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.

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.

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.

Designing rare disease care pathways in the Republic of Ireland: a co-operative model.

BACKGROUND: Rare diseases (RDs) are often complex, serious, chronic and multi-systemic conditions, associated with physical, sensory and intellectual disability. Patients require follow-up management from multiple medical specialists and health and social care professionals involving a high level of integrated care, service coordination and specified care pathways. METHODS AND OBJECTIVES: This pilot study aimed to explore the best approach for developing national RD care pathways in the Irish healthcare system in the context of a lack of agreed methodology. Irish clinical specialists and patient/lived experience experts were asked to map existing practice against evidence-based clinical practice guidelines (CPGs) and best practice recommendations from the European Reference Networks (ERNs) to develop optimal care pathways. The study focused on the more prevalent, multisystemic rare conditions that require multidisciplinary care, services, supports and therapeutic interventions. RESULTS: 29 rare conditions were selected across 18 ERNs, for care pathway development. Multidisciplinary input from multiple specialisms was relevant for all pathways. A high level of engagement was experienced from clinical leads and patient organisations. CPGs were identified for 26 of the conditions. Nurse specialist, Psychology, Medical Social Work and Database Manager roles were deemed essential for all care pathways. Access to the therapeutic Health Service Professionals: Physiotherapy, Occupational Therapy, and Speech and Language Therapy were seen as key requirements for holistic care. Genetic counselling was highlighted as a core discipline in 27 pathways demonstrating the importance of access to Clinical Genetics services for many people with RDs. CONCLUSIONS: This study proposes a methodology for Irish RD care pathway development, in collaboration with patient/service user advocates. Common RD patient needs and health care professional interventions across all pathways were identified. Key RD stakeholders have endorsed this national care pathway initiative. Future research focused on the implementation of such care pathways is a priority.

Pulmonary alveolar capillary dysplasia in infants: A rare and deadly missed diagnosis.

The pulmonary alveolocapillary dysplasia (ACD) with pulmonary vein misalignment (PVM) is a rare condition characterized by a congenital anomaly of the development of the pulmonary parenchyma. We present a case of an 8-month-old infant who died quickly from acute respiratory failure complicating an unknown ACD. We also describe its epidemiological characteristics in infants and we discuss the diagnosis's difficulties. In this case, a pulmonary arterial hypertension was decompensated by an infection. A medico-legal autopsy was performed. As for the Histological examination, it showed the features of ACD/PVM.

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.

The role of AIP variants in pituitary adenomas and concomitant thyroid carcinomas in the Netherlands: a nationwide pathology registry (PALGA) study.

PURPOSE: Germline mutations in the aryl-hydrocarbon receptor interacting protein (AIP) have been identified often in the setting of familial isolated pituitary adenoma (FIPA). To date there is no strong evidence linking germline AIP mutations to other neoplasms apart from the pituitary. Our primary objective was to investigate the prevalence of AIP gene mutations and mutations in genes that have been associated with neuroendocrine tumors in series of tumors from patients presenting with both pituitary adenomas and differentiated thyroid carcinomas (DTCs). METHODS: Pathology samples were retrieved from all pituitary adenomas in patients with concomitant DTCs, including one with a known germline AIP variant. Subsequently, two additional patients with known germline AIP variants were included, of which one presented only with a follicular thyroid carcinoma (FTC). RESULTS: In total, 17 patients (14 DTCs and 15 pituitary adenomas) were investigated by targeted next generation sequencing (NGS). The pituitary tumor samples revealed no mutations, while among the thyroid tumor samples BRAF (6/14, 42.9%) was the most frequently mutated gene, followed by NRAS (3/11, 27.3%). In one AIP-mutated FIPA kindred, the AIP-variant c.853C>T; p.Q285* was confirmed in the FTC specimen, including evidence of loss of heterozygosity (LOH) at the AIP locus in the tumor DNA. CONCLUSION: Although most observed variants in pituitary adenomas and DTCs were similar to those of sporadic DTCs, we confirmed in one AIP mutation-positive case the AIP-variant and LOH at this locus in an FTC specimen, which raises the potential role of the AIP mutation as a rare initiating event.

