosystemic pressure gradient decreased from 16.8  ±  5.1 mmHg to 7.5  ±  3.3 mmHg (P <  0.01). There were no major procedural complications. Overall clinical success was achieved in 77% of patients (mean follow-up of 21.1 months). Encephalopathy was observed in 16 patients (34%), grade II-III encephalopathy in 7 patients (15%). TIPS revision was performed in 15 patients (32%). Overall survival rate was 75%. CONCLUSION: In our experience, the use of real-time ultrasound guidance allowed the majority of the TIPS to be performed via a transjugular approach alone with a reasonably low radiation exposure considering the high technical difficulties of the selected cohort of patients with CVPT or PC.

Transjugular Intrahepatic Portosystemic Shunts in Patients with Cirrhosis with Refractory Ascites: Comparison of Clinical Outcomes by Using 8- and 10-mm PTFE-covered Stents.

Purpose To compare the efficacy and complications of transjugular intrahepatic portosystemic shunt (TIPS) creation performed by using a 10-mm or an 8-mm-diameter polytetrafluoroethylene (PTFE)-covered stent in a consecutive series of patients with cirrhosis with refractory ascites (RA). Materials and Methods The institutional review board approved this retrospective study and informed consent was waived. One hundred seventy-one patients with RA (mean age, 58.7 years ± 10.3; 95% confidence interval [CI]: 57.2 years, 60.3 years) had undergone TIPS placement by using 10-mm (60 patients) or 8-mm (111 patients) covered stent between January 2004 and December 2012. Median follow-up time was 16.8 months (range, 3.4-84.8 months). Hemodynamic changes, incidence of hepatic encephalopathy, and long-term (>3 months) need for paracentesis after TIPS placement were evaluated and calculated by using the Kaplan-Meier method and were compared by using the log-rank test. Results Pre-TIPS demographics and clinical characteristics of the two groups were comparable. The portosystemic gradient before TIPS was 17.0 mm Hg ± 4.2 (95% CI: 15.9 mm Hg, 18.1 mm Hg) in the 10-mm group versus 16.1 mm Hg ± 3.7 (95% CI: 15.4 mm Hg, 16.8 mm Hg) in the 8-mm group (P = .164). After TIPS, the portosystemic gradient was 6.5 mm Hg ± 3.4 (95% CI: 5.7 mm Hg, 7.4 mm Hg) in the 10-mm group versus 7.5 mm Hg ± 2.6 (95% CI: 6.9 mm Hg, 7.9 mm Hg) in the 8-mm group (P = .039). The long-term need for paracentesis was greater in the 8-mm group (64 of 111 patients [58%] vs 18 of 60 patients [31%], P = .003). Overall, hepatic encephalopathy was similar in both groups (45 of 111 patients [41%] vs 26 of 60 patients [44%], P = .728). Conclusion A10-mm PTFE-covered stent leads to better control of RA secondary to portal hypertension in patients with cirrhosis, compared with an 8-mm stent, without increasing the incidence of hepatic encephalopathy. © RSNA, 2017.

Ultrasonographic findings in the ovine udder during lactogenesis in healthy ewes or ewes with pregnancy toxaemia.

Objective of the study was to record, by means of ultrasonographic examination, changes occurring during lactogenesis in the udder of healthy ewes and of ewes with pregnancy toxaemia. The work was carried out in 28 ewes, 16 with pregnancy toxaemia (group A) and 12 healthy controls (group B). B-mode and Doppler ultrasonographic examination of the udder of ewes was performed. During the last month of pregnancy, grey-scale intensity values of mammary parenchyma in group A were significantly greater than in group B (P = 0.007), as was also the progressive increase in grey-scale intensity values in both groups (P < 0.001). Blood mammary input was significantly greater in ewes of group B than in ewes of group A (P < 0.05), as was also the progressive increase in blood input in both groups (P < 0.001). Further, differences between the two groups were identified in pulsatility index (P = 0.007) and in mean blood velocity (P = 0.036), but only during the last fortnight of pregnancy. After lambing, grey-scale values decreased sharply compared to those in pregnancy (P < 0.01), whilst blood input, pulsatility index and mean blood velocity continued the same trend as at the last stage of pregnancy, with differences between the two groups still prevalent (P < 0.05). There was a reverse correlation between grey-scale intensity values and milk quantities (P < 0.035) and a correlation between blood input and milk quantities (P < 0.07). The progressive increase in the diameter of the external pudendal artery was significant (P < 0.001), but no significant differences were evident between the two groups (P > 0.35). Differences between group A and group B in all other haemodynamic parameters studied were not significant, neither throughout the last month of pregnancy (P > 0.25), nor during the first week of lactation (P > 0.06). However, their progressive changes during the last month of pregnancy were significant (P < 0.02).

