Paediatric research sets new standards for therapy in paediatric and adult cholestasis.

Children with Alagille syndrome and progressive familial intrahepatic cholestasis (PFIC) experience debilitating pruritus, for which there have been few effective treatment options. In the past 2 years, the ileal bile acid transporter (IBAT) inhibitors maralixibat and odevixibat have been approved for the management of cholestatic pruritus in these individuals, representing an important step forward in improving their quality of life. Emerging data suggest these drugs might also improve event-free survival, therefore potentially altering the typical disease course currently seen in these disorders. This Review will discuss how genetic advances have clarified the molecular basis of cholestatic disorders, facilitating the development of new therapeutic options that have only been evaluated in children. We focus specifically on the newly licensed IBAT inhibitors for patients with Alagille syndrome and PFIC and explore the next steps for these drugs in relation to other paediatric and adult cholestatic disorders, recognising that they have the potential to benefit a wider group of patients with gastrointestinal and liver disease.

ATP7B Genotype and Chronic Liver Disease Treatment Outcomes in Wilson Disease: Worse Survival With Loss-of-Function Variants.

BACKGROUND AND AIMS: Although a good genotype-phenotype correlation has not been established in Wilson disease (WD), patients with loss-of-function (LOF) ATP7B variants demonstrate different clinical and biochemical characteristics. We aim to describe long-term treatment outcomes in the chronic liver disease (CLD) phenotype and evaluate an association with LOF variants. METHODS: This was a single-center retrospective review of WD patients with at least 1 variant in ATP7B. Demographic, biochemical, genetic, and clinical parameters were obtained. The composite clinical endpoint of liver transplantation or death was used for probands with CLD phenotype on chelators. RESULTS: Of 117 patients with hepatic WD: 71 had CLD, 27 had fulminant hepatic failure requiring urgent liver transplantation, and 19 were diagnosed through family screening. Median age at diagnosis was 13.1 (interquartile range, 9.7-17.6) years. In total, 91 variants in ATP7B were identified in the study population. At least 1 LOF variant was present in 60 (51.3%) patients. During median follow-up of 10.7 (interquartile range, 6.7-18.9) years, 10 (14.1%) of the probands with CLD reached the composite endpoint. There was a worse transplant-free survival for patients prescribed chelation therapy in patients with at least 1 LOF variant (P = .03). CONCLUSIONS: Patients with WD and CLD phenotype on chelators, who have at least 1 LOF variant in ATP7B, have a worse prognosis during long-term follow up. This subgroup of patients requires close monitoring for signs of progressive liver disease. Sequencing of ATP7B may be used in the diagnosis of WD, and in addition, it may provide useful prognostic information for patients with hepatic WD.

Nasobiliary drainage: an effective treatment for pruritus in cholestatic liver disease.

Introduction: Nasobiliary drains (NBDs) have been successfully used to manage intrahepatic cholestasis, bile leaks and obstructive cholangitis. It allows external drainage of bile, bypassing the ileum where bile salts are reabsorbed. We assessed the utility of placement with effect on markers of cholestasis and patient symptoms. Methods: Consecutive patients undergoing NBD over 12 years for the management of pruritus were retrospectively analysed. Recorded variables included patient demographics, procedural characteristics and response to therapy. Results: Twenty-three patients (14, 61% male) underwent 30 episodes of NBD. The median age was 26 years old (range 2-67 years old). A single procedure was carried out in 20. One patient each had two, three and five episodes of NBD. The most common aetiologies were hereditary cholestatic disease (n=17, 74%) and drug-induced cholestasis (n=5, 22%),NBD remained in situ for a median of 8 days (range 1-45 days). Significant improvement in bilirubin was seen at 7 days post-NBD (p=0.0324), maintained at day 30 (335 µmol/L vs 302 µmol/L vs 167 µmol/L). There was symptomatic improvement in pruritus in 20 (67%, p=0.0494) episodes. One patient underwent NBD during the first trimester of pregnancy after medical therapy failure with a good symptomatic response. The catheters were well tolerated in 27 (90%) of cases. Mild pancreatitis occurred in 4 (13%) cases. Conclusion: NBD can be used to provide symptomatic improvement to patients with pruritus associated with cholestasis. It is well tolerated by patients. They can be used in pregnancy where medical management has failed.

