Roadmap to DILI research in Europe. A proposal from COST action ProEuroDILINet.

In the current article the aims for a constructive way forward in Drug-Induced Liver Injury (DILI) are to highlight the most important priorities in research and clinical science, therefore supporting a more informed, focused, and better funded future for European DILI research. This Roadmap aims to identify key challenges, define a shared vision across all stakeholders for the opportunities to overcome these challenges and propose a high-quality research program to achieve progress on the prediction, prevention, diagnosis and management of this condition and impact on healthcare practice in the field of DILI. This will involve 1. Creation of a database encompassing optimised case report form for prospectively identified DILI cases with well-characterised controls with competing diagnoses, biological samples, and imaging data; 2. Establishing of preclinical models to improve the assessment and prediction of hepatotoxicity in humans to guide future drug safety testing; 3. Emphasis on implementation science and 4. Enhanced collaboration between drug-developers, clinicians and regulatory scientists. This proposed operational framework will advance DILI research and may bring together basic, applied, translational and clinical research in DILI.

Djeho, the Egyptian God's dancer with dwarfism from the thirtieth dynasty.

This manuscript presents some artistic and medical considerations about a representation of an individual with apparent dwarfism. He was found in Saqqara by the British Egyptologist James Edward Quibell, in 1910/11. The naked figure of this individual, Djeho, is carved in profile on the lid of his sarcophagus. He has a height of 120 cm and has characteristic clinical features suggesting achondroplasia.

Lyapunov exponents of multi-state cellular automata.

In order to describe the sensitivity of a cellular automaton (CA) to a small change in its initial configuration, one can attempt to extend the notion of Lyapunov exponents as defined for continuous dynamical systems to a CA. So far, such attempts have been limited to a CA with two states. This poses a significant limitation on their applicability, as many CA-based models rely on three or more states. In this paper, we generalize the existing approach to an arbitrary N-dimensional k-state CA with either a deterministic or probabilistic update rule. Our proposed extension establishes a distinction between different kinds of defects that can propagate, as well as the direction in which they propagate. Furthermore, in order to arrive at a comprehensive insight into CA's stability, we introduce additional concepts, such as the average Lyapunov exponent and the correlation coefficient of the difference pattern growth. We illustrate our approach for some interesting three-state and four-state rules, as well as a CA-based forest-fire model. In addition to making the existing methods generally applicable, our extension makes it possible to identify some behavioral features that allow us to distinguish a Class IV CA from a Class III CA (according to Wolfram's classification), which has been proven to be difficult.

Acromegaly in the setting of Tatton-Brown-Rahman Syndrome.

PURPOSE: Tatton-Brown-Rahman syndrome (TBRS) is a newly defined genetic entity characterized by overgrowth and intellectual disability, resulting from germline mutations in the gene encoding DNA methyltransferase 3 alpha (DNMT3A). Affected individuals with benign and malignant tumors have been reported; to our knowledge pituitary adenomas (and other tumors identified in our patient) have not yet been described in this syndrome. CASE: We report the case of a 34-year-old woman with TBRS who developed a GH-secreting pituitary macroadenoma and other benign tumors and cystic lesions involving diverse organ systems. Whole-exome sequencing revealed a heterozygous, likely pathogenic variant (c.700_709 del10, p. Gly234ArgfsX79) in exon7 of DNMT3A, and a heterozygous variant of uncertain significance (c.25 C>T, p.Arg9Trp) in exon 1 of the gene encoding aryl hydrocarbon receptor-interacting protein (AIP). The patient failed somatostatin analog treatment, and underwent surgery. The tumor retained AIP expression, and analysis of tumor DNA indicated the presence of both AIP alleles, consistent with no loss of heterozygosity. These findings suggest that the AIP variant was not the primary driver of pituitary adenoma development. CONCLUSION: Our case suggests that TBRS might be associated with pituitary adenoma and a broader spectrum of tumors than previously thought, making long-term follow up of these patients crucial to identify tumors early, and to elucidate the clinical spectrum of the disorder for optimization of management.

The Impact of the New State Body for Transplantation on Lung Transplantation Waiting List Mortality.