Liver Transplantation for Hemoperitoneum Secondary to Huge Multiple Hemangiomatosis: A Case Report of a Tele-intensive Care Unit in Deceased-Donor Management.

BACKGROUND: Patients with growing and nonresectable liver hemangiomas should be followed up by a transplant center with extensive experience in complex liver disease. They could be treated on an emergency basis with orthotopic liver transplantation, with an expectation of good long-term results. MATERIALS AND METHODS: We describe the case of a 37-year-old woman with liver hemangiomatosis followed up for 8 years, who presented with bleeding requiring transfusions and developed hemodynamic instability. We listed her for emergency transplant before her sister's living donor work-up could be completed. A liver from a cadaveric donor became available at a small local hospital with no experience in organ donation. Tele-intensive care unit (tele-ICU) technology was used for providing clinical data electronically to physicians, nurses, and other critical care specialists, creating medication orders, and communicating with on-site caregivers to implement changes in donor care. RESULTS: The recipient was transplanted on an emergency basis with a specific customization and application of the telemedicine system in the management of the organ procurement by the recipient team. Tele-ICU technology was used for providing an effective intensive care unit service, managing and stabilizing the deceased donor and allowing the procurement to be carried out uneventfully. CONCLUSIONS: Tele-ICU technology could be a promising resource for emergency transplantation, reducing the urgent need for a living donation and allowing prompt recipient team management of the deceased donor. Our first tele-ICU case offers early confirmation of the feasibility of the telemedicine system in deceased-donor management.

Administration of antibiotics to ewes at the beginning of the dry-period.

The objective of the present paper is to review the significance of administration of antibiotics at the end of a lactation period/beginning of the dry-period in ewes. During the stage of active involution, there is an increased risk of new mastitis cases and recrudescence of subclinical infections that had occurred during the previous lactation period. The main pathogens involved in the so-called 'dry-period mastitis' are coagulase-negative staphylococci. The principle of antibiotic administration at the end of a lactation period involves the intramammary infusion of a preparation to both mammary glands of ewes in the flock. Although a variety of products is licensed for administration in ewes, preferably the product for administration should be selected on the results of susceptibility testing of bacteria to be isolated from samples from ewes in the flock. In many clinical studies from around the world, performed in dairy- or mutton-production flocks, administration of antimicrobial agents at the end of a lactation period has been found beneficial in curing intramammary infections present at cessation of a lactation period, as well as in minimising the risk for intramammary infections during the dry-period. In dairy flocks, there are also benefits from increase in milk yield and decrease flock bulk milk mean somatic cell counts during the subsequent lactation period. Antibiotic administration at drying-off may be performed to all animals in a flock ('complete') or only to those considered to be infected ('selective'). In all cases, after administration of the antibiotic, definite and complete cessation of the lactation period is essential for success of the procedure. Moreover, maintenance of the prescribed withdrawal periods is essential to safeguard public health. The procedure should always be applied as part of a strategic udder health management plan in a flock; implementation improves the welfare of animals and affords significant financial benefits to the farmer. A mastitis prevention scheme during lactation will minimise the incidence of the disease; effective treatment of cases of the disease during lactation will decrease the bacterial populations in the flock and limit risk of infection of other animals. Administration of antibiotics at the end of a lactation period will complement the above procedures and will contribute to improved mammary health for the forthcoming lactation period.

Ultrasonographic findings in the ovine udder during involution.