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.

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.

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.

Home delivery service of low protein foods in inherited metabolic disorders: Does it help?

BACKGROUND: In the UK, the customary method of obtaining special low protein (LP) foods was by dispensing through a pharmacist (until 2010) for patients with inherited metabolic disorders (IMD) requiring LP diets. Recently, different home delivery services have been introduced to support patient access of low protein foods, but the effectiveness of these services is unclear. AIM: A prospective, longitudinal, observational study to examine the effectiveness and safety of patient home delivery services for LP foods over 12 months in IMD patients requiring a LP diet. METHODS: IMD patients/caregivers had the choice of 2 home delivery services (Homeward® and Vitaflo at Home®) as well as access to primary care pharmacy services. Both home delivery services provided a limited range of LP foods. Over a 12-month period, a member of the IMD dietetic team conducted 4 home visits to IMD patients on LP diets using home delivery services for low protein foods. At each visit, caregivers completed a questionnaire consisting of 20 multiple choice and open questions about their prescription experience with special LP foods. The researchers also completed stock checks, assessed 'use by dates' and adequacy of home storage for LP foods. RESULTS: In total, 58 patients participated in this study. Over 12 months, 95% (n = 55/58) of caregivers used their local pharmacy, 93% (n = 54/58) Homeward® and 78% (n = 45/58) Vitaflo at Home® to access LP foods. Two home delivery services were used by 41 (71%) caregivers and the remaining 17 (29%) only used one of the home delivery service companies. Each patient only stored a median of 6 (range 0-22) different LP foods at home. Overall, 45% (n = 26/58) of caregivers reported problems with their GP prescriptions. 30% (n = 16/53) of caregivers received at least one incorrect prescription when using their pharmacy (e.g. gluten-free foods instead of LP, incorrect product or incorrect product amount), 6% errors (n = 3/53) with Homeward® and 2% (n = 1/48) with Vitaflo at Home®. 49% (n = 26/53) of caregivers said they experienced delayed receipt of LP foods from their pharmacy, compared with 11% (n = 6/55) from Homeward® and 8% (n = 4/48) Vitaflo at Home®. CONCLUSIONS: Although home delivery services for special LP foods are associated with less errors and delay compared with pharmacies, inaccuracies and inefficiencies still occur and the overall system is complex. We suggest a new, simpler, less fragmented system whereby metabolic dietitians prescribe LP foods. This is likely to result in less burden on NHS resources and ensure a better treatment delivered to IMD patients.

Glycomacropeptide: long-term use and impact on blood phenylalanine, growth and nutritional status in children with PKU.

In phenylketonuria, casein glycomacropeptide (CGMP) requires modification with the addition of some essential and semi essential amino acids to ensure suitability as a protein substitute. The optimal amount and ratio of additional amino acids is undefined. AIM: A longitudinal, parallel, controlled study over 12 months evaluating a CGMP (CGMP-AA2) formulation compared with phenylalanine-free L-amino acid supplements (L-AA) on blood Phe, Tyr, Phe:Tyr ratio, biochemical nutritional status and growth in children with PKU. The CGMP-AA2 contained 36 mg Phe per 20 g protein equivalent. METHODS: Children with PKU, with a median age of 9.2 y (5-16y) were divided into 2 groups: 29 were given CGMP-AA2, 19 remained on Phe-free L-AA. The CGMP-AA2 formula gradually replaced L-AA, providing blood Phe concentrations were maintained within target range. Median blood Phe, Tyr, Phe:Tyr ratio and anthropometry, were compared within and between the two groups at baseline, 26 and 52 weeks. Nutritional biochemistry was studied at baseline and 26 weeks only. RESULTS: At the end of 52 weeks only 48% of subjects were able to completely use CGMP-AA2 as their single source of protein substitute. At 52 weeks CGMP-AA2 provided a median of 75% (30-100) of the total protein substitute with the remainder being given as L-AA. Within the CGMP-AA2 group, blood Phe increased significantly between baseline and 52 weeks: [baseline to 26 weeks; baseline Phe 270 µmol/L (170-430); 26 weeks, Phe 300 µmol/L (125-485) p = 0.06; baseline to 52 weeks: baseline, Phe 270 µmol/L (170-430), 52 weeks Phe 300 µmol/L (200-490), p < 0.001)]. However, there were no differences between the CGMP-AA2 and L-AA group for Phe, Tyr, Phe:Tyr ratio or anthropometry at any of the three measured time points. Within the CGMP-AA2 group only weight (p = 0.0001) and BMI z scores (p = 0.0001) increased significantly between baseline to 52 weeks. Whole blood and plasma selenium were significantly higher (whole blood selenium [p = 0.0002]; plasma selenium [p = 0.0007]) at 26 weeks in the CGMP-AA2 group compared L-AA. No differences were observed within the L-AA group for any of the nutritional markers. CONCLUSIONS: CGMP-AA increases blood Phe concentrations and so it can only be used partly to contribute to protein substitute in some children with PKU. CGMP-AA should be carefully introduced in children with PKU and close monitoring of blood Phe control is essential.

