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Objectives Polycystic liver disease (PLD) is characterized by growth of hepatic cysts, causing hepatomegaly. Disease severity is determined using total liver volume (TLV), which can be measured from computed tomography (CT). The gold standard is manual segmentation which is time-consuming and requires expert knowledge of the anatomy. This study aims to validate the commercially available semi-automatic MMWP (Multimodality Workplace) Volume tool for CT scans of PLD patients. Methods We included adult patients with one (n = 60) or two (n = 46) abdominal CT scans. Semi-automatic contouring was compared with manual segmentation, using comparison of observed volumes (cross-sectional) and growth (longitudinal), correlation coefficients (CC), and Bland-Altman analyses with bias and precision, defined as the mean difference and SD from this difference. Inter- and intra-reader variability were assessed using coefficients of variation (CV) and we assessed the time to perform both procedures. Results Median TLV was 5292.2 mL (IQR 3141.4–7862.2 mL) at baseline. Cross-sectional analysis showed high correlation and low bias and precision between both methods (CC 0.998, bias 1.62%, precision 2.75%). Absolute volumes were slightly higher for semi-automatic segmentation (manual 5292.2 (3141.4–7862.2) versus semi-automatic 5432.8 (3071.9–7960.2) mL, difference 2.7%, p < 0.001). Longitudinal analysis demonstrated that semi-automatic segmentation accurately measures liver growth (CC 0.908, bias 0.23%, precision 4.04%). Inter- and intra-reader variability were small (2.19% and 0.66%) and comparable to manual segmentation (1.21% and 0.63%) (p = 0.26 and p = 0.37). Semi-automatic segmentation was faster than manual tracing (19 min versus 50 min, p = 0.009). Conclusions Semi-automatic liver segmentation is a fast and accurate method to determine TLV and liver growth in PLD patients. Key Points • Semi-automatic liver segmentation using the commercially available MMWP volume tool accurately determines total liver volume as well as liver growth over time in polycystic liver disease patients. • This method is considerably faster than manual segmentation through the use of Hounsfield unit settings. • We used a real-life CT set for the validation and showed that the semi-automatic tool measures accurately regardless of contrast used for the CT scan or not, presence of polycystic kidneys, liver volume, and previous invasive treatment for polycystic liver disease.

Contains fulltext : 291391.pdf (Publisher’s version ) (Open Access) OBJECTIVE: To describe health-related quality of life (HRQoL), post-traumatic stress and post-traumatic growth of parents of long-term survivors of childhood cancer (CCS) and study associated factors. METHODS: Parents of survivors of the Dutch Childhood Cancer Survivor Study LATER cohort below 30 years and diagnosed 1986-2001 were invited to complete the TNO-AZL Questionnaire for Adult's HRQoL (e.g., sleep and aggressive emotions), Self-Rating Scale for Post-traumatic Stress Disorder, Post-traumatic Growth Inventory, and Illness Cognition Questionnaire. HRQoL domain scores were compared to references using Mann-Whitney U tests. Correlations between post-traumatic stress, growth and HRQoL were evaluated. Medical characteristics of their child and illness cognitions were studied as associated factors of HRQOL, post-traumatic stress and growth. p

Epithelioid haemangioendothelioma (EHE) is a rare vascular soft tissue malignant tumour with unknown etiology; the estimated prevalence of EHE is less than one in 1 million. A 56-year-old man was admitted in our department due to pain in the right side of the abdomen lasting for two years and weight loss up to 10 kg. Since 2012, the patient underwent lung and abdominal CT scanning as well as biopsy, however the diagnosis was challenging. In 2015, repeated abdominal CT scanning and a liver core biopsy was performed. The epithelioid haemangioendothelioma was diagnosed based by histopathological examination with subsequent radiological and clinical correlation. Therefore, accurate histopathological examination with radiological and clinical correlation is essential in the diagnosis of epithelioid haemangioendothelioma.

DNA interstrand crosslinks (ICLs) pose a major obstacle for DNA replication and transcription if left unrepaired. The cellular response to ICLs requires the coordination of various DNA repair mechanisms. Homologous recombination (HR) intermediates generated in response to ICLs, require efficient and timely conversion by structure-selective endonucleases. Our knowledge on the precise coordination of this process remains incomplete. Here, we designed complementary genetic screens to map the machinery involved in the response to ICLs and identified FIRRM/C1orf112 as an indispensable factor in maintaining genome stability. FIRRM deficiency leads to hypersensitivity to ICL-inducing compounds, accumulation of DNA damage during S-G 2 phase of the cell cycle, and chromosomal aberrations, and elicits a unique mutational signature previously observed in HR-deficient tumors. In addition, FIRRM is recruited to ICLs, controls MUS81 chromatin loading, and thereby affects resolution of HR intermediates. FIRRM deficiency in mice causes early embryonic lethality and accelerates tumor formation. Thus, FIRRM plays a critical role in the response to ICLs encountered during DNA replication.

Interprofessioneel samenwerken is van belang voor kwalitatieve zorg bij kwetsbare ouderen. Een goede professionele identiteit (PI) ligt hieraan ten grondslag. Tijdens deze workshop leren paramedici wat de professionele en interprofessionele identiteit (IPI) inhoud en gaan ze met elkaar aan de slag om te bepalen hoe het met hun eigen PI en IPI gesteld staat.