Introduction Organ Donation Transplant Ireland (ODTI) was established in 2014 to provide leadership and governance of the transplant programme in Ireland. We aim to establish if the implementation of ODTI translates into a decrease in waiting list mortality. Methods A retrospective analysis of all patients listed for lung transplantation on the Irish Heart and Lung Transplant Programme, between January 2011 and December 2016, was performed. We compared mortality on the waiting list before and after the establishment of ODTI. Results During the study period, a total of 259 patients were on the lung transplant list. Sixty percent of patients underwent lung transplantation. Following establishment of ODTI, there was a statistically significant reduction of waiting list mortality from 46% in the era prior to ODTI to 33% after ODTI formation (p=0.02). Conclusion This study demonstrates the establishment of the governing body ODTI reduced mortality on the lung transplant waiting list.

Metastatic Solitary Fibrous Tumour of the Kidney Presenting more than a Decade Later with Pulmonary Disease

Introduction Solitary fibrous tumours are rare mesenchymal tumours that most commonly originate from the visceral pleura. Extra-thoracic primary sites including; head and neck, soft tissue, retroperitoneum and the urological tract, are associated with late recurrence. Case We present a case of metastatic pulmonary Solitary Fibrous Tumour presenting 11 years post resection of renal primary Solitary Fibrous Tumour. The patient underwent apical segmentectomy of the right lower lobe extending to wedge excision of right upper lobe due to fissure involvement with lymphadenectomy. The patient was discharged day 12 post surgery. Discussion Robust guidance regarding long-term management of solitary fibrous tumours is lacking. Salvage resection offers favourable long-term prognosis. This case demonstrates the importance of long-term surveillance.

Congenital Atrial Haemangioma

Introduction Primary cardiac tumours are rare. We report the first known case of congenital cardiac haemangioma in Ireland. Case A neonate presented with symptoms arising from a congenital atrial haemangioma on day three of life. The mass was successfully excised via median sternotomy and bicaval cannulation for cardiopulmonary bypass. The patient was discharged day ten postoperatively and remained well at one year follow-up. Discussion The degree of debulking surgery required varies depending on tumour type. This report serves to aid clinicians in accurately suspecting, investigating and diagnosing patients with cardiac tumours.

A Profile of Psychiatric In-Patient Admissions With No Fixed Abode (NFA) 2007-2016

Aims This paper examines admissions for the last ten years for those recorded as of no fixed abode (NFA) on the National Psychiatric In-Patient Reporting System (NPIRS). Methods The Health Research Board's (HRB) NPIRS data were analysed using SPSS to develop an overview of admissions with NFA recorded for the years 2007-2016 (n=2,176). Results In the period 2007-2016 there were 2,176 admissions with NFA recorded. In that 10-year period there was a 44% increase in admissions with NFA from 188 in 2007 to 271 in 2016. The analysis shows that the characteristics of this cohort have remained largely unchanged in the 10 years; almost three-quarters (1,598; 73.4%) were male, almost half (1,068; 49.1%) were less than 35 years of age and three-quarters (1,638; 75.2%) were less than 45 years. Three-quarters (1,643; 75.5%) were single and a similar proportion was unemployed (1,640; 75.4%). In addition, the highest proportion had a diagnosis of schizophrenia (621; 28.5%) followed by drugs/alcohol disorders (590; 27.1%). These characteristics are consistent with the single 'chronically homeless' people described in the literature. Discussion The paper concludes the need to use routinely collected data to help understand and address the need of specific homeless sub-groups particularly those on institutional circuits that include psychiatric in-patient facilities. To enable this it recommends the implementation of the individual health identifier as a matter of urgency.

Cannabis use and Associated Health Problems ­ What's the Harm?

Aim Cannabis is the most widely used illegal drug in Ireland. We sought to describe the changing pattern of cannabis use and cannabis related health harms. Methods Data was collated from two national population surveys and three national treatment databases, focusing on people under 34 years. Results Past month cannabis use among adolescents and young adults increased after 2011, coinciding with a decline in perceived risk of regular use. The prevalence estimate for cannabis dependence increased from 1.1% to 3.6% from 2011 to 2015. From 2008 to 2016, there were increases in the rates of cannabis related addiction treatment episodes among adolescents and among young adults of 40% and 168% respectively. Cannabis related admissions to general and psychiatric hospitals increased by 90% and 185% respectively. Conclusion A concerted public health response is required to address escalating cannabis related health harms which have coincided with the arrival of more potent cannabis.

