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Background & Aims: Biochemical response to ursodeoxycholic acid (UDCA) therapy is associated with good prognosis in people living with primary biliary cholangitis (PBC). Biochemical response is typically assessed early in disease and it is not known what proportion of patients lose previously attained biochemical response, nor whether this impacts long-term liver transplant (LT)-free survival. Methods: We identified all UDCA-treated patients with PBC from the Canadian Network for Autoimmune Liver disease with biochemical measurements at 1 year, and evaluated their liver biochemistry over time. Inadequate biochemical response was defined as serum alkaline phosphatase ≥1.67x the upper limit of normal or abnormal serum total bilirubin at 1 year of UDCA therapy and all time points thereafter. Multistate Markov models were used to estimate transition rates between biochemical response states and from each state to LT or death. Results were validated in an external cohort (GLOBAL PBC registry). Results: A total of 823 patients from eight centers were included. Mean age at diagnosis was 53 years, 91% were female, 33% had inadequate biochemical response to UDCA at 1 year (n = 269). Patients who retained initial adequate response had lower rates of LT or death compared to patients who subsequently lost response (relative rate 0.102, 95% CI 0.047-0.223). Patients who regained adequate response had lower rates than patients who did not (0.016, 95% CI 0.001-0.568), and patients who lost response once more (0.010, 95% CI 0.001-0.340). Patients who regained adequate response for a third time also had lower rates than patients who did not (0.151, 95% CI 0.040-0.566). Analyses in the GLOBAL PBC registry (n = 2,237) validated these results. Conclusion: Loss of biochemical response at any time is associated with heightened risks of LT or death in people living with PBC. Achievement of biochemical response is an important goal throughout follow-up, regardless of biochemical response profile early in therapy. Impact and implications:: Early biochemical response to ursodeoxycholic acid is associated with good prognosis in patients with primary biliary cholangitis (PBC). Our work demonstrates that patients with PBC transition between biochemical response states over time, and that these transitions correspond with changes in risk of liver transplantation or death. Clinicians should re-evaluate risk and optimize treatment decisions for patients with PBC throughout follow-up, regardless of early biochemical response to therapy.

Liver transplantation is a highly complex, life-saving, treatment for many patients with advanced liver disease. Liver transplantation requires multidisciplinary teams, system-wide adaptations and significant investment, as well as being an expensive treatment. Several metrics have been proposed to monitor processes and outcomes, however these lack patient focus and do not capture all aspects of the process. Most of the reported outcomes do not capture those outcomes that matter to the patients. Adopting the principles of Value-Based Health Care (VBHC), may provide an opportunity to develop those metrics that matter to patients. In this article, we present a Consensus Statement on Outcome Measures in Liver Transplantation following the principles of VBHC, developed by a dedicated panel of experts under the auspices of the European Society of Organ Transplantation (ESOT) Guidelines’ Taskforce. The overarching goal is to provide a framework to facilitate the development of outcome measures as an initial step to apply the VMC paradigm to liver transplantation.

AA amyloidosis may complicate several chronic inflammatory conditions. From a clinical point of view, causality between inflammatory pathology and AA amyloidosis can be assumed because of the data described in the literature; some of the best known include rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, and chronic infections. Singles cases of inflammatory diseases have been found at AA amyloidosis. Causality becomes more plausible if at least two different cases with AA amyloidosis are both found to have the same rare inflammatory disease. We describe the case of a patient with primary sclerosing cholangitis (PSC) with development of AA amyloidosis conditioning a nephrotic syndrome, likely secondary to failure to control the chronic inflammatory process. Only two cases in the literature describe the association of this rare disease and the appearance of AA amyloidosis. The treatment of AA amyloidosis consists in treating the underlying inflammatory disorder; to date, few effective treatments are available for PSC. Therefore, and in view of the limited data in the literature, we believe it is important to describe its association.