Met de toenemende vergrijzing in ons land zal er ook een toename plaatsvinden van het aantal ouderen met dementie. Dementie, met als voornaamste oorzaak de ziekte van Alzheimer, wordt in het algemeen vooral gezien als een ziekte waarbij cognitieve problemen optreden. Dat er ook al in een vroeg stadium motorische stoornissen optreden is veel minder bekend. Pas in een laat stadium worden de motorische problemen dusdanig groot dat de fysiotherapeut wordt ingeschakeld. Het is van belang om als fysiotherapeut kennis te hebben van de verschillende vormen van dementie en de daarmee gepaard gaande verschillen in motorische stoornissen. Daarnaast is het van belang om inzicht te krijgen in werkzame interventies en de juiste meetinstrumenten in te kunnen zetten. In deze masterclass wordt inzicht gegeven in de motorische problemen bij dementie (o.a. paratonie) en worden handvatten voor de praktijk gegeven.

Overview of the sequenced tumor samples, including sample IDs, treatment information and the type of transplanted material.

Mutations (SNVs) identified for RTKs and genes involved in the MAPK-ERK signaling pathway in the donor, vehicle- and AZD4547-treated tumors.

List of primers used for cloning and genotyping

This file describes Supplementary experimental details regarding the cell viability, clonogenic and competition assays, preparation of membrane vesicles and vesicular transport assays, immunohistochemistry, immunoblotting, RNA sequencing and analysis, amplification of SB transposon insertions and analysis, validation of the Fgfr2-Tbc1d1 fusion, Met qPCR copy number analysis and statistical analysis.

Overview of insertions identified in the donor, vehicle- and AZD4547-treated tumors.

The BRCA1 tumor suppressor gene encodes a multidomain protein for which several functions have been described. These include a key role in homologous recombination repair (HRR) of DNA double-strand breaks, which is shared with two other high-risk hereditary breast cancer suppressors, BRCA2 and PALB2. Although both BRCA1 and BRCA2 interact with PALB2, BRCA1 missense variants affecting its PALB2-interacting coiled-coil domain are considered variants of uncertain clinical significance (VUS). Using genetically engineered mice, we show here that a BRCA1 coiled-coil domain VUS, Brca1 p.L1363P, disrupts the interaction with PALB2 and leads to embryonic lethality. Brca1 p.L1363P led to a similar acceleration in the development of Trp53-deficient mammary tumors as Brca1 loss, but the tumors showed distinct histopathologic features, with more stable DNA copy number profiles in Brca1 p.L1363P tumors. Nevertheless, Brca1 p.L1363P mammary tumors were HRR incompetent and responsive to cisplatin and PARP inhibition. Overall, these results provide the first direct evidence that a BRCA1 missense variant outside of the RING and BRCT domains increases the risk of breast cancer.Significance:These findings reveal the importance of a patient-derived BRCA1 coiled-coil domain sequence variant in embryonic development, mammary tumor suppression, and therapy response.See related commentary by Mishra et al., p. 6080

Supplementary Figures S1-5 show additional information regarding the Fgfr2-Tbc1d1 fusion, the effect of AZD4547 on established WESB and WESB-Fgfr2 tumors and tumor-derived cells, the causes of death observed with the different AZD4547 treatment schedules, differential gene expression analysis of multiple RTK family members and the overview of insertions in genes across all tumors used in this study.

In human cancers, FGFR signaling is frequently hyperactivated by deregulation of FGF ligands or by activating mutations in the FGFR receptors such as gene amplifications, point mutations, and gene fusions. As such, FGFR inhibitors are considered an attractive therapeutic strategy for patients with mutations in FGFR family members. We previously identified Fgfr2 as a key driver of invasive lobular carcinoma (ILC) in an in vivo insertional mutagenesis screen using the Sleeping Beauty transposon system. Here we explore whether these FGFR-driven ILCs are sensitive to the FGFR inhibitor AZD4547 and use transposon mutagenesis in these tumors to identify potential mechanisms of resistance to therapy. Combined with RNA sequencing-based analyses of AZD4547-resistant tumors, our in vivo approach identified several known and novel potential resistance mechanisms to FGFR inhibition, most of which converged on reactivation of the canonical MAPK–ERK signaling cascade. Observed resistance mechanisms included mutations in the tyrosine kinase domain of FGFR2, overexpression of MET, inactivation of RASA1, and activation of the drug-efflux transporter ABCG2. ABCG2 and RASA1 were identified only from de novo transposon insertions acquired during AZD4547 treatment, demonstrating that insertional mutagenesis in mice is an effective tool for identifying potential mechanisms of resistance to targeted cancer therapies.Significance: These findings demonstrate that a combined approach of transcriptomics and insertional mutagenesis in vivo is an effective method for identifying potential targets to overcome resistance to therapy in the clinic. Cancer Res; 78(19); 5668–79. ©2018 AACR.

