Development and deployment of a histopathology-based deep learning algorithm for patient prescreening in a clinical trial.

Accurate identification of genetic alterations in tumors, such as Fibroblast Growth Factor Receptor, is crucial for treating with targeted therapies; however, molecular testing can delay patient care due to the time and tissue required. Successful development, validation, and deployment of an AI-based, biomarker-detection algorithm could reduce screening cost and accelerate patient recruitment. Here, we develop a deep-learning algorithm using >3000 H&E-stained whole slide images from patients with advanced urothelial cancers, optimized for high sensitivity to avoid ruling out trial-eligible patients. The algorithm is validated on a dataset of 350 patients, achieving an area under the curve of 0.75, specificity of 31.8% at 88.7% sensitivity, and projected 28.7% reduction in molecular testing. We successfully deploy the system in a non-interventional study comprising 89 global study clinical sites and demonstrate its potential to prioritize/deprioritize molecular testing resources and provide substantial cost savings in the drug development and clinical settings.

Accelerating pharmaceutical R&D with a user-friendly AI system for histopathology image analysis.

A system for analysis of histopathology data within a pharmaceutical R&D environment has been developed with the intention of enabling interdisciplinary collaboration. State-of-the-art AI tools have been deployed as easy-to-use self-service modules within an open-source whole slide image viewing platform, so that non-data scientist users (e.g., clinicians) can utilize and evaluate pre-trained algorithms and retrieve quantitative results. The outputs of analysis are automatically cataloged in the database to track data provenance and can be viewed interactively on the slide as annotations or heatmaps. Commonly used models for analysis of whole slide images including segmentation, extraction of hand-engineered features for segmented regions, and slide-level classification using multi-instance learning are included and new models can be added as needed. The source code that supports running inference with these models internally is backed up by a robust CI/CD pipeline to ensure model versioning, robust testing, and seamless deployment of the latest models. Examples of the use of this system in a pharmaceutical development workflow include glomeruli segmentation, enumeration of podocyte count from WT-1 immuno-histochemistry, measurement of beta-1 integrin target engagement from immunofluorescence, digital glomerular phenotyping from periodic acid-Schiff histology, PD-L1 score prediction using multi-instance learning, and the deployment of the open-source Segment Anything model to speed up annotation.

Retrospective fractional dose reduction in Tc-99m cardiac perfusion SPECT/CT patients: A human and model observer study.

BACKGROUND: In the ongoing efforts to reduce cardiac perfusion dose (injected radioactivity) for conventional SPECT/CT systems, we performed a human observer study to confirm our clinical model observer findings that iterative reconstruction employing OSEM (ordered-subset expectation-maximization) at 25% of the full dose (quarter-dose) has a similar performance for detection of hybrid cardiac perfusion defects as FBP at full dose. METHODS: One hundred and sixty-six patients, who underwent routine rest-stress Tc-99m sestamibi cardiac perfusion SPECT/CT imaging and clinically read as normally perfused, were included in the study. Ground truth was established by the normal read and the insertion of hybrid defects. In addition to the reconstruction of the 25% of full-dose data using OSEM with attenuation (AC), scatter (SC), and spatial resolution correction (RC), FBP and OSEM (with AC, SC, and RC) both at full dose (100%) were done. Both human observer and clinical model observer confidence scores were obtained to generate receiver operating characteristics (ROC) curves in a task-based image quality assessment. RESULTS: Average human observer AUC (area under the ROC curve) values of 0.725, 0.876, and 0.890 were obtained for FBP at full dose, OSEM at 25% of full dose, and OSEM at full dose, respectively. Both OSEM strategies were significantly better than FBP with P values of 0.003 and 0.01 respectively, while no significant difference was recorded between OSEM methods (P = 0.48). The clinical model observer results were 0.791, 0.822, and 0.879, respectively, for the same patient cases and processing strategies used in the human observer study. CONCLUSIONS: Cardiac perfusion SPECT/CT using OSEM reconstruction at 25% of full dose has AUCs larger than FBP and closer to those of full-dose OSEM when read by human observers, potentially replacing the higher dose studies during clinical reading.

Improving Diagnostic Accuracy in Low-Dose SPECT Myocardial Perfusion Imaging With Convolutional Denoising Networks.