Abstract Recently, an expert panel proposed diagnostic criteria for metabolic dysfunction–associated fatty liver disease (MAFLD) in the pediatric population. The aim of this study was to evaluate the prevalence of MAFLD among US adolescents and to investigate whether the new MAFLD definition is able to identify individuals with more advanced liver disease. We analyzed data from participants 12–18 years old included in the 2017–2020 cycles of the National Health and Nutrition Examination Survey, a large survey aimed at including individuals representative of the non‐institutionalized general US population. Participants with a complete vibration‐controlled transient elastography exam were included. Steatosis was evaluated through the median controlled attenuation parameter (CAP) and fibrosis through median liver stiffness measurement (LSM). Recently proposed criteria for the diagnosis of MAFLD were applied. Multivariable logistic regression analysis was performed to evaluate the impact of the new MAFLD definition on the odds of significant liver fibrosis. We included a total of 1446 adolescents (mean age: 14.9 years; 52.0% male; 47.3% overweight or obese). No participant reported a previous history of viral hepatitis. Steatosis (CAP ≥ 248 dB/m) was present in 25.9% (95% confidence interval [CI] 23.3–28.9) of individuals, and among these, 87.7% met the MAFLD criteria. Only 22.9% of patients with steatosis had elevated alanine aminotransferase levels. Among participants with steatosis, prevalence of significant liver fibrosis (LSM ≥ 7.4 kPa) did not differ significantly according to whether they met MAFLD criteria (9.7% vs. 15.2%, p = 0.276). In the multivariable model, odds of significant fibrosis did not differ significantly between these two groups. MAFLD criteria are met by most US adolescents with elastographic evidence of steatosis. Nonetheless, these criteria do not appear to improve detection of subjects with more advanced liver disease. Further longitudinal studies are needed to evaluate whether metabolic dysfunction is associated with faster progression toward inflammation, fibrosis, and liver‐related events.

Background:. There is a real unmet need for primary biliary cholangitis (PBC) treatments that can improve quality of life impacting symptoms. In this post hoc analysis, we evaluated potential effects of the NADP oxidase 1/4 inhibitor, setanaxib, on patient-reported quality of life from a phase 2 trial in PBC. Patients and Methods:. The underpinning double-blind, randomized, placebo-controlled trial (NCT03226067) recruited 111 patients with PBC and inadequate response/intolerance to ursodeoxycholic acid. Patients self-administered oral placebo (n=37), setanaxib 400 mg once daily (OD; n=38), or setanaxib 400 mg twice daily (BID; n=36), in addition to ursodeoxycholic acid for 24 weeks. Quality of life outcomes were assessed using the validated PBC-40 questionnaire. Patients were stratified post hoc by baseline fatigue severity. Results:. At week 24, patients treated with setanaxib 400 mg BID reported greater mean (SE) absolute reductions from baseline in PBC-40 fatigue domain score [–3.6 (1.3)] versus those receiving setanaxib 400 mg OD [–0.8 (1.0)]) or placebo [0.6 (0.9)]. Similar observations were made across all PBC-40 domains except itch. In the setanaxib 400 mg BID arm, patients with moderate-to-severe fatigue at baseline had a greater reduction in mean fatigue score at week 24 [–5.8 (2.1)] versus those with mild fatigue [–0.6 (0.9)]; results were similar across all domains. Reduced fatigue was correlated with emotional, social, symptom, and cognitive improvements. Conclusions:. These results support further investigation of setanaxib as a treatment for patients with PBC, particularly for those with clinically significant fatigue.

BackgroundEarly onset scoliosis (EOS) can lead to marked spine and chest wall deformity and often to profound cardiopulmonary compromise. Nowadays, treatment benefits from the possibility of a growth-friendly surgical approach to avoid early spinal fusion. Growing rod spinal implants allow maximizing spine and thorax growth during childhood, performing lengthening procedures traditionally approximately every 6 months.MethodsWe retrospectively evaluated 40 patients affected by EOS who underwent growing rod implantations from 2000 to 2020. A 1-year interval between lengthening procedures was adopted. Data about the age at the first and final surgeries, T1-T12 length pre- and post-surgery, T1-S1 pre- and post-surgery, major coronal curve, pre- and post-surgery rate of complications, and unplanned surgeries were collected and compared with those reported in the literature to determinate the effectiveness and safety of this long period between distractions.ResultsThe lengthening procedures were performed, on average, every 12.3 months; children underwent an average of 4.6 lengthening procedures each. Major curve pre-first surgery was 78°, post-first surgery 45°, pre-final surgery 55°, and post-final surgery 43°. The mean absolute difference between pre-initial to post-final major curve was 35°, representing a mean relative difference of 42%. On average, the T1-T12 segment measured 15 cm before the first surgery and 24 cm after the final surgery, while the T1-S1 segment was 25 cm before the growing rods implantation and reached 37 cm after treatment. During treatment, the adverse events affected 27 of the 40 total patients (67%) who experienced at least one complication. No differences were shown concerning both outcomes and complications, comparing these data with the available literature concerning most frequent elongations. This approach avoided four to five surgical procedures in this population.ConclusionOur results related to deformity correction and complication rate are comparable with those found in the literature, where lengthening procedures are performed approximately every 6 months rather than with a 1-year interval between distractions. We also demonstrate a higher risk of complications for patients with implants before the age of 6.