Invasive lobular carcinoma (ILC) accounts for 8%–14% of all breast cancer cases. The main hallmark of ILCs is the functional loss of the cell–cell adhesion protein E-cadherin. Nonetheless, loss of E-cadherin alone does not predispose mice to mammary tumor development, indicating that additional perturbations are required for ILC formation. Previously, we identified an N-terminal truncation variant of ASPP2 (t-ASPP2) as a driver of ILC in mice with mammary-specific loss of E-cadherin. Here we showed that expression of t-ASPP2 induced actomyosin relaxation, enabling adhesion and survival of E-cadherin–deficient murine mammary epithelial cells on stiff matrices like fibrillar collagen. The induction of actomyosin relaxation by t-ASPP2 was dependent on its interaction with protein phosphatase 1, but not on t-ASPP2–induced YAP activation. Truncated ASPP2 collaborated with both E-cadherin loss and PI3K pathway activation via PTEN loss in ILC development. t-ASPP2–induced actomyosin relaxation was required for ILC initiation, but not progression. Conversely, YAP activation induced by t-ASPP2 contributed to tumor growth and progression while being dispensable for tumor initiation. Together, these findings highlight two distinct mechanisms through which t-ASPP2 promotes ILC initiation and progression.Significance:Truncated ASPP2 cooperates with E-cadherin and PTEN loss to drive breast cancer initiation and progression via two distinct mechanisms. ASPP2-induced actomyosin relaxation drives tumor initiation, while ASPP2-mediated YAP activation enhances tumor progression.

Criteria for histopathological classification of tumors

Included are the supplementary methods, tables, and figures.

GSK-296692 intervention study dosing overview

Supplementary Figures 1-7

Item does not contain fulltext Premenstrual Syndrome (PMS) comprises psychological, somatic, and behavioral symptoms during the luteal phase of almost every menstrual cycle. PMS and premenstrual dysphoric disorder (PMDD) may be associated with substance use. Between 2018 and 2020 we studied the relationship between PMS and substance use within a prospective case-control design comparing a consecutive series of women having a substance use disorder and being treated in an addiction treatment center (ATC group, n = 151)) and one with community dwelling women attending their general practitioner (GP group, n = 101). The psychoactive substance use disorder women in the ATC were most frequently treated for was alcohol (39.7 percent), cannabis (20.5) and cocaine 7.9 percent) respectively. The relationship between PMS, problematic alcohol use, and craving for alcohol was explored with the Alcohol Use Disorders Identification Test (AUDIT), Premenstrual Screening Symptoms Tool (PSST), and Penn Alcohol Craving Scale (PACS). Descriptive analyses were used to report demographic variables, and the prevalence and nature of SUD according to DSM-5 and PMS in the two study populations and a two-step multiple hierarchical linear regression to assess the contribution of the variance of the AUDIT and PSST to craving, as measured with PACS. The frequency of PMS and PMDD is significantly higher in the ATC group than in the GP group (48.3 versus 26.7 percent and 16.6 versus 5.9 percent). Craving in the ATC group is better predicted (50 percent) by alcohol-related problems as measured by the AUDIT than in the GP group (25 percent). PMS complaints do contribute to craving in ATC group and not in GP group. There is a high prevalence of PMS/PMDD in the population with a substance use disorder. If these patients with PMS symptoms experience higher levels of craving, it may increase the risk of substance use relapse. 9 p.

Blood disease in bananas caused by Ralstonia syzygii subsp. celebesensis is a bacterial wilt disease that causes major yield losses of banana in Indonesia and peninsular Malaysia. The disease has significantly increased its geographic distribution in the past decade. Diagnostic methods are an important component of disease management in vegetatively propagated crops such as banana to constrain incursions of plant pathogens. Therefore, the objectives of this study were (i) to design and rigorously validate a novel banana Blood disease (BBD) real-time PCR assay with a high level of specificity and sensitivity of detection and (ii) to validate published PCR-based diagnostic methods targeting the intergenic region in the megaplasmid (“121 assay” with primer set 121) or the phage tail protein-coding sequence in the bacterial chromosome (“Kubota assay” and “BDB2400 assay” with primer set BDB2400). Assay validation included 339 samples (174 Blood disease bacteria, 51 bacteria associated with banana plants, 51 members of the Ralstonia solanacearum species complex, and 63 samples from symptomatic and healthy plant material). Validation parameters were analytical specificity (inclusivity and exclusivity), selectivity, limit of detection, accuracy, and ruggedness. The 121 assay and our newly developed BBD real-time PCR assay detected all R. syzygii subsp. celebesensis strains with no cross-specificity during validation. Two different PCR assays using the primer set BDB2400 lacked specificity and selectivity. This study reveals that our novel BBD real-time PCR assay and the conventional PCR 121 assay are reliable methods for Blood disease diagnostics, as they comply with all tested validation parameters.