Setting the top 10 research priorities to improve the health of people with Type 2 diabetes: a Diabetes UK-James Lind Alliance Priority Setting Partnership.

AIMS: To describe processes and outcomes of a priority setting partnership to identify the 'top 10 research priorities' in Type 2 diabetes, involving people living with the condition, their carers, and healthcare professionals. METHODS: We followed the four-step James Lind Alliance Priority Setting Partnership process which involved: gathering uncertainties using a questionnaire survey distributed to 70 000 people living with Type 2 diabetes and their carers, and healthcare professionals; organizing the uncertainties; interim priority setting by resampling of participants with a second survey; and final priority setting in an independent group of participants, using the nominal group technique. At each step the steering group closely monitored and guided the process. RESULTS: In the first survey, 8227 uncertainties were proposed by 2587 participants, of whom 18% were from black, Asian and minority ethnic groups. Uncertainties were formatted and collated into 114 indicative questions. A total of 1506 people contributed to a second survey, generating a shortlist of 24 questions equally weighted to the contributions of people living with diabetes and their carers and those of healthcare professionals. In the final step the 'top 10 research priorities' were selected, including questions on cure and reversal, risk identification and prevention, and self-management approaches in Type 2 diabetes. CONCLUSION: Systematic and transparent methodology was used to identify research priorities in a large and genuine partnership of people with lived and professional experience of Type 2 diabetes. The top 10 questions represent consensus areas of research priority to guide future research, deliver responsive and strategic allocation of research resources, and improve the future health and well-being of people living with, and at risk of, Type 2 diabetes.

Fifteen years of using a second stage protein substitute for weaning in phenylketonuria: a retrospective study.

BACKGROUND: In phenylketonuria (PKU), during weaning, it is necessary to introduce a second stage phenylalanine (Phe)-free protein substitute (PS) to help meet non-Phe protein requirements. Semi-solid weaning Phe-free PS have been available for >15 years, although no long-term studies have reported their efficacy. METHODS: Retrospective data from 31 children with PKU who commenced a weaning PS were collected from clinical records from age of weaning to 2 years, on: gender; birth order; weaning age; anthropometry; blood Phe levels; age commenced and dosage of weaning PS and Phe-free infant L-amino acid formula; natural protein intake; and issues with administration of PS or food. RESULTS: Median commencement age for weaning was 17 weeks (range 12-25 weeks) and, for weaning PS, 20 weeks (range 13-37 weeks). Median natural protein was 4 g day-1 (range 3-11 g day-1 ) and total protein intake was >2 g kg-1 day-1 from weaning to 2 years of age. Children started on 2-4 g day-1 protein equivalent (5-10 g day-1 of powder) from weaning PS, increasing by 0.2 g kg-1 day-1 (2 g day-1 ) monthly to 12 months of age. Teething and illness adversely affected the administration of weaning PS and the acceptance of solid foods. Altogether, 32% of children had delayed introduction of more textured foods, associated with birth order (firstborn 80% versus 38%; P = 0.05) and food refusal when teething (80% versus 29%; P = 0.02). CONCLUSIONS: Timing of introduction of solid foods and weaning PS, progression onto more textured foods and consistent feeding routines were important in aiding their acceptance. Any negative behaviour with weaning PS was mainly associated with food refusal, teething and illness. Parental approach influenced the acceptance of weaning PS.

Glycomacropeptide in children with phenylketonuria: does its phenylalanine content affect blood phenylalanine control?