Lowering the administered dose in SPECT myocardial perfusion imaging (MPI) has become an important clinical problem. In this study we investigate the potential benefit of applying a deep learning (DL) approach for suppressing the elevated imaging noise in low-dose SPECT-MPI studies. We adopt a supervised learning approach to train a neural network by using image pairs obtained from full-dose (target) and low-dose (input) acquisitions of the same patients. In the experiments, we made use of acquisitions from 1,052 subjects and demonstrated the approach for two commonly used reconstruction methods in clinical SPECT-MPI: 1) filtered backprojection (FBP), and 2) ordered-subsets expectation-maximization (OSEM) with corrections for attenuation, scatter and resolution. We evaluated the DL output for the clinical task of perfusion-defect detection at a number of successively reduced dose levels (1/2, 1/4, 1/8, 1/16 of full dose). The results indicate that the proposed DL approach can achieve substantial noise reduction and lead to improvement in the diagnostic accuracy of low-dose data. In particular, at 1/2 dose, DL yielded an area-under-the-ROC-curve (AUC) of 0.799, which is nearly identical to the AUC = 0.801 obtained by OSEM at full-dose ( p -value = 0.73); similar results were also obtained for FBP reconstruction. Moreover, even at 1/8 dose, DL achieved AUC = 0.770 for OSEM, which is above the AUC = 0.755 obtained at full-dose by FBP. These results indicate that, compared to conventional reconstruction filtering, DL denoising can allow for additional dose reduction without sacrificing the diagnostic accuracy in SPECT-MPI.

Application of Dried Human Amnion Graft to Improve Post-Prostatectomy Incontinence and Potency: A Randomized Exploration Study Protocol.

INTRODUCTION: Incontinence (up to 20%) and erectile dysfunction (up to 70%) occur frequently after radical prostatectomy (RP) in patients with localized prostate cancer. Human amniotic membrane (HAM) can improve tissue regeneration and functional outcome after RP owing to the growth factors and unique immune tolerance. Preliminary studies showed the potential value of HAM in the reconstruction of the urinary tract and nerve protection during RP. METHODS: A protocol is developed for a prospective, randomized, single-blind, single-surgeon, placebo-controlled exploration study of the efficacy and safety of dehydrated human amnion membrane placed around the neurovascular bundle (NVB) and vesicourethral anastomosis (VUA) during RP for the treatment of localized prostate cancer. Eligible for inclusion are patients with localized prostate cancer, requiring a surgical procedure and exclusion of preoperative incontinence and erectile dysfunction. The patients are randomized 1:1 to HAM vs. placebo and blinded during the study period. According to the T test with an alpha of 0.05 and a power of 80% and expecting a dropout of 20% of the patients, an adjusted sample size per arm of 164 patients is required. PLANNED OUTCOMES: The primary outcome is a postoperative continence measured as 24-h pad test up to 12 months postoperatively. Secondary outcomes are potency, time of postoperative catheter removal, postoperative complications, and biochemical recurrence. The protocol for this randomized exploration study defines the conditions to assess the efficacy and safety of HAM application during RP in order to improve the postoperative functional outcome. This trial should pave the way for future studies of tissue engineering in an effort to reduce the morbidity of RP. TRIAL REGISTRATION: Clinicaltrials.gov, identifier NCT03864939.

Evaluation of the effect of reducing administered activity on assessment of function in cardiac gated SPECT.

BACKGROUND: We previously optimized several reconstruction strategies in SPECT myocardial perfusion imaging (MPI) with low dose for perfusion-defect detection. Here we investigate whether reducing the administered activity can also maintain the diagnostic accuracy in evaluating cardiac function. METHODS: We quantified the myocardial motion in cardiac-gated stress 99m-Tc-sestamibi SPECT studies from 163 subjects acquired with full dose (29.8 ± 3.6 mCi), and evaluated the agreement of the obtained motion/thickening and ejection fraction (EF) measures at various reduced dose levels (uniform reduction or personalized dose) with that at full dose. We also quantified the detectability of abnormal motion via a receiver-operating characteristics (ROC) study. For reconstruction we considered both filtered backprojection (FBP) without correction for degradations, and iterative ordered-subsets expectation-maximization (OS-EM) with resolution, attenuation and scatter corrections. RESULTS: With dose level lowered to 25% of full dose, the obtained results on motion/thickening, EF and abnormal motion detection were statistically comparable to full dose in both reconstruction strategies, with Pearson's r > 0.9 for global motion measures between low dose and full dose. CONCLUSIONS: The administered activity could be reduced to 25% of full dose without degrading the function assessment performance. Low dose reconstruction optimized for perfusion-defect detection can be reasonable for function assessment in gated SPECT.