Rare Inherited Cholestatic Disorders and Molecular Links to Hepatocarcinogenesis.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer affecting adults and the second most common primary liver cancer affecting children. Recent years have seen a significant increase in our understanding of the molecular changes associated with HCC. However, HCC is a complex disease, and its molecular pathogenesis, which likely varies by aetiology, remains to be fully elucidated. Interestingly, some inherited cholestatic disorders that manifest in childhood are associated with early HCC development. This review will thus explore how three genes that are associated with liver disease in childhood (ABCB11, TJP2 and VPS33B) might play a role in the initiation and progression of HCC. Specifically, chronic bile-induced damage (caused by ABCB11 changes), disruption of intercellular junction formation (caused by TJP2 changes) and loss of normal apical-basal cell polarity (caused by VPS33B changes) will be discussed as possible mechanisms for HCC development.

The Genetics of Inherited Cholestatic Disorders in Neonates and Infants: Evolving Challenges.

Many inherited conditions cause cholestasis in the neonate or infant. Next-generation sequencing methods can facilitate a prompt diagnosis in some of these cases; application of these methods in patients with liver diseases of unknown cause has also uncovered novel gene-disease associations and improved our understanding of physiological bile secretion and flow. By helping to define the molecular basis of certain cholestatic disorders, these methods have also identified new targets for therapy as well patient subgroups more likely to benefit from specific therapies. At the same time, sequencing methods have presented new diagnostic challenges, such as the interpretation of single heterozygous genetic variants. This article discusses those challenges in the context of neonatal and infantile cholestasis, focusing on difficulties in predicting variant pathogenicity, the possibility of other causal variants not identified by the genetic screen used, and phenotypic variability among patients with variants in the same genes. A prospective, observational study performed between 2010-2013, which sequenced six important genes (ATP8B1, ABCB11, ABCB4, NPC1, NPC2 and SLC25A13) in an international cohort of 222 patients with infantile liver disease, is given as an example of potential benefits and challenges that clinicians could face having received a complex genetic result. Further studies including large cohorts of patients with paediatric liver disease are needed to clarify the spectrum of phenotypes associated with, as well as appropriate clinical response to, single heterozygous variants in cholestasis-associated genes.

Outcomes in Clinical Trials Evaluating Interventions for the Prevention and Treatment of Hepatic Encephalopathy.

Randomised clinical trials and systematic reviews of research findings can provide high-quality evidence for decision-making in the management of patients with hepatic encephalopathy. A large number of clinical trials have been undertaken, over the last 50 years, relative to the prevention and treatment of this condition. However, changes have been made, during this time, in the classification of hepatic encephalopathy, diagnostic criteria and assessment measures. These temporally based changes and the consequent lack of standardisation make it difficult to compare interventions and to evaluate their comparative efficacy and safety. While some consensus has been reached in relation to the diagnostic evaluation, classification and monitoring of patients in clinical trials, there is less surety about the choice of clinical endpoints. These outcome measures should be universally applicable, easily measured and clinically relevant. This article reviews the current recommendations regarding outcome selection and outlines some of the potential problems and pitfalls inherent in clinical trial evaluating interventions for the management of hepatic encephalopathy.

Carvedilol versus traditional, non-selective beta-blockers for adults with cirrhosis and gastroesophageal varices.