Quambalaria are fungal pathogens of Corymbia, Eucalyptus and related genera of Myrtaceae. They are smut fungi (Ustilaginomycota) described from structures that resemble conidia and conidiophores. Whether these spore forms have asexual or sexual roles in life cycles of Quambalaria is unknown. An epidemic of Q. pitereka destroyed plantations of Corymbia in New South Wales and Queensland (Australia) in 2008. We sampled 177 individuals from three plantations of C. variegata and used AFLPs to test hypotheses that the epidemic was spread by asexual reproduction and dominated by a single genotype. There was high genotypic diversity across ≥600 AFLP loci in the pathogen populations at each plantation, and evidence of sexual reproduction based on neighbour-net analyses and rejection of linkage disequilibrium. The populations were not structured by host or location. Our data did not support a hypothesis of asexual reproduction but instead that Q. pitereka spreads exclusively by sexual reproduction, similar to life cycles of other smut fungi. Epidemics were exacerbated by monocultures of Corymbia established from seed collected from a single provenance. This study showcases an example of an endemic pathogen, Q. pitereka, with a strictly outbreeding life cycle that has caused epidemics when susceptible hosts were planted in large monoculture plantations.

Item does not contain fulltext OBJECTIVE: This study aimed to develop and investigate the performance of a deep learning model based on a convolutional neural network (CNN) for the automatic segmentation of polycystic livers at CT imaging. METHOD: This retrospective study used CT images of polycystic livers. To develop the CNN, supervised training and validation phases were performed using 190 CT series. To assess performance, the test phase was performed using 41 CT series. Manual segmentation by an expert radiologist (Rad1a) served as reference for all comparisons. Intra-observer variability was determined by the same reader after 12 weeks (Rad1b), and inter-observer variability by a second reader (Rad2). The Dice similarity coefficient (DSC) evaluated overlap between segmentations. CNN performance was assessed using the concordance correlation coefficient (CCC) and the two-by-two difference between the CCCs; their confidence interval was estimated with bootstrap and Bland-Altman analyses. Liver segmentation time was automatically recorded for each method. RESULTS: A total of 231 series from 129 CT examinations on 88 consecutive patients were collected. For the CNN, the DSC was 0.95 ± 0.03 and volume analyses yielded a CCC of 0.995 compared with reference. No statistical difference was observed in the CCC between CNN automatic segmentation and manual segmentations performed to evaluate inter-observer and intra-observer variability. While manual segmentation required 22.4 ± 10.4 min, central and graphics processing units took an average of 5.0 ± 2.1 s and 2.0 ± 1.4 s, respectively. CONCLUSION: Compared with manual segmentation, automated segmentation of polycystic livers using a deep learning method achieved much faster segmentation with similar performance. KEY POINTS: • Automatic volumetry of polycystic livers using artificial intelligence method allows much faster segmentation than expert manual segmentation with similar performance. • No statistical difference was observed between automatic segmentation, inter-observer variability, or intra-observer variability.

Phytophthora root rot caused by Phytophthora medicaginis is an important disease of chickpeas (Cicer arietinum) in Australia with limited management options, increasing reliance on breeding for improved levels of genetic resistance. Resistance based on chickpea–Cicer echinospermum crosses is partial with a quantitative genetic basis provided by C. echinospermum and some disease tolerance traits originating from C. arietinum germplasm. Partial resistance is hypothesised to reduce pathogen proliferation, while tolerant germplasm may contribute some fitness traits, such as an ability to maintain yield despite pathogen proliferation. To test these hypotheses, we used P. medicaginis DNA concentrations in the soil as a parameter for pathogen proliferation and disease assessments on lines of two recombinant inbred populations of chickpea–C. echinospermum crosses to compare the reactions of selected recombinant inbred lines and parents. Our results showed reduced inoculum production in a C. echinospermum backcross parent relative to the C. arietinum variety Yorker. Recombinant inbred lines with consistently low levels of foliage symptoms had significantly lower levels of soil inoculum compared to lines with high levels of visible foliage symptoms. In a separate experiment, a set of superior recombinant inbred lines with consistently low levels of foliage symptoms was tested for soil inoculum reactions relative to control normalised yield loss. The in-crop P. medicaginis soil inoculum concentrations across genotypes were significantly and positively related to yield loss, indicating a partial resistance-tolerance spectrum. Disease incidence and the rankings for in-crop soil inoculum were correlated strongly to yield loss. These results indicate that soil inoculum reactions may be useful to identify genotypes with high levels of partial resistance.

BACKGROUND Frailty and multimorbidity are common among patients in geriatric rehabilitation care (GRC). Proper care of these patients involves multiple professionals which requires optimal interprofessional collaboration to provide the best possible support. Interprofessional collaboration (IPC) goes beyond multi-professional collaboration. It requires professionals to think beyond the expertise of their own discipline and work on joint outcomes in which the patient is actively involved. This study describes the development of the GRC teams of an elderly care organization towards the IPC. METHODS Mixed method pre-post study of 15 months. The interprofessional training program comprised team trainings, webinars, and online team sessions. Data was aggregated by administering the EPIS (interprofessional identity) and QuickScan (QS) (aspects of collaboration) measurements to GRC staff and by observations of the multi-professional team consultation (MPC) meetings of six GRC teams of an organization for elderly care in the Netherlands. ADL independence (Barthel Index) and number of inpatient days were analyzed before and after the project. RESULTS Pretest response was 106; posttest was 84. The EPIS shows improvement on "interprofessional belonging" (P=.001, 95%CI: .566 - 2.208), "interprofessional commitment" (P=.027, 95%CI: .117 – 1.899), and overall “interprofessional identity” (P=.013, 95%CI: .622 - 5.197). On the QS, all domains improved; "shared values" (P= .009, 95%CI: .067 - .474), "context" (P= .005, 95%CI: .077 - .435), "structure & organization" (P= .001, 95%CI: .141 - .560), “group dynamics & interaction” (P

Interprofessioneel samenwerken is van belang voor kwalitatieve zorg bij kwetsbare ouderen. Een goede professionele identiteit (PI) ligt hieraan ten grondslag. Tijdens deze workshop leren verpleegkundigen wat de professionele en interprofessionele identiteit (IPI) inhoud en gaan ze met elkaar aan de slag om te bepalen hoe het met hun eigen PI en IPI gesteld staat.