Personalized Models for Injected Activity Levels in SPECT Myocardial Perfusion Imaging.

We propose a patient-specific ("personalized") approach for tailoring the injected activities to individual patients in order to achieve dose reduction in SPECT-myocardial perfusion imaging (MPI). First, we develop a strategy to determine the minimum dose levels required for each patient in a large set of clinical acquisitions (857 subjects) such that the reconstructed images are sufficiently similar to that obtained at conventional clinical dose. We then apply machine learning models to predict the required dose levels on an individual basis based on a set of patient attributes which include body measurements and various clinical variables. We demonstrate the personalized dose models for two commonly used reconstruction methods in clinical SPECT-MPI: 1) conventional filtered backprojection (FBP) with post-filtering and 2) ordered-subsets expectation-maximization (OS-EM) with corrections for attenuation, scatter and resolution, and evaluate their performance in perfusion-defect detection by using the clinical Quantitative Perfusion SPECT software package. The results indicate that the achieved dose reduction can vary greatly among individuals from their conventional clinical dose and that the personalized dose models can achieve further reduction on average compared with a global (non-patient specific) dose reduction approach. In particular, the average personalized dose level can be reduced to 58% and 54% of the full clinical dose, respectively, for FBP and OS-EM reconstruction, while without deteriorating the accuracy in perfusion-defect detection. Furthermore, with the average personalized dose further reduced to only 16% of full dose, OS-EM can still achieve a detection accuracy level comparable to that of FBP with full dose.

Improving perfusion defect detection with respiratory motion correction in cardiac SPECT at standard and reduced doses.

BACKGROUND: In cardiac SPECT perfusion imaging, respiratory motion can cause non-uniform blurring in the reconstructed myocardium. We investigate the potential benefit of respiratory correction with respiratory-binned acquisitions, both at standard dose and at reduced dose, for defect detection and for left ventricular (LV) wall resolution. METHODS: We applied two reconstruction methods for respiratory motion correction: post-reconstruction motion correction (PMC) and motion-compensated reconstruction (MCR), and compared with reconstruction without motion correction (Non-MC). We quantified the presence of perfusion defects in reconstructed images by using the total perfusion deficit (TPD) scores and conducted receiver-operating-characteristic (ROC) studies using TPD. We quantified the LV spatial resolution by using the FWHM of its cross-sectional intensity profile. RESULTS: The values in the area-under-the-ROC-curve (AUC) achieved by MCR, PMC, and Non-MC at standard dose were 0.835, 0.830, and 0.798, respectively. Similar AUC improvements were also obtained by MCR and PMC over Non-MC at 50%, 25%, and 12.5% of full dose. Improvements in LV resolution were also observed with motion correction. CONCLUSIONS: Respiratory-binned acquisitions can improve perfusion-defect detection accuracy over traditional reconstruction both at standard dose and at reduced dose. Motion correction may contribute to achieving further dose reduction while maintaining the diagnostic accuracy of traditional acquisitions.

Investigation of dose reduction in cardiac perfusion SPECT via optimization and choice of the image reconstruction strategy.

BACKGROUND: We investigated the extent to which the administered dose (activity) level can be reduced without sacrificing diagnostic accuracy for three reconstruction strategies for SPECT-myocardial perfusion imaging (MPI). METHODS: We optimized the parameters of the three reconstruction strategies for perfusion-defect detection over a range of simulated administered dose levels using a set of hybrid studies (derived from 190 subjects) consisting of clinical SPECT-MPI data modified to contain realistic simulated lesions. The optimized strategies we considered are filtered backprojection (FBP) with no correction for degradations, ordered-subsets expectation-maximization (OS-EM) with attenuation correction (AC), scatter correction (SC), and resolution correction (RC), and OS-EM with scatter and resolution correction only. Each study was evaluated using a total perfusion deficit (TPD) score computed by the Quantitative Perfusion SPECT (QPS) software package. We conducted a receiver operating characteristics (ROC) study based on the TPD scores for each dose level and reconstruction strategy. RESULTS: For FBP, the achieved optimum values of the area under the ROC curve (AUC) at 100%, 50%, 25%, and 12.5% of standard dose were 0.75, 0.74, 0.72, and 0.70, respectively, compared to 0.81, 0.79, 0.76, and 0.74 for OS-EM with AC-SC-RC and 0.78, 0.77, 0.74, 0.72 for OS-EM with SC-RC. CONCLUSIONS: Our results suggest that studies reconstructed by OS-EM with AC-SC-RC could possibly be reduced, on average, to 25% of the originally administered dose without causing diagnostic accuracy (AUC) to decrease below that of FBP.