BACKGROUND: Non-selective beta-blockers are recommended for the prevention of bleeding in people with cirrhosis, portal hypertension and gastroesophageal varices. Carvedilol is a non-selective beta-blocker with additional intrinsic alpha1-blocking effects, which may be superior to traditional, non-selective beta-blockers in reducing portal pressure and, therefore, in reducing the risk of upper gastrointestinal bleeding. OBJECTIVES: To assess the beneficial and harmful effects of carvedilol compared with traditional, non-selective beta-blockers for adults with cirrhosis and gastroesophageal varices. SEARCH METHODS: We combined searches in the Cochrane Hepato-Biliary's Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, LILACS, and Science Citation Index with manual searches. The last search update was 08 May 2018. SELECTION CRITERIA: We included randomised clinical trials comparing carvedilol versus traditional, non-selective beta-blockers, irrespective of publication status, blinding, or language. We included trials evaluating both primary and secondary prevention of upper gastrointestinal bleeding in adults with cirrhosis and verified gastroesophageal varices. DATA COLLECTION AND ANALYSIS: Three review authors (AZ, RJ and LH), independently extracted data. The primary outcome measures were mortality, upper gastrointestinal bleeding and serious adverse events. We undertook meta-analyses and presented results using risk ratios (RR) or mean differences (MD), both with 95% confidence intervals (CIs), and I2 values as a marker of heterogeneity. We assessed bias control using the Cochrane Hepato-Biliary domains and the quality of the evidence with GRADE. MAIN RESULTS: Eleven trials fulfilled our inclusion criteria. One trial did not report clinical outcomes. We included the remaining 10 randomised clinical trials, involving 810 participants with cirrhosis and oesophageal varices, in our analyses. The intervention comparisons were carvedilol versus propranolol (nine trials), or nadolol (one trial). Six trials were of short duration (mean 6 (range 1 to 12) weeks), while four were of longer duration (13.5 (6 to 30) months). Three trials evaluated primary prevention; three evaluated secondary prevention; while four evaluated both primary and secondary prevention. We classified all trials as at 'high risk of bias'. We gathered mortality data from seven trials involving 507 participants; no events occurred in four of these. Sixteen of 254 participants receiving carvedilol and 19 of 253 participants receiving propranolol or nadolol died (RR 0.86, 95% CI 0.48 to 1.53; I2 = 0%, low-quality evidence). There appeared to be no differences between carvedilol versus traditional, non-selective beta-blockers and the risks of upper gastrointestinal bleeding (RR 0.77, 95% CI 0.43 to 1.37; 810 participants; 10 trials; I2 = 45%, very low-quality evidence) and serious adverse events (RR 0.97, 95% CI 0.67 to 1.42; 810 participants; 10 trials; I2 = 14%, low-quality evidence). Significantly more deaths, episodes of upper gastrointestinal bleeding and serious adverse events occurred in the long-term trials but there was not enough information to determine whether there were differences between carvedilol and traditional, non-selective beta-blockers, by trial duration. There was also insufficient information to detect differences in the effects of these interventions in trials evaluating primary or secondary prevention. There appeared to be no differences in the risk of non-serious adverse events between carvedilol versus its comparators (RR 0.55, 95% CI 0.23 to 1.29; 596 participants; 6 trials; I2 = 88%; very low-quality evidence). Use of carvedilol was associated with a greater reduction in hepatic venous pressure gradient than traditional, non-selective beta-blockers both in absolute (MD -1.75 mmHg, 95% CI -2.60 to -0.89; 368 participants; 6 trials; I2 = 0%; low-quality evidence) and percentage terms (MD -8.02%, 95% CI -11.49% to -4.55%; 368 participants; 6 trials; I2 = 0%; low-quality evidence). However, we did not observe a concomitant reduction in the number of participants who failed to achieve a sufficient haemodynamic response (RR 0.76, 95% CI 0.57 to 1.02; 368 participants; 6 trials; I2 = 42%; very low-quality evidence) or in clinical outcomes. AUTHORS' CONCLUSIONS: We found no clear beneficial or harmful effects of carvedilol versus traditional, non-selective beta-blockers on mortality, upper gastrointestinal bleeding, serious or non-serious adverse events despite the fact that carvedilol was more effective at reducing the hepatic venous pressure gradient. However, the evidence was of low or very low quality, and hence the findings are uncertain. Additional evidence is required from adequately powered, long-term, double-blind, randomised clinical trials, which evaluate both clinical and haemodynamic outcomes.

Nanotechnology in neurosurgery: thinking small, dreaming big.

Nanotechnology has the power to transform neurosurgery by facilitating intervention at the cellular and subcellular level. The unique properties of nanomaterials will not only improve the management of conditions traditionally treated through neurosurgery, but also make neurosurgical intervention possible for diseases where there are currently limited treatment options. Specifically, nanotechnology appears to be a promising tool for improving molecular imaging, seamlessly integrating diagnosis and therapy in neuro-oncology, identifying targets for selective neuromodulation, as well as promoting neuroregeneration. Despite the vast potential benefits of nanotechnology in neurosurgery, problems related to neurotoxicity and the long-term medical and social consequences must be adequately addressed before nanotechnology becomes a component of surgical care.

Pharmaceuticals and Stem Cells in Autism Spectrum Disorders: Wishful Thinking?