Autoimmune liver diseases (AiLDs) are rare autoimmune conditions of the liver and the biliary tree with unknown etiology and limited treatment options. AiLDs are inherently characterized by a high degree of complexity, which poses great challenges in understanding their etiopathogenesis, developing novel biomarkers and risk-stratification tools, and, eventually, generating new drugs. Artificial intelligence (AI) is considered one of the best candidates to support researchers and clinicians in making sense of biological complexity. In this review, we offer a primer on AI and machine learning for clinicians, and discuss recent available literature on its applications in medicine and more specifically how it can help to tackle major unmet needs in AiLDs.

Background & Aims: Primary biliary cholangitis (PBC) is a chronic cholangiopathy characterised by immuno-mediated injury of interlobular bile ducts leading to intrahepatic cholestasis and progressive liver fibrosis. PBC histology is characterised by portal inflammation, progressive fibrosis, ductopenia, and the appearance of the so-called ductular reaction. The aim of the present study was to investigate the pathogenetic relevance of ductular reaction in PBC. Methods: Liver biopsies were collected from naïve people with PBC (N = 87). Clinical–serological parameters were obtained at diagnosis and after 1 year of ursodeoxycholic acid (UDCA) treatment. Histological staging was performed on all slides according to multiple scoring systems and criteria for PBC. Liver samples were obtained from Mdr2−/− mice treated with or without UDCA. Samples were processed for histology, immunohistochemistry, and immunofluorescence. Results: Ductular reaction in people with PBC correlated with the disease stage and liver fibrosis, but not with disease activity; an extensive ductular reaction correlated with serum alkaline phosphatase levels at diagnosis, response to UDCA, and individuals’ estimated survival, independently from other histological parameters, including disease stage. In people with PBC, reactive ductules were associated with the establishment of junctions with bile canaliculi and with fibrogenetic cell activation. Consistently, in a mouse model of intrahepatic cholestasis, UDCA treatment was effective in reducing ductular reaction and fibrosis and increasing ductular–canalicular junctions. Conclusions: Extensive ductular reaction outlines a severe histologic phenotype in PBC and is associated with an inadequate therapy response and a worse estimated prognosis. Lay summary: In people affected by primary biliary cholangitis (PBC), the histological appearance of extensive ductular reaction identifies individuals at risk of progressive fibrosis. Ductular reaction at diagnosis correlates with the lack of response to first-line therapy with ursodeoxycholic acid and serves to restore ductular–canalicular junctions in people with PBC. Assessing ductular reaction extension at diagnosis may add valuable information for clinicians.

Background: Hip dislocation is a common source of pain in children with neurologic impairment. When medical interventions fail, orthopedic surgery does not guarantee a definitive result as the displacement may continue postoperatively and a second operation is often required. Methods: Retrospective analysis of data regarding the safety and effectiveness of an intra-articular corticosteroid injection (IACI) in 11 patients, aged 15 ± 5 years old, collected through a telephonic questionnaire administered to parents. Results: 21 IACIs were performed, a mean number of 1.9 ± 1.5 times for each patient, at a mean age (of the first IACI) of 13.5 ± 5 years. According to the parents, the IACI significantly lowered the number of participants experiencing pain (82% reduction) and using analgesics (60% reduction). There was also a significant improvement in the children’s hip mobility (63% reduction in patients experiencing stiffness), decubitus (90% reduction in obligated positioning), behavior (80% reduction in lamenting or crying patients), sleep quality (87.5% reduction in patients awakening every night), and caregivers’ quality of life (91% reduction in worried parents). The mean reported duration of the IACIs’ benefit was 5.4 ± 2.4 months (range 1–9), with a positive correlation with the number of IACIs (r = 0.48; p-value = 0.04) and a negative correlation with the age at the first injection (r = −0.71; p-value = 0.02). The only reported adverse event was mild local swelling in one child. Conclusions: the IACI could represent a safe and effective intervention for painful hip dislocation, both before and after surgery, with a long-lasting benefit which seems to increase as multiple IACIs are performed.

Abstract Background Neonatal infectious spondylodiscitis is a rare bony infection with atypical clinical presentation and non-specific systemic symptoms. Diagnosis and treatment are often delayed resulting in vertebral destruction and severe complications. We retrospectively reviewed the case of an infant with infectious spondylodiscitis resulting in T12 body destruction and marked angular kyphosis. Case-report A 4-week-old infant developed an infectious spondylodiscitis resulting in destruction of the T12 vertebral body and involvement of disc between T12 and L1. At 6 months of age, X-ray showed a marked thoracolumbar angular kyphosis above 50 Cobb degrees. Therefore, the patient underwent single time surgery with double anterior and posterior approach. At 9 years follow up, clinical and radiological findings show a stable correction with good aesthetic appearance. Conclusion Neonatal spondylodiscitis could lead to marked kyphosis similar to the congenital one. Since treatment with casts and tutors is often inefficacious, prompt surgery should be considered. The double anterior and posterior approach is the best option in this condition.