Contains fulltext : 290866.pdf (Publisher’s version ) (Open Access) BACKGROUND: Management of focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA), is multidisciplinary and subject to practice variation. We aimed to evaluate variation in clinical management of FNH and HCA in Europe. METHODS: We distributed an online survey (November 2021-March 2022) among 294 European experts. The survey included questions on local practice and included eight clinical vignettes. The clinical vignettes focused on FNH or HCA management in the setting of sex, lifestyle modification, and pregnancy. RESULTS: The response rate was 32% and respondents included surgeons (38%), gastroenterologists/hepatologists (25%), radiologists (32%), and pathologists (1.6%) from ten European countries. We observed practice variation with regard to lifestyle modification and imaging follow-up in patients with FNH, and with regard to the management of HCA >5 cm before and during pregnancy. Finally, the management of HCA >5 cm after lifestyle modification deviated from EASL guideline recommendations. CONCLUSION: Our survey illustrates variability in FNH and HCA management in Europe. Several areas were identified for future research and guideline recommendations, including FNH follow-up and the management of HCA >5 cm. We propose the organization of Delphi consensus meetings to prioritize areas of research and update current guidelines to optimize management for all patients with benign liver tumors.

Contains fulltext : 291177.pdf (Publisher’s version ) (Open Access) BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is a progressive, cholestatic liver disease which greatly impacts the lives of individuals. Burden of disease due to shortened life expectancy and impaired quality of life is ill-described. The aim of this study was to assess long-term disease burden in a large population-based registry with regard to survival, clinical course, quality adjusted life years (QALYs), medical consumption and work productivity loss. METHODS: All PSC patients living in a geographically defined area covering ~50% of the Netherlands were included, together with patients from the three liver transplant centres. Survival was estimated by competing risk analysis. Proportional shortfall of QALYs during disease course was measured relative to a matched reference cohort using validated questionnaires. Work productivity loss and medical consumption were evaluated over time. RESULTS: A total of 1208 patients were included with a median follow-up of 11.2 year. Median liver transplant-free survival was 21.0 years. Proportional shortfall of QALYs increased to 48% >25 years after diagnosis. Patients had on average 12.4 hospital contact days among which 3.17 admission days per year, annual medical costs were €12 169 and mean work productivity loss was 25%. CONCLUSIONS: Our data quantify for the first time disease burden in terms of QALYs lost, clinical events, medical consumption, costs as well as work productivity loss, and show that all these are substantial and increase over time.

Additional file 1. Spirit checklist.

Contains fulltext : 294361.pdf (Publisher’s version ) (Open Access) This study aimed to quantify the confirmation of gallstones on ultrasound (US) in patients with suspicion of gallstone disease. To aid general practitioners (GPs) in diagnostic workup, a model to predict gallstones was developed. A prospective cohort study was conducted in two Dutch general hospitals. Patients (≥18 years) were eligible for inclusion when referred by GPs for US with suspicion of gallstones. The primary outcome was the confirmation of gallstones on US. A multivariable regression model was developed to predict the presence of gallstones. In total, 177 patients were referred with a clinical suspicion of gallstones. Gallstones were found in 64 of 177 patients (36.2%). Patients with gallstones reported higher pain scores (VAS 8.0 vs. 6.0, p < 0.001), less frequent pain (21.9% vs. 54.9%, p < 0.001), and more often met criteria for biliary colic (62.5% vs. 44.2%, p = 0.023). Predictors for the presence of gallstones were a higher pain score, frequency of pain less than weekly, biliary colic, and an absence of heartburn. The model showed good discrimination between patients with and without gallstones (C-statistic 0.73, range: 0.68-0.76). Clinical diagnosis of symptomatic gallstone disease is challenging. The model developed in this study may aid in the selection of patients for referral and improve treatment related outcomes.