The objective of the study was to record, by means of ultrasonographic examination, changes occurring in the udder of ewes during involution and to compare differences between progressive or abrupt udder drying-off. In group A ewes, udder drying-off took place progressively during a period of 22 d; ewes were milked twice daily for the last time on day(D) 0; then, they were hand-milked once daily for a week (D1-D7), which was followed by another week during which ewes were hand-milked once every 2 d (D9, D11, D13), followed by a third week during which ewes were hand-milked once every 3 d (D16, D19, D22). In group B ewes, the procedure took place abruptly; ewes were milked twice daily for the last time on D0 and no milking was carried out after that. B-mode and Doppler ultrasonographic examination of the udder of all ewes was performed throughout the drying-off procedure. Appropriate data management and analysis were performed. Progressive changes of the various parameters evaluated throughout the study period were significant in both groups (P<0.005). Gray-scale results of mammary parenchyma progressively decreased during the study and differed significantly between group A and group B (P=0.049). A temporary increase in cistern volume was evident after cessation of lactation, but differences were not significant between the two groups (P>0.3). Diameter of the external pudendal artery progressively decreased during the study and differed significantly between the two groups (P=0.037). Both resistance index and pulsatility index progressively increased throughout the study period in both groups; for both parameters, differences between the two groups were significant (P<0.0005). B-mode ultrasonographic examination indicated differences in remodelling of the extracellular matrix in relation to the procedure for udder drying-off. Volume of the gland cistern did not appear to be affected by the procedure for udder drying-off. Doppler ultrasonographic examination confirmed that blood flow during initiated involution was lower than during a progressive procedure for drying-off.

Lameness in Adult Sheep and Goats in Greece: Prevalence, Predictors, Treatment, Importance for Farmers.

The present study refers to an extensive investigation of lameness performed countrywide in Greece, on 325 sheep and 119 goat farms. The specific objectives of this work were to present data on the occurrence of lameness on sheep and goat farms and to identify variables (including variables related to climatic factors) associated with the disorder on the farms. Farms were visited and animals on the farm were assessed for the presence of lameness; further, an interview was carried out with the farmer to obtain information regarding practices applied on the farm. Climatic variables at the location of each farm were derived from NASA research. The within farm prevalence rate varied from 0.0% to 25.0% in sheep flocks and from 0.0% to 30.0% in goat herds. The mean ± standard error (median (interquartile range)) within farm prevalence rate among sheep farms was 1.9% ± 0.2 (0.0% (0.0%)); among goat farms, it was 2.6% ± 0.5% (0.0% (0.0%)). Multivariable analysis for within farm prevalence of lameness revealed three significant predictors in sheep farms: application of vaccination against foot-rot, increased precipitation at the farm location and longer annual grazing period for sheep, and one in goat farms: increased precipitation at the farm location. Treatment of lameness involved mostly administration of antibiotics (on 104 farms); the antibiotics administered most often were lincomycin (on 69 farms) and oxytetracycline (on 33 farms). There was a tendency for higher median within farm prevalence of lameness among farms where no antibiotic administration was practiced. Finally, 6.2% of sheep farmers and 4.2% of goat farmers considered lameness as an important health problem for the animals, specifically the third and fifth most important problem on the respective farms.

Human Biomonitoring Data in Health Risk Assessments Published in Peer-Reviewed Journals between 2016 and 2021: Confronting Reality after a Preliminary Review.

Human biomonitoring (HBM) is a rapidly developing field that is emphasized as an important approach for the assessment of health risks. However, its value for health risk assessment (HRA) remains to be clarified. We performed a review of publications concerned with applications of HBM in the assessment of health risks. The selection of publications for this review was limited by the search engines used (only PubMed and Scopus) and a timeframe of the last five years. The review focused on the clarity of 10 HRA elements, which influence the quality of HRA. We show that the usage of HBM data in HRA is limited and unclear. Primarily, the key HRA elements are not consistently applied or followed when using HBM in such assessments, and secondly, there are inconsistencies regarding the understanding of fundamental risk analysis principles and good practices in risk analysis. Our recommendations are as follows: (i) potential usage of HBM data in HRA should not be non-critically overestimated but rather limited and aligned to a specific value for exposure assessment or for the interpretation of health damage; (ii) improvements to HRA approaches, using HBM information or not, are needed and should strictly follow theoretical foundations of risk analysis.

An exposome connectivity paradigm for the mechanistic assessment of the effects of prenatal and early life exposure to metals on neurodevelopment.