Abstract Background Respiratory failure due to COVID-19 pneumonia is associated with high mortality and may overwhelm health care systems, due to the surge of patients requiring advanced respiratory support. Shortage of intensive care unit (ICU) beds required many patients to be treated outside the ICU despite severe gas exchange impairment. Helmet is an effective interface to provide continuous positive airway pressure (CPAP) noninvasively. We report data about the usefulness of helmet CPAP during pandemic, either as treatment, a bridge to intubation or a rescue therapy for patients with care limitations (DNI). Methods In this observational study we collected data regarding patients failing standard oxygen therapy (i.e., non-rebreathing mask) due to COVID-19 pneumonia treated with a free flow helmet CPAP system. Patients’ data were recorded before, at initiation of CPAP treatment and once a day, thereafter. CPAP failure was defined as a composite outcome of intubation or death. Results A total of 306 patients were included; 42% were deemed as DNI. Helmet CPAP treatment was successful in 69% of the full treatment and 28% of the DNI patients (P

Chronic immunosuppression is associated with increased and more severe viral infections. However, little is known about the association between immunosuppression and severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection. Our aim was to describe the clinical course of patients with immunosuppressed autoimmune hepatitis (AIH) during coronavirus disease 2019 (COVID‐19) infection in Italy. Our study is a case series of patients with AIH treated with immunosuppression, who tested positive for SARS‐CoV‐2 in March 2020 during the outbreak of COVID‐19. Ten patients from seven different hospitals in Italy were diagnosed with COVID‐19 during the outbreak of SARS‐CoV‐2 in March 2020. Seven subjects were female (70%), and age ranged from 27 to 73 years. Before the onset of SARS‐CoV‐2 infection, all patients were taking immunosuppressive therapy for AIH, and eight of them were on biochemical remission. Two other patients had recent acute onset of their AIH, and consequently started high‐dose steroids, as per induction protocol. All patients had a respiratory syndrome and a positive nasal swab for SARS‐CoV‐2. Five patients developed a computed tomography–confirmed COVID‐19 pneumonia. Six subjects received a combination of antiretroviral and antimalarial drugs. In seven patients, the dosage of immunosuppressive medication was changed. Liver enzymes were repeated during SARS‐CoV‐2 infection in all hospitalized cases; they remained within the normal range in all cases, and improved in the two acute cases treated with high‐dose steroids. The clinical outcome was comparable to the reported cases occurring in non‐immunosuppressed subjects. Conclusion: Patients under immunosuppressive therapy for AIH developing COVID‐19 show a disease course presumptively similar to that reported in the non‐immunosuppressed population. These data might aid in medical decisions when dealing with SARS‐CoV‐2 infection in immunocompromised patients.

Primary biliary cholangitis and primary sclerosing cholangitis are rare diseases affecting the bile ducts and the liver. The limited knowledge of their pathogenesis leads to limited therapeutic options. Nevertheless, the landscape of novel therapies for these cholangiopathies is now rapidly changing, providing new treatment opportunities for patients and clinicians involved in their care. The aim of this review is to summarize the evidence of novel molecules under investigation for primary biliary cholangitis and primary sclerosing cholangitis and to discuss how they can potentially change current treatment paradigms.

Epidemiological studies on primary biliary cholangitis (PBC) have been based primarily on tertiary referral case series. We aimed to estimate the incidence and prevalence and describe comorbidities in hospitalized patients with PBC in Italy using a national hospital‐based data source. Data were extracted from the National Hospital Discharge Database, which includes all Italian individuals discharged from any hospital in the country. All adults diagnosed with biliary cirrhosis (International Classification of Diseases, Ninth Revision, Clinical Modification, 571.6) as the primary or secondary diagnosis from 2011 to 2015 were included. To determine whether a comorbidity was either more or less frequent in PBC patients compared with the general hospitalized Italian population, the standardized hospitalization ratio (SHR) was calculated. A total of 5,533 incident cases were identified from 2011 to 2015, 3,790 of whom were females (68.5%; female to male [F:M] ratio, 2.2:1). Prevalent cases were 9,664, of whom 7,209 were females (74.6%; F:M ratio, 2.9:1). The incident rate was 1.03 × 100,000 in males and 1.92 × 100,000 in females; prevalence was 1.89 × 100,000 in males and 4.75 × 100,000 in females. Extrahepatic autoimmune diseases, malignant neoplasms of liver and intrahepatic biliary ducts, and malignant neoplasms of gallbladder and extrahepatic bile ducts were found more frequently in PBC patients than in the general hospitalized population (SHR > 100), whereas cerebrovascular diseases and ischemic heart diseases were less frequent in PBC individuals (SHR