Simple Summary The incidence of hepatocellular carcinoma (HCC) in patients with non-alcoholic fatty liver disease (NAFLD) has increased in recent years. Compared to HCC caused by other chronic liver diseases, NAFLD-related HCC is often detected later, because it more commonly arises before cirrhosis has occurred. Because of this late diagnosis, NAFLD-related HCC is often more advanced at time of diagnosis, resulting in fewer curative treatment options. Most research in the pathogenesis of HCC has focused on the disease processes in hepatocytes, the most abundant type of liver cells. However, other cell types, such as cells of the immune system and cells that regulate connective tissue formation, also play an important role in the development of NAFLD-related HCC, both by contributing to the development of HCC itself and by interfering with the immune system's ability to attack cancer cells. In this paper, we review the role of different cell types in the development of NAFLD-related HCC. Hepatocellular carcinoma (HCC) in the setting of non-alcoholic fatty liver disease (NAFLD)-related cirrhosis and even in the pre-cirrhotic state is increasing in incidence. NAFLD-related HCC has a poor clinical outcome as it is often advanced at diagnosis due to late diagnosis and systemic treatment response is poor due to reduced immune surveillance. Much of the focus of molecular research has been on the pathological changes in hepatocytes; however, immune cells, hepatic stellate cells, liver sinusoidal endothelial cells and the extracellular matrix may play important roles in the pathogenesis of NAFLD-related HCC as well. Here, we review the role of non-parenchymal cells in the liver in the pathogenesis of HCC in the context of NAFLD-NASH, with a particular focus on the innate and the adaptive immune system, fibrogenesis and angiogenesis. We review the key roles of macrophages, hepatic stellate cells (HSCs), T cells, natural killer (NK) cells, NKT cells and liver sinusoidal endothelial cells (LSECs) and the role of the extracellular matrix in hepatocarcinogenesis within the steatotic milieu.

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Contains fulltext : 293808.pdf (Publisher’s version ) (Open Access) Autoimmune hepatitis (AIH) is a rare autoimmune liver disease that is characterised by a chronic inflammatory immune reaction directed against hepatocytes. The disease results in a substantial reduction in quality of life and potentially leads to liver-related complications or death. The International Autoimmune Hepatitis Group (IAIHG) initiated a series of research workshops to uncover the scientific gaps and opportunities in AIH. This review summarises the results of the latest workshop in Maastricht in 2022 and reviews the current challenges in adult AIH, particularly in relation to four important aspects of AIH: diagnostics; new immunomodulatory therapies; clinical trial design; and unmet clinical needs. This review also summarises the progress made since the AIH workshop in 2017. Patients and patient representatives were actively involved in the parallel working groups alongside clinicians and researchers. Despite 40 years of experience with diagnosing and treating AIH, false diagnoses occur and treatment is still based on nonselective immunosuppression. In addition to the need for more specific diagnostic tests, prognostic markers and tailor-based treatments, a major unmet clinical need was identified in areas of care delivery and health-related quality of life. 01 juli 2023

Item does not contain fulltext Background Accumulation of lipid in the liver (ie, hepatic steatosis) is the basis of nonalcoholic fatty liver disease (NAFLD). Asymptomatic steatosis can lead to nonalcoholic steatohepatitis and downstream complications. Purpose To assess the diagnostic performance of calibrated US (CAUS) as a method for detection and staging of hepatic steatosis in comparison with liver biopsy. Materials and Methods Two-dimensional US images in 223 consecutive patients who underwent US-guided liver biopsy from May 2012 to February 2016 were retrospectively analyzed by two observers using CAUS. CAUS semiautomatically estimates echo-level and texture parameters, with particular interest in the residual attenuation coefficient (RAC), which is the remaining steatosis-driven attenuation obtained after correction of the beam profile. Data were correlated with patient characteristics and histologically determined steatosis grades and fibrosis stages. The data were equally divided into training and test sets to independently train and test logistic regression models for detection (>5% fat) and staging (>33% and >66% fat) of hepatic steatosis by using area under the receiver operating characteristic curve (AUC) analysis. Results A total of 195 patients (mean age, 50 years ± 13 [SD]; 110 men) were included and divided into a training set (n = 97 [50%]) and a test set (n = 98 [50%]). The average CAUS interobserver correlation coefficient was 0.95 (R range, 0.87-0.99). The best correlation with steatosis was found for the RAC parameter (R = 0.78, P < .01), while no correlation was found for fibrosis (R = 0.14, P = .054). Steatosis detection using RAC showed an AUC of 0.97 (95% CI: 0.94, 1.00), and the multivariable AUC was found to be 0.97 (95% CI: 0.95, 1.00). The predictive performance for moderate and severe hepatic steatosis using RAC was 0.93 (95% CI: 0.88, 0.98) and 0.93 (95% CI: 0.87, 0.98), respectively. Conclusion The calibrated US parameter residual attenuation coefficient detects and stages steatosis accurately with limited interobserver variability, and performance is not hampered by the presence of fibrosis. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Grant in this issue.