Protocol for a Randomized Phase II Trial for Mesh Optimization by Autologous Plasma Coating in Prolapse Repair: IDEAL Stage 3.

INTRODUCTION: Mesh-related complications especially after vaginal implantation have raised awareness lately because of severe adverse reactions and legal aspects. About 20% of patients suffer from complications after mesh insertion in the anterior vaginal wall. Autologous plasma coating of meshes prior to implantation has shown potential to improve the biocompatibility of meshes in vivo and in vitro. This innovative approach has been developed according to the IDEAL recommendations for surgical innovations. The method has still to be assessed at stage 3 accordingly. METHODS: A protocol is developed for a prospective single-blinded randomized controlled phase II trial for biocompatibility optimization of anterior vaginal meshes for prolapse repair by autologous plasma coating versus non-coated meshes. RESULTS: The protocol aims at fulfilling the requirements for stage 3 (assessment) according to IDEAL. Eligible for inclusion are women with primary cystocele, requiring a surgical procedure, suitable for randomization, and willing to be randomized. Participants will be followed up by postal questionnaires (6 months post surgery and 12 months post randomization) and will also be reviewed in clinic 12 and 24 months post surgery. Primary endpoint is the assessment of mesh-related complications following the Clavien-Dindo classifications. QoL, sexual function assessment, efficacy, and validation of an already developed long-term register are considered secondary endpoints. To afford a calculated 10% reduction of postoperative complications through plasma-coated meshes vs. non-coated meshes at 1-year follow-up, a total 214 women in each arm will be necessary to achieve 80% power at a significance level of 5%. CONCLUSION: The protocol for this randomized clinical trial represents the conditions to assess the surgical innovation of plasma coating of meshes in order to improve the meshes' biocompatibility at stage 3 according to the IDEAL recommendations.

CD4+ROR γ t++ and Tregs in a Mouse Model of Diet-Induced Nonalcoholic Steatohepatitis.

BACKGROUND AND AIMS: Inflammatory mediators that cross-talk in different metabolically active organs are thought to play a crucial role in the pathogenesis of Nonalcoholic Steatohepatitis (NASH). This study was aimed at investigating the CD4+RORγt+ T-helper cells and their counterpart, the CD4+CD25+FOXP3+ regulatory T cells in the liver, subcutaneous adipose tissue (SAT), and abdominal adipose tissue (AAT) in a high fat diet (HFD) mouse model. METHODS: C57BL6 mice were fed a HFD or a normal diet (ND). Liver enzymes, metabolic parameters, and liver histology were assessed. The expression of CD4+RORγt+ cells and regulatory T cells in different organs (blood, liver, AAT, and SAT) were analyzed by flow cytometry. Cytokine and adipokine tissue expression were studied by RT-PCR. RESULTS: Mice fed a HFD developed NASH and metabolic alterations compared to normal diet. CD4+RORγt++ cells were significantly increased in the liver and the AAT while an increase of regulatory T cells was observed in the SAT of mice fed HFD compared to ND. Inflammatory cytokines were also upregulated. CONCLUSIONS: CD4+RORγt++ cells and regulatory T cells are altered in NASH with a site-specific pattern and correlate with the severity of the disease. These site-specific differences are associated with increased cytokine expression.

Coating of mesh grafts for prolapse and urinary incontinence repair with autologous plasma: exploration stage of a surgical innovation.