Abstract Background In all patients with mucopolysaccharidosis type I (MPS I), skeletal disease (dysostosis multiplex) is a prominent, debilitating, condition related complication that may impact strongly on activities of daily living. Unfortunately, it is not alleviated by treatment with hematopoietic cell transplantation (HCT) or enzyme replacement therapy (ERT). Although early kyphosis is one of the key features of dysostosis multiplex, there is no international consensus on the optimal management. Therefore, an international consensus procedure was organized with the aim to develop the first clinical practice guideline for the management of thoracolumbar kyphosis in MPS I patients. Methods A literature review was conducted to identify all available information about kyphosis and related surgery in MPS I patients. Subsequently, a modified Delphi procedure was used to develop consensus statements. The expert panel included 10 spinal orthopedic surgeons, 6 pediatricians and 3 physiotherapists, all experienced in MPS I. The procedure consisted of 2 written rounds, a face-to-face meeting and a final written round. The first 2 rounds contained case histories, general questions and draft statements. During the face-to-face meeting consensus statements were developed. In the final round, the panel had the opportunity to anonymously express their opinion about the proposed statements. Results Eighteen case series and case reports were retrieved from literature reporting on different surgical approaches and timing of thoracolumbar kyphosis surgery in MPS I. During the face-to-face meeting 16 statements were discussed and revised. Consensus was reached on all statements. Conclusion This international consensus procedure resulted in the first clinical practice guideline for the management of thoracolumbar kyphosis in MPS I patients, focusing on the goals and timing of surgery, as well as the optimal surgical approach, the utility of bracing and required additional assessments (e.g. radiographs). Most importantly, it was concluded that the decision for surgery depends not only on the kyphotic angle, but also on additional factors such as the progression of the deformity and its flexibility, the presence of symptoms, growth potential and comorbidities. The eventual goal of treatment is the maintenance or improvement of quality of life. Further international collaborative research related to long-term outcome of kyphosis surgery in MPS I is essential as prognostic information is lacking.

Background & aims: Obeticholic acid (OCA) is the second-line treatment approved for patients with primary biliary cholangitis (PBC) and an inadequate response or intolerance to ursodeoxycholic acid. We aimed to evaluate the effectiveness and safety of OCA under real-world conditions. Methods: Patients were recruited into the Italian PBC Registry, a multicentre, observational cohort study that monitors patients with PBC at national level. The primary endpoint was the biochemical response according to Poise criteria; the secondary endpoint was the biochemical response according to normal range criteria, defined as normal levels of bilirubin, alkaline phosphatase (ALP), and alanine aminotransferase (ALT) at 12 months. Safety and tolerability were also assessed. Results: We analysed 191 patients until at least 12 months of follow-up. Median age was 57 years, 94% female, 61 (32%) had cirrhosis, 28 (15%) had histologically proven overlap with autoimmune hepatitis (PBC-AIH). At 12 months, significant median reductions of ALP (-32.3%), ALT (-31.4%), and bilirubin (-11.2%) were observed. Response rates were 42.9% according to Poise criteria, and 11% by normal range criteria. Patients with cirrhosis had lower response than patients without cirrhosis (29.5% vs. 49.2%, p = 0.01), owing to a higher rate of OCA discontinuation (30% vs. 12%, p = 0.004), although with similar ALP reduction (29.4% vs. 34%, p = 0.53). Overlap PBC-AIH had a similar response to pure PBC (46.4% vs. 42.3%, p = 0.68), with higher ALT reduction at 6 months (-38% vs. -29%, p = 0.04). Thirty-three patients (17%) prematurely discontinued OCA because of adverse events, of whom 11 experienced serious adverse events. Treatment-induced pruritus was the leading cause of OCA discontinuation (67%). Conclusions: Effectiveness and safety of OCA under real-world conditions mirror those in the Poise trial. Patients with cirrhosis had lower tolerability. Overlap PBC-AIH showed higher ALT reduction at 6 months compared with patients with pure PBC. Lay summary: Obeticholic acid (OCA) was shown to be effective in more than one-third of patients not responding to ursodeoxycholic acid in a real-world context in Italy. Patients with cirrhosis had more side effects with OCA, and this led to suspension of the drug in one-third of patients. OCA was also effective in patients who had overlap between autoimmune hepatitis and primary biliary cholangitis.