Among the most economically relevant and environmentally devastating diseases globally are those caused by Phytophthora species. In Australia, production losses in agriculture and forestry results from several well-known cosmopolitan Phytophthora species and infestation of natural ecosystems by Phytophthora cinnamomi have caused irretrievable loss to biodiversity, especially in proteaceous dominated heathlands. For this review, all available records of Phytophthora in Australia were collated and curated, resulting in a database of 7869 records, of which 2957 have associated molecular data. Australian databases hold records for 99 species, of which 20 are undescribed. Eight species have no records linked to molecular data, and their presence in Australia is considered doubtful. The 99 species reside in 10 of the 12 clades recognised within the complete phylogeny of Phytophthora. The review includes discussion on each of these species? status and additional information provided for another 29 species of concern. The first species reported in Australia in 1900 was Phytophthora infestans. By 2000, 27 species were known, predominantly from agriculture. The significant increase in species reported in the subsequent 20 years has coincided with extensive surveys in natural ecosystems coupled with molecular taxonomy and the recognition of numerous new phylogenetically distinct but morphologically similar species. Routine and targeted surveys within Australian natural ecosystems have resulted in the description of 27 species since 2009. Due to the new species descriptions over the last 20 years, many older records have been reclassified based on molecular identification. The distribution of records is skewed toward regions with considerable activity in high productivity agriculture, horticulture and forestry, and native vegetation at risk from P. cinnamomi. Native and exotic hosts of different Phytophthora species are found throughout the phylogeny; however, species from clades 1, 7 and 8 are more likely to be associated with exotic hosts. One of the most difficult challenges to overcome when establishing a pest status is a lack of reliable data on the current state of a species in any given country or location. The database compiled here for Australia and the information provided for each species overcomes this challenge. This review will aid federal and state governments in risk assessments and trade negotiations by providing a comprehensive resource on the current status of Phytophthora species in Australia.

The BRCA1 tumor suppressor gene encodes a multidomain protein for which several functions have been described. These include a key role in homologous recombination repair (HRR) of DNA double-strand breaks, which is shared with two other high-risk hereditary breast cancer suppressors, BRCA2 and PALB2. Although both BRCA1 and BRCA2 interact with PALB2, BRCA1 missense variants affecting its PALB2-interacting coiled-coil domain are considered variants of uncertain clinical significance (VUS). Using genetically engineered mice, we show here that a BRCA1 coiled-coil domain VUS, Brca1 p.L1363P, disrupts the interaction with PALB2 and leads to embryonic lethality. Brca1 p.L1363P led to a similar acceleration in the development of Trp53-deficient mammary tumors as Brca1 loss, but the tumors showed distinct histopathologic features, with more stable DNA copy number profiles in Brca1 p.L1363P tumors. Nevertheless, Brca1 p.L1363P mammary tumors were HRR incompetent and responsive to cisplatin and PARP inhibition. Overall, these results provide the first direct evidence that a BRCA1 missense variant outside of the RING and BRCT domains increases the risk of breast cancer. Significance: These findings reveal the importance of a patient-derived BRCA1 coiled-coil domain sequence variant in embryonic development, mammary tumor suppression, and therapy response. See related commentary by Mishra et al., p. 6080

The PATENT-CHILD study investigated riociguat in children aged ≥6 to18 years with pulmonary arterial hypertension (PAH) treated with tablets or an oral pediatric suspension based on bodyweight-adjusted dosing of up to 2.5 mg TID. PATENT-CHILD demonstrated an acceptable riociguat safety profile and individual plasma concentrations in pediatric patients were consistent with those in adult patients.Using the dataset from PATENT-CHILD and building on existing population pharmacokinetic (PK) models for riociguat and its major metabolite (M1) in adults with PAH, a coupled riociguat-M1 PK model was developed. The final model developed incorporated a one-compartment model for riociguat, coupled to a one-compartment model for M1, allowing for pre-systemic formation of M1. It included allometric scaling exponents for bodyweight.Apparent clearance of riociguat was similar in children and adult patients with PAH (median [interquartile range] 2.20 [1.75-3.44] and 2.08 L/h [1.55-2.97]). Factors contributing to lower PK exposure were lower riociguat maintenance dose in PATENT-CHILD, and a higher riociguat clearance in some adolescent patients, compared with adult patients. No effects of formulation, sex, or age on riociguat PK were observed. An exploratory PK/pharmacodynamics analysis found the increase in 6-minute walking distance in pediatric patients treated with riociguat was not related to riociguat PK.Body size is the main determinant of PK in growing children, and the model supports clinical data that, for children weighing50 kg, a bodyweight-adjusted dose of riociguat should be used to achieve a similar exposure to that observed in adults with PAH. This article is protected by copyright. All rights reserved.

Background We investigated associations between baseline use of immunosuppressive drugs and severity of Coronavirus Disease 2019 (COVID-19) in autoimmune hepatitis (AIH). Patients and methods Data of AIH patients with laboratory confirmed COVID-19 were retrospectively collected from 15 countries. The outcomes of AIH patients who were on immunosuppression at the time of COVID-19 were compared to patients who were not on AIH medication. The clinical courses of COVID-19 were classified as (i)-no hospitalization, (ii)-hospitalization without oxygen supplementation, (iii)-hospitalization with oxygen supplementation by nasal cannula or mask, (iv)-intensive care unit (ICU) admission with non-invasive mechanical ventilation, (v)-ICU admission with invasive mechanical ventilation or (vi)-death and analysed using ordinal logistic regression. Results We included 254 AIH patients (79.5%, female) with a median age of 50 (range, 17-85) years. At the onset of COVID-19, 234 patients (92.1%) were on treatment with glucocorticoids (n = 156), thiopurines (n = 151), mycophenolate mofetil (n = 22) or tacrolimus (n = 16), alone or in combinations. Overall, 94 (37%) patients were hospitalized and 18 (7.1%) patients died. Use of systemic glucocorticoids (adjusted odds ratio [aOR] 4.73, 95% CI 1.12-25.89) and thiopurines (aOR 4.78, 95% CI 1.33-23.50) for AIH was associated with worse COVID-19 severity, after adjusting for age-sex, comorbidities and presence of cirrhosis. Baseline treatment with mycophenolate mofetil (aOR 3.56, 95% CI 0.76-20.56) and tacrolimus (aOR 4.09, 95% CI 0.69-27.00) were also associated with more severe COVID-19 courses in a smaller subset of treated patients. Conclusion Baseline treatment with systemic glucocorticoids or thiopurines prior to the onset of COVID-19 was significantly associated with COVID-19 severity in patients with AIH., Italian Ministry of University and Research (MIUR)-Department of Excellence project PREMIA (PREcision MedIcine Approach: bringing biomarker research to clinic), A. Gerussi, L. Cristoferi, and P. Invernizzi acknowledge that this research was partially supported by the Italian Ministry of University and Research (MIUR)-Department of Excellence project PREMIA (PREcision MedIcine Approach: bringing biomarker research to clinic).