PURPOSE: Optimized biocompatibility is a major requirement for alloplastic materials currently applied for stress urinary incontinence (SUI) and pelvic organ prolapse (POP) repair. In the preliminary studies the mesh modification by coating with autologous plasma resulted in the increased adherence score in vitro and improved biocompatibility in an animal model. The first use of plasma coated meshes in human is presented. MATERIALS AND METHODS: Between 04/2013 and 05/2014, 20 patients with the indication for SUI and POP repair were selected in a single institution. The applied meshes were modified by autologous plasma coating prior to implantation. A retrospective chart review for peri- and early postoperative complications was performed. Functional outcome and QoL were evaluated pre- and postoperatively. RESULTS: The functional outcome and QoL improved significantly in all groups. Two reoperations (Grade IIIB) with the release of TVT-mesh in anesthesia due to the obstruction were needed. No other severe complications were registered. CONCLUSION: For the first time we applied a mesh modification in a human setting according to IDEAL criteria of surgical innovations. The procedure of mesh coating with autologous plasma is safe and a prospective randomized trial proving a positive effect of plasma coating on the biocompatibility and morbidity outcome with long-term registry is planned.

Inflammatory reaction as determinant of foreign body reaction is an early and susceptible event after mesh implantation.

PURPOSE: To investigate and relate the ultrashort-term and long-term courses of determinants for foreign body reaction as biocompatibility predictors for meshes in an animal model. MATERIALS AND METHODS: Three different meshes (TVT, UltraPro, and PVDF) were implanted in sheep. Native and plasma coated meshes were placed bilaterally: (a) interaperitoneally, (b) as fascia onlay, and (c) as muscle onlay (fascia sublay). At 5 min, 20 min, 60 min, and 120 min meshes were explanted and histochemically investigated for inflammatory infiltrate, macrophage infiltration, vessel formation, myofibroblast invasion, and connective tissue accumulation. The results were related to long-term values over 24 months. RESULTS: Macrophage invasion reached highest extents with up to 60% in short-term and decreased within 24 months to about 30%. Inflammatory infiltrate increased within the first 2 hours, the reached levels and the different extents and ranking among the investigated meshes remained stable during long-term follow up. For myofibroblasts, connective tissue, and CD31+ cells, no activity was detected during the first 120 min. CONCLUSION: The local inflammatory reaction is an early and susceptible event after mesh implantation. It cannot be influenced by prior plasma coating and does not depend on the localisation of implantation.

Increased intrahepatic resistance in severe steatosis: endothelial dysfunction, vasoconstrictor overproduction and altered microvascular architecture.

Non-alcoholic fatty liver disease can progress to steatohepatitis and fibrosis, and is also associated with impaired liver regeneration. The pathophysiology remains elusive. We recently showed that severe steatosis is associated with an increase in portal pressure, suggesting liver flow impairment. The objective of this study is to directly assess total intrahepatic resistance and its potential functional and structural determinants in an in situ perfusion model. Male Wistar rats fed a control (n = 30) or a methionine-choline-deficient (MCD) diet (n = 30) for 4 weeks were compared. Liver tissue and serum analysis, in vivo haemodynamic measurements, in situ perfusion experiments and vascular corrosion casts were performed. The MCD group showed severe steatosis without inflammation or fibrosis on histology. Serum levels and liver tissue gene expression of interleukin (IL)-6, tumour necrosis factor-α, IL-1ß and interferon-γ, liver tissue myeloperoxidase activity and liver immunohistochemistry with anti-CD68 and anti-α smooth muscle actin were comparable between groups, excluding significant inflammation. Flow-pressure curves were significantly different between groups for all flows (slope values: 0.1636 ± 0.0605 mm Hg/ml/min in controls vs 0.7270 ± 0.0408 mm Hg/ml/min in MCD-fed rats, P < 0.001), indicating an increased intrahepatic resistance, which was haemodynamically significant (portocaval pressure gradient 2.2 ± 1.1 vs 8.2 ± 1.3 mm Hg in controls vs MCD, P<0.001). Dose-response curves to acetylcholine were significantly reduced in MCD-fed rats (P < 0.001) as was the responsiveness to methoxamine (P<0.001). Vascular corrosion casts showed a replacement of the regular sinusoidal anatomy by a disorganized pattern with multiple interconnections and vascular extensions. Liver phosphorylated endothelial NO synthase (eNOS)/eNOS and serum nitrite/nitrate were not increased in severe steatosis, whereas liver thromboxane synthase expression, liver endothelin-1 (ET-1) expression and serum andothelin-1 concentration were significantly increased. Severe steatosis induces a haemodynamically significant increase in intrahepatic resistance, which precedes inflammation and fibrogenesis. Both functional (endothelial dysfunction and increased thromboxane and ET-1 synthesis) and structural factors are involved. This phenomenon might significantly contribute to steatosis-related disease.