Session types, types for structuring communication between endpoints in distributed systems, are recently being integrated into mainstream programming languages. In practice, a very important notion for dealing with such types is that of subtyping, since it allows for typing larger classes of system, where a program has not precisely the expected behaviour but a similar one. Unfortunately, recent work has shown that subtyping for session types in an asynchronous setting is undecidable. To cope with this negative result, the only approaches we are aware of either restrict the syntax of session types or limit communication (by considering forms of bounded asynchrony). Both approaches are too restrictive in practice, hence we proceed differently by presenting an algorithm for checking subtyping which is sound, but not complete (in some cases it terminates without returning a decisive verdict). The algorithm is based on a tree representation of the coinductive definition of asynchronous subtyping; this tree could be infinite, and the algorithm checks for the presence of finite witnesses of infinite successful subtrees. Furthermore, we provide a tool that implements our algorithm. We use this tool to test our algorithm on many examples that cannot be managed with the previous approaches, and to provide an empirical evaluation of the time and space cost of the algorithm.

Background & aims: Several symptoms impair the quality of life (QoL) of patients with primary biliary cholangitis (PBC). They are reported to vary significantly in different countries. Aim of our study was to explore whether there is a geographical clustering that accounts for symptoms in PBC. Methods: Data was analysed from four cohorts of PBC patients from the UK, Spain, Japan and Italy using the PBC-27 scale. Results: Overall, 569 patients from four cohorts were identified, including 515 females (90.5%) with a mean age of 61 years. The analysis provided evidence for strict factorial invariance of the scale, a robust indicator of its validity for cross-cultural research. The mean of the fatigue domain of British patients was significantly greater than that of the Japanese (p ​

Takayasu arteritis and primary sclerosing cholangitis are two rare disorders. The pathogenesis of Takayasu arteritis involves immune-mediated mechanisms, and corticosteroids represent the mainstay for treatment. Conversely, the aetiology of primary sclerosing cholangitis remains elusive, even if dysimmunity seems to be one of the contributors to bile duct damage. Despite this, immunosuppressants do not alter disease course. In this paper we describe the association of these two rare disorders, with an unexpected normalization of cholestatic enzymes following steroid treatment. This might hint a novel subtype of sclerosing cholangitis with a prevalent immunebackground, or a local manifestation of Takayasu arteritis.

Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are autoimmune cholangiopathies characterized by limited treatment options. A more accurate understanding of the several pathways involved in these diseases has fostered the development of novel and promising targeted drugs. For PBC, the characterization of the role of farnesoid X receptor (FXR) and perixosome-proliferator activated receptor (PPAR) has paved the way to several clinical trials including different molecules with choleretic and antinflammatory action. Conversely, different pathogenetic models have been proposed in PSC such as the “leaky gut” hypothesis, a dysbiotic microbiota or a defect in mechanisms protecting against bile acid toxicity. Along these theories, new treatment approaches have been developed, ranging from drugs interfering with trafficking of lymphocytes from the gut to the liver, fecal microbiota transplantation or new biliary acids with possible immunomodulatory potential. Finally, for both diseases, antifibrotic agents are under investigation. In this review, we will illustrate current understanding of molecular mechanisms in PBC and PSC, focusing on actionable biological pathways for which novel treatments are being developed.

Abstract Mucopolysaccharidoses (MPS) are a group of diseases characterized by abnormal accumulation of glycosaminoglycans (GAGs). Although there are differences among the various disease types, the osteoarticular system is always involved. The aim of the present study was to establish a framework for MPS-related orthopaedic manifestations and for their treatment. The authors, affiliated to three different Italian Orthopaedic Centres, report data taken from the literature reviewed in light of their accumulated professional experience. Bone alterations make up what is known as dysostosis multiplex, involving the trunk and limbs and with typical radiological findings. Joints are affected by pathological tissue infiltrations. The cervical spinal cord is involved, with stenosis and cervical and occipitocervical instability. In MPS there is a much higher incidence of scoliosis compared with healthy subjects without any particular distinctive feature. Kyphosis of the spine is more frequent and also more severe because of its possible neurological complications, and it is localized at the thoracolumbar level with a malformed vertebra at the top of the deformity. Evolving forms, and those associated with neurological damage, require anteroposterior spine fusion. The hip is invariably involved, with dysplasia affecting the femoral neck (coxa valga), the femoral epiphysis (loss of sphericity, osteonecrosis), and the femoral acetabulum which is flared. All these features explain the tendency to progressive hip migration. Genu valgum is often found (a deviation of the physiological axis with an obtuse angle opening laterally). This deformity is often localized at the proximal tibial metaphysis; it causes functional limitations and leads to an irregular erosion of the articular cartilage. In young patients who still have the growth plate, it is possible to execute a medial hemiepiphysiodesis, a temporary inhibition of cartilage growth, with progressive axis correction. In this paper, the characterisation of clinical features and the review of treatments are divided into separate sections based on the part of the body involved. The conclusions of each section are presented as a summary. One section discusses the high risk of anaesthesia-related complications requiring the collaboration of specifically trained personnel.

Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease characterized by the progressive destruction of the intrahepatic bile ducts. Currently, the first line drug for PBC is ursodeoxycholic acid (UDCA) characterized by anti-apoptotic, anti-inflammatory and protective actions on cholangiocytes. Despite its recognized therapeutic action, 30–40% of PBC patients only partially benefit from UDCA therapy. This has led to the identification of the role of the farnesoid x receptor (FXR) in cholestatic liver diseases and, consequently, to the development of obeticholic acid (OCA), a steroid FXR agonist that has been recently approved for the treatment of PBC. OCA though is not effective in all patients and can cause itch, which eventually induces treatment drop out. Therefore, the search for new therapeutic strategies for PBC has begun. This review, in addition to summarizing the current treatments for PBC, provides overview of the chemical characteristics of new steroid FXR agonist candidates that could represent a future perspective for the treatment of PBC.

The increasing imperviousness of urban areas reduces the infiltration and evapotranspiration capacity of urban catchments and results in increased runoff. In the last few decades, several solutions and techniques have been proposed to prevent such impacts by restoring the hydrological cycle. A limiting factor in spreading the use of such systems is the lack of proper modelling tools for design, especially for the infiltration processes in a growing medium. In this research, a physically-based model, employing the explicit Finite Volume Method (FVM), is proposed for modelling infiltration into growing media. The model solves a modified version of the Richards equation using a formulation which takes into account the main characteristics of green infrastructure substrates. The proposed model was verified against the HYDRUS-1D software and the comparison of results confirmed the suitability of the proposed model for correctly describing the hydraulic behaviour of soil substrates.

Choreography-based programming is a powerful paradigm for defining communication-based systems from a global viewpoint. A choreography can be checked against multiparty protocol specifications, given as behavioural types, that may be instantiated indefinitely at runtime. Each protocol instance is started with a synchronisation among the involved peers. We analyse a simple transformation from a choreography with a possibly unbounded number of protocol instantiations to a choreography instantiating a single protocol, which is the merge of the original ones. This gives an effective methodology for obtaining new protocols by composing existing ones. Moreover, by removing all synchronisations required for starting protocol instances, our transformation reduces the number of communications and resources needed to execute a choreography.

Motivated by the response pattern for property specifications and applications within flexible workflow management systems, we report upon an initial study of modal and mixed transition systems in which the must transitions are interpreted as must eventually, and in which implementations can contain may behaviors that are resolved at run-time. We propose Transition Systems with Responses (TSRs) as a suitable model for this study. We prove that TSRs correspond to a restricted class of mixed transition systems, which we refer to as the action-deterministic mixed transition systems. We show that TSRs allow for a natural definition of deadlocked and accepting states. We then transfer the standard definition of refinement for mixed transition systems to TSRs and prove that refinement does not preserve deadlock freedom. This leads to the proposal of safe refinements, which are those that preserve deadlock freedom. We exemplify the use of TSRs and (safe) refinements on a small medication workflow.

We explore logical reasoning for the global calculus, a coordination model based on the notion of choreography, with the aim to provide a methodology for specification and verification of structured communications. Starting with an extension of Hennessy-Milner logic, we present the global logic (GL), a modal logic describing possible interactions among participants in a choreography. We illustrate its use by giving examples of properties on service specifications. Finally, we show that, despite GL is undecidable, there is a significant decidable fragment which we provide with a sound and complete proof system for checking validity of formulae.

We investigate a graphical representation of session invocation interdependency in order to prove progress for the pi-calculus with sessions under the usual session typing discipline. We show that those processes whose associated dependency graph is acyclic can be brought to reduce. We call such processes transparent processes. Additionally, we prove that for well-typed processes where services contain no free names, such acyclicity is preserved by the reduction semantics. Our results encompass programs (processes containing neither free nor restricted session channels) and higher-order sessions (delegation). Furthermore, we give examples suggesting that transparent processes constitute a large enough class of processes with progress to have applications in modern session-based programming languages for web services.