Blood disease in bananas caused by Ralstonia syzygii subsp. celebesensis is a bacterial wilt causing significant crop losses in Indonesia and Malaysia. Disease symptoms include wilting of the plant and red-brown vascular staining, internal rot, and discoloration of green banana fruit. There is no known varietal resistance to this disease in the Musa genus, although variation in susceptibility has been observed, with the popular Indonesian cooking banana variety Kepok being highly susceptible. This study established the current geographic distribution of Blood disease in Indonesia and confirmed the pathogenicity of isolates by Koch’s postulates. The long-distance distribution of the disease followed an arbitrary pattern indicative of human-assisted movement of infected banana materials. In contrast, local or short-distance spread radiated from a single infection source, indicative of dispersal by insects and possibly contaminated tools, water, or soil. The rapid expansion of its geographical range makes Blood disease an emerging threat to banana production in Southeast Asia and beyond.

Interprofessional collaboration (IPC) is of great importance in the complex care of frail older people. IPC goes beyond multidisciplinary collaboration and ties in with trends and developments in health care that can further improve the quality of health care. However, IPC can be obstructed when it is perceived as a threat to one’s professional identity (PI). PI is seen as both prerequisite and inhibitor for the development of interprofessional identity (IPI). Facilitating IPI formation is likely to enhance IPC. An IPI is a social identity based on a widening circle of group membership that consists of more than one profession. There are strong indications that a distinct PI is inherent to an IPI. Nurses are key drivers of change towards IPC, which asks for confident and aware nurses. Strong PI and IPI is a prerequisite for the development of these qualities. These strong identities (PI and IPI) result in higher confidence in expressing professional values, effective interprofessional learning and collaboration and lower job retention. The development of an PI or IPI is a challenging process through socialization in groups. Some beneficial elements to their development like simulated IPE experiences and role modelling focused on team functioning, are known from literature. However there is a call for more in-depth knowledge about the processes that can contribute or hinder the development of these identities. ZuidOostZorg conducts own practical research in this field and facilitates a PhD research with this focus.Aim To improve understanding of the formation of PI and IPI of healthcare professionals through education.Which factors and interventions influence the formation of PI and IPI of healthcare professionals?What characterizes the development of professional and interprofessional development over time?ProcessIn an interactive online meeting we shared information about interprofessional collaboration, how it differs from multidisciplinary collaboration and what facilitators and barriers there are. We presented data and expert-observations to illustrate this. Furthermore we highlighted the importance of the professional identity of the nurse. We also discussed the PhD research and presented preliminary results.

Lector "Kortdurende Zorg en Interprofessionele Samenwerking bij Kwetsbare Ouderen" Dr. Hans Drenth en docent verpleegkunde/promovendus Lourens van der Weerd, verkennen samen de professionele identiteit van de deelnemers aan deze workshop. Wat is professionele identiteit en interprofessionele identiteit? Waarom is een sterke professionele identiteit belangrijk voor jou als verpleegkundige? In deze workshop verken je samen met je collega's jouw professionele identiteit.

Cancer-associated fibroblasts (CAFs) are abundantly present in the microenvironment of virtually all tumors and strongly impact tumor progression. Despite increasing insight into their function and heterogeneity, little is known regarding the origin of CAFs. Understanding the origin of CAF heterogeneity is needed to develop successful CAF-based targeted therapies. Through various transplantation studies in mice we determined that CAFs in both invasive lobular breast cancer and triple negative breast cancer originate from mammary tissue-resident normal fibroblasts (NFs). Single-cell transcriptomics, in vivo tracing and in vitro studies revealed the transition of CD26+ and CD26- NF populations into inflammatory CAFs (iCAFs) and myofibroblastic CAFs (myCAFs), respectively. In vitro functional assays showed that CD26+ NFs transition into pro-tumorigenic iCAFs which recruit myeloid cells in a CXCL12-dependent manner and enhance tumor cell invasion via matrix-metalloproteinase (MMP) activity. Together, our data show that CD26+ and CD26- NFs transform into distinct CAF subpopulations in breast cancer.