Epidemiology and treatment of autoimmune hepatitis.

Autoimmune hepatitis (AIH) is a chronic inflammatory disease of the liver that occurs worldwide with a low and probably underestimated prevalence. Although it typically affects young and middle-aged women, it can occur in both sexes and across all age groups. AIH runs a fluctuating course, but can present as severe and even fulminant hepatic failure or at a stage of advanced fibrosis or cirrhosis. Prognosis of severe AIH is poor if untreated. The pathogenesis is complex, combining environmental factors (external chemical or infectious triggers) and host genetic susceptibility. The diagnosis is based, after exclusion of other etiologies of chronic liver disease, on a combination of different elements, including the presence of elevated transaminases, elevated immunoglobulin G (IgG) levels, the presence and pattern of typical autoantibodies, and a liver biopsy showing interface hepatitis and other characteristic features. No single test can be used to make the diagnosis. Response to treatment can also help to establish the diagnosis. Simplified criteria can be used to make a bedside diagnosis with relatively high accuracy. Treatment consists of corticosteroids or other immunosuppressive regimens according to the severity of the disease, the response to the treatment, and the tolerance to therapy, with liver transplantation as an ultimate remedy in treatment-resistant cases with liver decompensation.

Evaluación de un Programa de Atención Farmacéutica en pacientes sometidos a trasplante hepático / Assessment of a Pharmaceutical Care Program for liver transplant patients

Objetivos: Detectar, prevenir y resolver posibles problemas relacionados con los medicamentos (PRM) que puedan surgir en el paciente trasplantado hepático durante su estancia en la unidad hepática. Métodos: Estudio longitudinal y prospectivo, de 9 meses de duración, realizado en pacientes ingresados tras un trasplante hepático en un hospital de tercer nivel y con la participación de un farmacéutico clínico a tiempo parcial (4-5 h diarias). Se incluyeron 30 pacientes, y los diagnósticos mayoritarios para el trasplante fueron la cirrosis y el hepatocarcinoma por el virus de la hepatitis C. El mayor riesgo de presentar morbilidad farmacoterapéutica a partir de ciertas premisas fue el criterio principal empleado para incluir a los pacientes en el estudio. Para llevar a cabo el Programa de Atención Farmacéutica se empleó una herramienta metodológica mixta basada tanto en la práctica clínica orientada a problemas terapéuticos como en la metodología Dáder. Con esta metodología se aplicó un procedimiento normalizado de trabajo estructurado en diferentes fases para poderlo aplicar a los pacientes. Resultados: La prevalencia de PRM del estudio fue de un 80%, identificándose un total de 43 PRM (una media de 1,8 PRM por paciente); los antibióticos y antivirales (54,7%) y los inmunosupresores (32,5%) fueron los grupos terapéuticos implicados con más frecuencia. La mayor parte de los PRM identificados fueron de seguridad (39,5%), debidos en su mayor parte a la utilización de dosis e intervalos posológicos inadecuados. Destacan las intervenciones preventivas para evitar efectos adversos (69,6%). El origen de los PRM estuvo relacionado en su mayor parte con el proceso de prescripción (90,7%), y la gravedad media se situó en un nivel de 2,15. El grado de aceptación de las intervenciones se situó en un 90,7%, y más de la mitad de ellas se consideraron importantes desde el punto de vista de la mejora del cuidado del paciente. Conclusión: La aplicación del programa mediante la participación del farmacéutico clínico en la unidad hepática a tiempo parcial, junto con el resto del equipo asistencial que atiende al paciente trasplantado hepático, permite identificar, prevenir y resolver PRM, evitando la morbilidad farmacoterapéutica y facilitando una educación y una información sanitaria de calidad (AU)