The exposome paradigm through an integrated approach to investigating the impact of perinatal exposure to metals on child neurodevelopment in two cohorts carried out in Slovenia (PHIME cohort) and Greece (HERACLES cohort) respectively, is presented herein. Heavy metals are well-known neurotoxicants with well-established links to impaired neurodevelopment. The links between in utero and early-life exposure to metals, metabolic pathway dysregulation, and neurodevelopmental disorders were drawn through urinary and plasma untargeted metabolomics analysis, followed by the combined application of in silico and biostatistical methods. Heavy metal prenatal and postnatal exposure was evaluated, including parameters indirectly related to exposure and health adversities, such as sociodemographic and anthropometric parameters and dietary factors. The primary outcome of the study was that the identified perturbations related to the TCA cycle are mainly associated with impaired mitochondrial respiration, which is detrimental to cellular homeostasis and functionality; this is further potentiated by the capacity of heavy metals to induce oxidative stress. Insufficient production of energy from the mitochondria during the perinatal period is associated with developmental disorders in children. The HERACLES cohort included more detailed data regarding diet and sociodemographic status of the studied population, allowing the identification of a broader spectrum of effect modifiers, such as the beneficial role of a diet rich in antioxidants such as lycopene and ω-3 fatty acids, the negative effect the consumption of food items such as pork and chicken meat has or the multiple impacts of fish consumption. Beyond diet, several other factors have been proven influential for child neurodevelopment, such as the proximity to pollution sources (e.g., waste treatment site) and the broader living environment, including socioeconomic and demographic characteristics. Overall, our results demonstrate the utility of exposome-wide association studies (EWAS) toward understanding the relationships among the multiple factors that determine human exposure and the underlying biology, reflected as omics markers of effect on neurodevelopment during childhood.

Dose- and Volume-Limiting Late Toxicity of FLASH Radiotherapy in Cats with Squamous Cell Carcinoma of the Nasal Planum and in Mini Pigs.

PURPOSE: The FLASH effect is characterized by normal tissue sparing without compromising tumor control. Although demonstrated in various preclinical models, safe translation of FLASH-radiotherapy stands to benefit from larger vertebrate animal models. Based on prior results, we designed a randomized phase III trial to investigate the FLASH effect in cat patients with spontaneous tumors. In parallel, the sparing capacity of FLASH-radiotherapy was studied on mini pigs by using large field irradiation. EXPERIMENTAL DESIGN: Cats with T1-T2, N0 carcinomas of the nasal planum were randomly assigned to two arms of electron irradiation: arm 1 was the standard of care (SoC) and used 10 × 4.8 Gy (90% isodose); arm 2 used 1 × 30 Gy (90% isodose) FLASH. Mini pigs were irradiated using applicators of increasing size and a single surface dose of 31 Gy FLASH. RESULTS: In cats, acute side effects were mild and similar in both arms. The trial was prematurely interrupted due to maxillary bone necrosis, which occurred 9 to 15 months after radiotherapy in 3 of 7 cats treated with FLASH-radiotherapy (43%), as compared with 0 of 9 cats treated with SoC. All cats were tumor-free at 1 year in both arms, with one cat progressing later in each arm. In pigs, no acute toxicity was recorded, but severe late skin necrosis occurred in a volume-dependent manner (7-9 months), which later resolved. CONCLUSIONS: The reported outcomes point to the caveats of translating single-high-dose FLASH-radiotherapy and emphasizes the need for caution and further investigations. See related commentary by Maity and Koumenis, p. 3636.

Changing picture of central nervous system complications in liver transplant recipients.

Central nervous system (CNS) complications are common after liver transplantation (LT). According to the literature, the most common causes are infections and the neurotoxicity of immunosuppressive drugs (cyclosporine and tacrolimus). The aim of this study was to evaluate the incidence, clinical presentations, etiologies, and outcomes of CNS complications in a series of 395 consecutive LT recipients whose immunosuppression regimen was designed for low tacrolimus blood levels. An analysis of the 12-hour trough concentrations of tacrolimus in the study population showed that the target drug levels, which were designed to maintain minimal immunosuppression, were usually achieved. In all, 64 patients (16.2%) developed major neurological symptoms (37 within 30 days of LT). None of the observed CNS complications were caused by infections (viral, bacterial, or fungal), and only 3 of the 395 patients (0.8%) received a diagnosis of tacrolimus-related leukoencephalopathy. Cerebrovascular disease was identified in 15 patients (3.8%; 8 had cerebral hemorrhages, 5 had ischemic strokes, and 2 had subdural hemorrhages). Pontine myelinolysis was found in 2 patients (0.5%). Notably, no clear cause was identified for the remaining 44 cases (11.1%): brain imaging was negative for 22 cases, and diffuse hypoxic changes were present for the other 22. CNS complications were significantly associated with a reduction in 3-month patient survival (88.8% versus 95.4%) and 5-year patient survival (57.3% versus 84.1%). Among the pretransplant variables that were analyzed, the incidence of portosystemic encephalopathy, the peak serum bilirubin levels, and the lowest serum total cholesterol levels were significantly different between the 64-patient group with CNS complications and the asymptomatic group of 331 patients.