OBJECTIVE: We provide a contemporary account of the key pathologic events pertaining to autism: the theory of oxidative stress and inflammatory causes, ideas of immune dysfunction, the probable biomarkers that can be used for diagnostics, and the use of pharmaceuticals and stem cells as possible candidates for the treatment of autism spectrum disorders (ASDs). METHODS: ASDs are a group of complex neurodevelopmental conditions characterized by abnormal patterns of attention and impaired social and communication skills. ASDs are also associated with numerous functional challenges and potentially harmful deficits, including restricted and repetitive behaviors, anxiety, irritability, seizures, and self-harm. RESULTS: Although the exact causes of ASDs are unknown, it is suggested that genetic, epigenetic, and environmental factors play critical roles. More recent findings support evidence for synaptic defects and impairments in brain information processing that are linked to social and perceptual skills. CONCLUSIONS: Owing to the clinical heterogeneity and lack of precise diagnostic tools, current therapeutic approaches aimed at managing ASD-associated conditions are not definitive.

Self-assembly and sequence length dependence on nanofibrils of polyglutamine peptides.

Huntington's disease (HD) is recognized as a currently incurable, inherited neurodegenerative disorder caused by the accumulation of misfolded polyglutamine (polyQ) peptide aggregates in neuronal cells. Yet, the mechanism by which newly formed polyQ chains interact and assemble into toxic oligomeric structures remains a critical, unresolved issue. In order to shed further light on the matter, our group elected to investigate the folding of polyQ peptides - examining glutamine repeat lengths ranging from 3 to 44 residues. To characterize these aggregates we employed a diverse array of technologies, including: nuclear magnetic resonance; circular dichroism; Fourier transform infrared spectroscopy; fluorescence resonance energy transfer (FRET), and atomic force microscopy. The data we obtained suggest that an increase in the number of glutamine repeats above 14 residues results in disordered loop structures, with different repeat lengths demonstrating unique folding characteristics. This differential folding manifests in the formation of distinct nano-sized fibrils, and on this basis, we postulate the idea of 14 polyQ repeats representing a critical loop length for neurotoxicity - a property that we hope may prove amenable to future therapeutic intervention. Furthermore, FRET measurements on aged assemblages indicate an increase in the end-to-end distance of the peptide with time, most probably due to the intermixing of individual peptide strands within the nanofibril. Further insight into this apparent time-dependent reorganization of aggregated polyQ peptides may influence future disease modeling of polyQ-related proteinopathies, in addition to directing novel clinical innovations.

Nanotechnology and regenerative therapeutics in plastic surgery: The next frontier.

The rapid ascent of nanotechnology and regenerative therapeutics as applied to medicine and surgery has seen an exponential rise in the scale of research generated in this field. This is evidenced not only by the sheer volume of papers dedicated to nanotechnology but also in a large number of new journals dedicated to nanotechnology and regenerative therapeutics specifically to medicine and surgery. Aspects of nanotechnology that have already brought benefits to these areas include advanced drug delivery platforms, molecular imaging and materials engineering for surgical implants. Particular areas of interest include nerve regeneration, burns and wound care, artificial skin with nanoelectronic sensors and head and neck surgery. This study presents a review of nanotechnology and regenerative therapeutics, with focus on its applications and implications in plastic surgery.

Vascularisation in regenerative therapeutics and surgery.

Vascularisation is often deemed the holy grail of tissue engineering because it is one of the key preconditions that determine the in vivo viability of tissue constructs. Given that a well-developed vascular network allows greater complexity in tissue design and helps regulate tissue metabolism, it appears that the overall outcome of engineered tissue implants depends on the success of microvessel formation, maturation and patterning. Current approaches to vascularising tissue include both in vivo and ex vivo techniques, where blood vessel formation is either spontaneous or guided by physical or biochemical factors. The success of these strategies can then be monitored and evaluated for clinical benefit through numerous standard and novel strategies. Despite the impressive progress in the field of tissue engineering in recent times, there are still numerous technical, immunological, surgical and ethical challenges to overcome. Future prospects in this field are likely to depend on the adoption of a wide-ranging approach incorporating a combination of salient themes such as genetic manipulation, modular assembly and bioreactor coupling. Where applicable, the potential contributions of nanobiotechnology to tissue vascularisation will be discussed as appropriate.