Objectives: To detect, prevent, and solve DRPs that may develop in liver transplant patients during their stay in the hepatology unit. Methods: Prospective, longitudinal, 9-month study with patients admitted after a liver transplant in a third-level hospital, with the participation of a part-time clinical pharmacist (4-5 hours/ day). Thirty patients were included; the most common diagnosis for transplant was cirrhosis and hepatocarcinoma by HCV. The main criterion for including patients in the study was a higher risk of pharmacotherapeutic morbidity based on certain premises. A mixed methodological tool based on therapeutic problem oriented clinical practice and the Dáder methodology was used to conduct the pharmaceutical care program. Based on this methodology, a standardized structured work procedure was developed in various phases to apply to patients. Results: The prevalence of DRPs in the study was 80%; there were a total of 43 DRPs (1.8 DRP/patient). The therapeutic groups most commonly implicated were antibiotics and antivirals (54.7%) and immunosuppressants (32.5%). Most of the DRPs identified were related to safety (39.5%), and were mostly due to inadequate doses and intervals. There were many preventive interventions to avoid adverse effects (69.6%). The cause of the DRP was most often found in the prescription process (90.7%); the mean severity of the DRP was 2.15. The degree of acceptance of interventions was of 90.7%, being more than half of them considered important from the point of view of the improvement in the patients care. Conclusion: The development of the program through the participation of a part-time clinical pharmacist in the hepatology unit, together with the rest of the care team for the patient with the liver transplant, allowing to detect, prevent, and solve DRPs, avoiding pharmacotherapeutic morbidity, and facilitating high quality health education and information (AU)

Non-alcoholic steatohepatitis induces non-fibrosis-related portal hypertension associated with splanchnic vasodilation and signs of a hyperdynamic circulation in vitro and in vivo in a rat model.

INTRODUCTION: Steatosis, without fibrosis, may lead to changes in liver blood flow, which are poorly understood, and to date have not been correlated to portal pressure and related haemodynamics. AIMS: To study the temporal relation between progressive steatosis, portal pressure, systemic haemodynamics, vascular responsiveness, mesenteric and portal blood flow in methionine-choline-deficient diet (MCDD)-fed rats. METHODS: Male Wistar rats fed the MCDD were examined at week (w) 0-1-2-3-4-5-6-7-8, respectively, including systemic haemodynamics and portal pressure. At w0-4-8, in vivo blood flow was measured in the portal vein and the superior mesenteric artery. Dose-response curves to phenylephrine (PE) were established in abdominal aortic rings. RESULTS: Histology showed 100% steatosis from w3 on. Fibrosis was absent. Significant inflammation was nearly absent upon w4. Portal pressure slightly increased at w2, reached a maximum at w4 [9.4 +/- 0.3 vs 2.9 +/- 0.6 mmHg at w0 (P=0.003)] and remained stable upon w8. Mean arterial blood pressure (MABP) decreased from w2 on [98.7 +/- 5.7 mmHg on w4 compared with 123.8 +/- 1.8 on w0 (P=0.002)]. Portal flow increased from 1.85 +/- 0.11 to 3.07 +/- 0.44 ml/min/100 g on w0 and w8 respectively (P=0.039). Mesenteric artery flow increased from 3.40 +/- 0.26 to 4.56 +/- 0.30 ml/min/100 g on w0 and w8 respectively (P=0.043). Vascular responsiveness to PE gradually decreased from 138 +/- 3% on w0 to 110 +/- 5% on w4 (P=0.013). CONCLUSION: Steatohepatitis induces significant portal hypertension (PHT) in the absence of fibrosis, associated with an increase in mesenteric arterial and portal venous flow, arterial hyporesponsiveness to vasoconstrictors and a decrease in MABP, indicating the presence of splanchnic vasodilation and hyperdynamic circulation. These alterations resemble those seen in cirrhotic PHT.

Human herpesvirus-6 has no apparent influence on course of HCV hepatitis, but may complicate HBV hepatitis and alcoholic liver disease. A pilot study.

Human herpesvirus-6 (HHV-6) is a widespread virus with occasional reactivation and a potential hepatotropism. The present study was undertaken to investigate the frequency of HHV-6 reactivation in viral (HCV, HBV) and alcoholic liver diseases and its implication for the course of the primary disease. Serological and immunohistochemical tests were done to document viral activity, hepatocellular apoptosis or proliferation, and autoantibody formation. While the course of HCV remains apparently uninfluenced by HHV-6, HBV hepatitis and alcoholic liver disease show a higher incidence of autoantibody formation if HHV-6 is present. The data of this pilot study warrant more extensive investigations of the clinical pathology of HHV-6 in liver diseases.