Lamivudine monoprophylaxis for de novo HBV infection in HBsAg-negative recipients with HBcAb-positive liver grafts.

We followed the efficacy of long-term lamivudine monotherapy in preventing development of de novo hepatitis B (DNHB) in a large cohort of hepatitis B surface antigen (HBsAg)-negative recipients with grafts from hepatitis B core antibody (HBcAb)-positive donors. Recipients were observed over a long follow-up. Between July 1999 and December 2008, 45 patients (median age 54, range 19-67) who were HBsAg negative before transplantation were included in the study of monoprophylaxis with lamivudine starting on post-operative day 1, and continuing for life. Mean follow-up: 37.9 months; median 32.1 months (range 2.4-117). No suspension of therapy was reported during the study. Post-transplantation, no DNHB was observed in follow-up: all 45 HBsAg-negative recipients remained HBsAg and HBV DNA negative. Thirty-four of these HBsAg-negative recipients were alive at conclusion of the study. A total of 11 patients died, five of HCV recurrence, two of hepatocellular carcinoma (HCC) recurrence, two of disseminated KSV infection, and two of multiorgan failure because of early graft dysfunction. Patient and graft survival of HBsAg-negative recipients with HBcAb-positive donor grafts (45 cases) were not significantly different from those of the HBsAg-negative recipients with HBcAb-negative donor grafts (302 cases). In our experience, lamivudine monoprophylaxis provided complete protection against HBV reactivation and showed long-term efficacy.

Mass spectrometry measurement of plasma hepcidin for the prediction of iron overload.

BACKGROUND: Hepcidin has emerged as the primary regulator of iron homeostasis. Previous studies on assessing urinary hepcidin are limited. We developed a method for quantifying hepcidin-25 (Hep-25) in plasma using surface-enhanced laser-desorption-ionization time-of-flight mass spectrometry (SELDI-TOF/MS) and a 25-AA peptide as reference standard. The aims of the study were 1) to assess the performance of this method in different conditions of iron metabolism disorders; 2) to assess the diagnostic validity of non-invasive serum biomarkers in the identification of iron overload. METHODS: Validation of the method was performed in 10 patients with type I hemochromatosis (HE) and in 177 subjects previously enrolled in a general population epidemiological study. Among the latter group, 17 had non-alcoholic fatty liver disease, 10 had chronic hepatitis C, and 150 subjects had normal ultrasound, normal liver function tests (LFTs), an alcohol intake < 20 g ethanol/day and were negative for the C282Y mutation. The following biomarkers were assayed in each case: plasma Hep-25, C282Y and H63D mutations of the HFE gene; serum iron, ferritin (SF), transferrin saturation, transaminases, γ-glutamyltransferase (GGT), glucose, insulin, total cholesterol, high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol and triglycerides. RESULTS: Plasma Hep-25 concentrations were higher in HCV+ patients (26.3 ± 7.2 nmol/L) than in controls, and correlated positively with SF (p < 0.001). H63D heterozygous subjects revealed a pattern of iron overload that was significantly higher than H63D wild type subjects. Analyzing the data with the Biomarker Pattern 5.0.2. software to identify the most significant biomarkers for discriminating between HE cases and controls allowed us to produce an algorithm with four terminal nodes, which included glucose > 4.8 mmol/L and Hep-25/SF ratio ≤ 6.6 as the main splitters. These variables enabled the correct diagnosis of HE with 100% sensitivity, 93% specificity and an area under the receiver operating characteristic (ROC) curve of 0.993. CONCLUSIONS: Our plasma Hep-25 mass spectrometry method yields measurements that reflect pathological and genetic influences; simple non-invasive biomarkers (Hep-25/SF ratio and glucose) can predict the presence of HE.