A choreography describes a transaction in which several principals interact. Since choreographies frequently describe business processes affecting substantial assets, we need a security infrastructure in order to implement them safely. As part of a line of work devoted to generating cryptoprotocols from choreographies, we focus here on the execution models suited to the two levels. We give a strand-style semantics for choreographies, and propose a special execution model in which choreography-level messages are faithfully delivered exactly once. We adapt this model to handle multiparty protocols in which some participants may be compromised. At level of cryptoprotocols, we use the standard Dolev-Yao execution model, with one alteration. Since many implementations use a "nonce cache" to discard multiply delivered messages, we provide a semantics for at-most-once delivery.

We equip choreography-level session descriptions with a simple abstraction of a security infrastructure. Message components may be enclosed within (possibly nested) ''boxes'' annotated with the intended source and destination of those components. The boxes are to be implemented with cryptography. Strand spaces provide a semantics for these choreographies, in which some roles may be played by compromised principals. A skeleton is a partially ordered structure containing local behaviors (strands) executed by regular (non-compromised) principals. A skeleton is realized if it contains enough regular strands so that it could actually occur, in combination with any possible activity of compromised principals. It is delivery guaranteed (DG) realized if, in addition, every message transmitted to a regular participant is also delivered. We define a novel transition system on skeletons, in which the steps add regular strands. These steps solve tests, i.e. parts of the skeleton that could not occur without additional regular behavior. We prove three main results about the transition system. First, each minimal DG realized skeleton is reachable, using the transition system, from any skeleton it embeds. Second, if no step is possible from a skeleton A, then A is DG realized. Finally, if a DG realized B is accessible from A, then B is minimal. Thus, the transition system provides a systematic way to construct the possible behaviors of the choreography, in the presence of compromised principals.

Design storms are very useful in many hydrological and hydraulic practices and are obtained from statistical analysis of precipitation records. However considering design storms, which are often quite unlike the natural rainstorms, may result in designing oversized or undersized drainage facilities. For these reasons, in this study, a two-parameter double exponential function is proposed to parameterize historical storm events. The proposed function has been assessed against the storms selected from 5-year rainfall time series with a 1-minute resolution, measured by three meteorological stations located in Calabria, Italy. In particular, a nonlinear least square optimization has been used to identify parameters. In previous studies, several evaluation methods to measure the goodness of fit have been used with excellent performances. One parameter is related to the centroid of the rain distribution; the second one is related to high values of the standard deviation of the kurtosis for the selected events. Finally, considering the similarity between the proposed function and the Gumbel function, the two parameters have been computed with the method of moments; in this case, the correlation values were lower than those computed with nonlinear least squares optimization but sufficiently accurate for designing purposes.

Hepatitis C virus (HCV) infection is relatively common among patients with end-stage kidney disease (ESKD) on dialysis and kidney transplant recipients. HCV infection in hemodialysis patients is associated with an increased mortality due to liver cirrhosis and hepatocellular carcinoma. The severity of hepatitis C-related liver disease in kidney transplant candidates may predict patient and graft survival after transplant. Liver biopsy remains the gold standard in the assessment of liver fibrosis in this setting. Kidney transplantation, not haemodialysis, seems to be the best treatment for HCV+ve patients with ESKD. Transplantation of kidneys from HCV+ve donors restricted to HCV+ve recipients is safe and associated with a reduction in the waiting time. Simultaneous kidney/liver transplantation (SKL) should be considered for kidney transplant candidates with HCV-related decompensated cirrhosis. Treatment of HCV is more complex in hemodialysis patients, whereas treatment of HCV recurrence in SLK recipients appears effective and safe.

End-stage liver disease due to hepatitis C (HCV) and cirrhosis from alcohol (ALD) are the commonest indications for liver transplantation in the western countries. Up to one third of HCV-infected transplant candidates have a history of significant alcohol intake prior to transplantation. However, there are few data available about the possible interaction between alcohol and HCV in the post-transplant setting. Patients with both HCV and alcohol are more likely to die on the waiting list than those with ALD and HCV alone. However, after transplantation, non-risk adjusted graft and patient survival of patients with HCV + ALD are comparable to those of patients with HCV cirrhosis or ALD cirrhosis alone. In the short and medium term HCV recurrence after transplant in patients with HCV + ALD cirrhosis does not seem more aggressive than that in patients with HCV cirrhosis alone. A relapse in alcohol consumption in patients with HCV + ALD cirrhosis does not have a major impact on graft survival. The evidence shows that, as is currently practiced, HCV + ALD as an appropriate indication for liver transplantation. However, these data are based on retrospective analyses with relatively short follow-up so the conclusions must be treated with caution.