Weaning practices in phenylketonuria vary between health professionals in Europe.

BACKGROUND: In phenylketonuria (PKU), weaning is considered more challenging when compared to feeding healthy infants. The primary aim of weaning is to gradually replace natural protein from breast milk or standard infant formula with solids containing equivalent phenylalanine (Phe). In addition, a Phe-free second stage L-amino acid supplement is usually recommended from around 6 months to replace Phe-free infant formula. Our aim was to assess different weaning approaches used by health professionals across Europe. METHODS: A cross sectional questionnaire (survey monkey®) composed of 31 multiple and single choice questions was sent to European colleagues caring for inherited metabolic disorders (IMD). Centres were grouped into geographical regions for analysis. RESULTS: Weaning started at 17-26 weeks in 85% (n = 81/95) of centres, >26 weeks in 12% (n = 11/95) and < 17 weeks in 3% (n = 3/95). Infant's showing an interest in solid foods, and their age, were important determinant factors influencing weaning commencement. 51% (n = 48/95) of centres introduced Phe containing foods at 17-26 weeks and 48% (n = 46/95) at >26 weeks. First solids were mainly low Phe vegetables (59%, n = 56/95) and fruit (34%, n = 32/95).A Phe exchange system to allocate dietary Phe was used by 52% (n = 49/95) of centres predominantly from Northern and Southern Europe and 48% (n = 46/95) calculated most Phe containing food sources (all centres in Eastern Europe and the majority from Germany and Austria). Some centres used a combination of both methods.A second stage Phe-free L-amino acid supplement containing a higher protein equivalent was introduced by 41% (n = 39/95) of centres at infant age 26-36 weeks (mainly from Germany, Austria, Northern and Eastern Europe) and 37% (n = 35/95) at infant age > 1y mainly from Southern Europe. 53% (n = 50/95) of centres recommended a second stage Phe-free L-amino acid supplement in a spoonable or semi-solid form. CONCLUSIONS: Weaning strategies vary throughout European PKU centres. There is evidence to suggest that different infant weaning strategies may influence longer term adherence to the PKU diet or acceptance of Phe-free L-amino acid supplements; rendering prospective long-term studies important. It is essential to identify an effective weaning strategy that reduces caregiver burden but is associated with acceptable dietary adherence and optimal infant feeding development.

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.

A Comparison of Inpatient and Outpatient-Based Chemotherapy Regimens for the Treatment of Acute Myeloid Leukaemia In The Elderly.