BACKGROUND: In phenylketonuria (PKU), there are no data available for children with respect to evaluating casein glycomacropeptide (CGMP) as an alternative to phenylalanine-free protein substitutes [Phe-free L-amino acid (AA)]. CGMP contains a residual amount of phenylalanine, which may alter blood phenylalanine control. METHODS: In a prospective 6-month pilot study, we investigated the effect on blood phenylalanine control of CGMP-amino acid (CGMP-AA) protein substitute in 22 PKU subjects (13 boys, nine girls), median age (range) 11 years (6-16 years). Twelve received CGMP-AA and nine received Phe-free L-AA, (1 CGMP-AA withdrawal). Subjects partially or wholly replaced Phe-free L-AA with CGMP-AA. If blood phenylalanine exceeded the target range, the CGMP-AA dose was reduced and replaced with Phe-free L-amino acids. The control group remained on Phe-free L-AAs. Phenylalanine, tyrosine and Phe : Tyr ratio concentrations were compared with the results for the previous year. RESULTS: In the CGMP-AA group, there was a significant increase in blood phenylalanine concentrations (pre-study, 275 µmol L-1 ; CGMP-AA, 317 µmol L-1 ; P = 0.02), a decrease in tyrosine concentrations (pre-study, 50 µmol L-1 ; CGMP-AA, 40 µmol L-1 ; P = 0.03) and an increase in Phe : Tyr ratios (pre-study, Phe : Tyr 4.9:1; CGMP-AA, Phe : Tyr 8:1; P = 0.02). In the control group there was a non-significant fall in phenylalanine concentrations (pre-study 325µmol/L: study 280µmol/L [p = 0.9], and no significant changes for tyrosine or phe/tyr ratios [p = 0.9]. Children taking the CGMP-AA found it more acceptable to L-AA. CONCLUSIONS: Blood phenylalanine control declined with CGMP-AA but, by titrating the dose of CGMP-AA, blood phenylalanine control remained within target range. The additional intake of phenylalanine may have contributed to the change in blood phenylalanine concentration. CGMP-AA use requires careful monitoring in children.

What are the dietary treatment research priorities for inflammatory bowel disease? A short report based on a priority setting partnership with the James Lind Alliance.

BACKGROUND: Treatment of inflammatory bowel disease (IBD) involves a multidisciplinary approach comprising medical management and sometimes surgery. Although diet is central to IBD management, the optimal diet for patients with IBD is uncertain. A UK collaborative partnership within the James Lind Alliance was set up between patients, clinicians and other stakeholders to develop research priorities in IBD. The aim of this short report is to provide a comprehensive summary of the research priority findings relating to diet in the treatment of IBD. METHODS: The James Lind Alliance Priority Setting Partnership process was used to develop research priorities in IBD. In brief, patients, clinicians and other stakeholders were invited to provide up to five treatment uncertainties in IBD. These uncertainties were collated, revised and ranked, leading to a final top 10 research questions in IBD. RESULTS: A total of 1671 uncertainties from 531 participants were collected and refined to exclude duplicates leaving 1253 uncertainties. Of these, 348 were categorised as diet-related and grouped according to topic. There were 206 uncertainties related to how diet can be used to treat IBD or alleviate symptoms. Seventy-two percent of diet-related questions came from patients. One broadly diet-related and two diet-specific treatment uncertainties were included in the top 10 research priorities for IBD. CONCLUSIONS: Dietary treatment options in the management of IBD are important research priorities. Almost three-quarters of diet related questions came from patients, who were particularly interested in how diet can impact disease activity and symptom control.

The challenge of nutritional profiling of a protein-free feed module for children on low protein tube feeds with organic acidaemias.

BACKGROUND: Enteral tube feeding for children with organic acidaemias (OA) is recommended. Protein restriction, providing minimum safe levels of protein intake, is advocated. Standard paediatric tube feeding formulae provide more than the minimum safe protein requirements and are unsuitable in OA without modification. Modified paediatric enteral feeds consist of several modular ingredients. The aim of this prospective longitudinal interventional study was to assess the efficacy of a premeasured novel protein-free module developed for children aged over 12 months compared to conventional practice. METHODS: In total, 15 children with OA (11.6-31 kg) needing enteral feeding were recruited. The protein-free module, from either a protein-free infant feed or modular ingredients, was replaced by the study feed. To ensure metabolic stability, energy and protein intake were unchanged. Dietary intake, anthropometry and nutritional biochemistry were recorded at baseline and week 26. RESULTS: Dietary intakes of magnesium (P = 0.02), sodium (P = 0.005), vitamin D (P = 0.04), docosahexaenoic acid (P = 0.01) and arachidonic acid (P = 0.001) significantly improved; plasma selenium (P = 0.002) and whole blood glutathione peroxidase (P = 0.02) significantly increased. Feed preparation accuracy as measured by composition analysis showed consistent errors both in pre- and study feeds. CONCLUSIONS: A protein-free module improved nutritional intake and biochemistry, although feed preparation errors remained a common finding.