INTRODUCTION: Acute myeloid leukaemia (AML) is an aggressive haematological malignancy which is more common in the elderly and has a poor 5-year survival. There are no established beneficial interventions to treat AML in elderly patients. It is unclear whether outpatient delivery of palliative chemotherapies could reduce the burden of disease and hospitalisation for this group. AIMS: To compare overall survival, response to treatment and supportive care needs between inpatient and outpatient-based treatments for AML in elderly patients. MATERIALS & METHODS: We undertook a retrospective cohort study in the Haematology Department at Belfast City Hospital comparing overall survival (OS), treatment responses and supportive care needs between inpatient and outpatient treatments for AML in elderly patients. Consecutive entrants to outpatient and inpatient based clinical trials between February 2013 and January 2017 were included. Case notes, chemotherapy charts, clinic letters, blood bank and electronic care records were analysed. RESULTS: OS and rates of CR (complete remission), CRi (CR with incomplete count recovery) and PR (partial response) was not significantly different between inpatient and outpatient regimens with a median OS of 201 vs. 124 days, respectively. No response was observed in 35% of patients in the inpatient group compared with 65% of the outpatient group, however this did not reach significance. Of patients who achieved CR/CRi in the outpatient group, 75% relapsed at a median of 271 days, compared with 60% of the inpatient group at a median of 209 days. At least one grade 3-4 toxicity was experienced by 90% and 83.3% of inpatient and outpatient groups, respectively. There was no difference in six common grade 3-4 toxicities. Patients on the outpatient regimen spent fewer days in hospital but had a median packed red cell use of more than twice that of the inpatient group. No difference was noted in infections, days on antibiotics or platelet use. DISCUSSION: Our data suggests that outpatient chemotherapy is safe and can reduce hospitalisation for elderly patients with AML, without a decline in OS or response rates. These results provide an important rationale to test the comparative efficacy of outpatient chemotherapy. Chemotherapy related toxicities remain a significant source of morbidity in this population and highlight the need to develop novel, targeted therapies for this age group.

Patient eligibility for hematopoietic stem cell transplantation: a review of patient-associated variables.

Assessing patient eligibility for hematopoietic stem cell transplantation (HSCT) remains a complex, multifaceted challenge. Among these challenges, the paucity of comprehensive clinical data to guide decision making remains problematic coupled with unclear trade-offs between patient, disease and local HSCT center factors. Moreover, it is unclear that the modification of poor patient characteristics will improve post-HSCT outcomes. However, the use of Comorbidity Indices and Comprehensive Geriatric Assessments helps meet this challenge, but may be limited by overlapping patient characteristics. The increasing consideration for pre-HSCT psychosocial assessments and interventions remains to be studied. Ultimately, the decision to proceed with a HSCT remains interdisciplinary while considering the available evidence discussed in this review.

Early feeding practices in infants with phenylketonuria across Europe.

BACKGROUND: In infants with phenylketonuria (PKU), dietary management is based on lowering and titrating phenylalanine (Phe) intake from breast milk or standard infant formula in combination with a Phe-free infant formula in order to maintain blood Phe levels within target range. Professionals use different methods to feed infants with PKU and our survey aimed to document practices across Europe. METHODS: We sent a cross sectional, survey monkey® questionnaire to European health professionals working in IMD. It contained 31 open and multiple-choice questions. The results were analysed according to different geographical regions. RESULTS: Ninety-five centres from 21 countries responded. Over 60% of centres commenced diet in infants by age 10 days, with 58% of centres implementing newborn screening by day 3 post birth. At diagnosis, infant hospital admission occurred in 61% of metabolic centres, mainly in Eastern, Western and Southern Europe. Breastfeeding fell sharply following diagnosis with only 30% of women still breast feeding at 6 months.53% of centres gave pre-measured Phe-free infant formula before each breast feed and 23% alternated breast feeds with Phe-free infant formula. With standard infant formula feeds, measured amounts were followed by Phe-free infant formula to satiety in 37% of centres (n = 35/95), whereas 44% (n = 42/95) advised mixing both formulas together. Weaning commenced between 17 and 26 weeks in 85% centres, ≥26 weeks in 12% and < 17 weeks in 3%. DISCUSSION: This is the largest European survey completed on PKU infant feeding practices. It is evident that practices varied widely across Europe, and the practicalities of infant feeding in PKU received little focus in the PKU European Guidelines (2017). There are few reports comparing different feeding techniques with blood Phe control, Phe fluctuations and growth. Controlled prospective studies are necessary to assess how different infant feeding practices may influence longer term feeding development.