Isolated Unilateral Pulmonary Artery Agenesis complicated by Symptomatic Aspergilloma.

Isolated unilateral pulmonary artery agenesis is a rare diagnosis. Poor blood flow to the lung parenchyma renders the tissue susceptible to opportunistic infections. We present the unusual case of isolated unilateral pulmonary artery agenesis complicated by aspergilloma. Management options and considerations are discussed.

Acute Respiratory Failure Post Single Lung Transplantation: An Unusual Cause.

Vascular complications of pulmonary vessels post-transplant are rare but are associated with high morbidity and mortality. We describe the first published case of surgical management of pulmonary vein stenosis complicated by early thrombosis post single lung transplantation. This report describes early diagnostic techniques and subsequent management options in such patients where pulmonary vascular complications are a potential.

GPR101 Mutations are not a Frequent Cause of Congenital Isolated Growth Hormone Deficiency.

Patients with Xq26.3 microduplication present with X-linked acrogigantism (X-LAG) syndrome, an early-childhood form of gigantism due to marked growth hormone (GH) hypersecretion from mixed GH-PRL adenomas and hyperplasia. The microduplication includes GPR101, which is upregulated in patients' tumor tissue. The GPR101 gene codes for an orphan G protein coupled receptor that is normally highly expressed in the hypothalamus. Our aim was to determine whether GPR101 loss of function mutations or deletions could be involved in patients with congenital isolated GH deficiency (GHD). Taking advantage of the cohort of patients from the GENHYPOPIT network, we studied 41 patients with unexplained isolated GHD. All patients had Sanger sequencing of the GPR101 gene and array comparative genome hybridization (aCGH) to look for deletions. Functional studies (cell culture with GH secretion measurements, cAMP response) were performed. One novel GPR101 variant, c.589 G>T (p.V197L), was seen in the heterozygous state in a patient with isolated GHD. In silico analysis suggested that this variant could be deleterious. Functional studies did not show any significant difference in comparison with wild type for GH secretion and cAMP response. No truncating, frameshift, or small insertion-deletion (indel) GPR101 mutations were seen in the 41 patients. No deletion or other copy number variation at chromosome Xq26.3 was found on aCGH. We found a novel GPR101 variant of unknown significance, in a patient with isolated GH deficiency. Our study did not identify GPR101 abnormalities as a frequent cause of GH deficiency.

Feeling angry about current health status: using a population survey to determine the association with demographic, health and social factors.

BACKGROUND: Feeling angry about their health status may influence disease progression in individuals, creating a greater burden on the health care system. Identifying associations between different variables and feeling angry about health status may assist health professionals to improve health outcomes. This study used path analysis to explore findings from a population-based survey, informed by qualitative descriptions obtained from focus groups, to determine the prevalence of health-related anger within the community and variables associated with reporting health-related anger. METHODS: A population-based Computer Assisted Telephone Interview (CATI) survey of 3003 randomly selected adults Australia-wide was conducted to examine the prevalence of health-related anger. A wide range of other covariates were included in the survey. Multivariable logistic regression and path analysis were undertaken to identify the relationships between different variables associated with feeling angry about the health status of people, to explore the direction of these associations and as a consequence of the results, consider implications for health service use and delivery. RESULTS: Overall, 18.5 % of the population reported feeling angry about their health "some of the time", "most of the time" or "all of the time". People who felt angry about their health were more likely to have a severe health condition, at least one chronic condition, high psychological distress, fair to poor health status, and needed to adjust their daily lives because of a health condition. Having a tertiary level education was protective. Receiving some form of social support, usually from a support group, and not always doing as advised by a doctor, were also associated with a higher likelihood of being angry about their health. CONCLUSIONS: People living with significant health problems are more likely to feel angry about their health. The path between illness and anger is, however, complex. Further research is needed to understand the extent that feeling angry influences the progression of health problems and, if necessary, how to minimise this progression. What also needs examining is whether identifying people who feel angry in the general population could be a predictor of persons most likely to develop significant health problems.