Niemann-Pick type C disease as proof-of-concept for intelligent biomarker panel selection in neurometabolic disorders.

AIM: Using Niemann-Pick type C disease (NPC) as a paradigm, we aimed to improve biomarker discovery in patients with neurometabolic disorders. METHOD: Using a multiplexed liquid chromatography tandem mass spectrometry dried bloodspot assay, we developed a selective intelligent biomarker panel to monitor known biomarkers N-palmitoyl-O-phosphocholineserine and 3ß,5α,6ß-trihydroxy-cholanoyl-glycine as well as compounds predicted to be affected in NPC pathology. We applied this panel to a clinically relevant paediatric patient cohort (n = 75; 35 males, 40 females; mean age 7 years 6 months, range 4 days-19 years 8 months) presenting with neurodevelopmental and/or neurodegenerative pathology, similar to that observed in NPC. RESULTS: The panel had a far superior performance compared with individual biomarkers. Namely, NPC-related established biomarkers used individually had 91% to 97% specificity but the combined panel had 100% specificity. Moreover, multivariate analysis revealed long-chain isoforms of glucosylceramide were elevated and very specific for patients with NPC. INTERPRETATION: Despite advancements in next-generation sequencing and precision medicine, neurological non-enzymatic disorders remain difficult to diagnose and lack robust biomarkers or routine functional testing for genetic variants of unknown significance. Biomarker panels may have better diagnostic accuracy than individual biomarkers in neurometabolic disorders, hence they can facilitate more prompt disease identification and implementation of emerging targeted, disease-specific therapies. WHAT THIS PAPER ADDS: Intelligent biomarker panel design can help expedite diagnosis in neurometabolic disorders. In Niemann-Pick type C disease, such a panel performed better than individual biomarkers. Biomarker panels are easy to implement and widely applicable to neurometabolic conditions.

A persistent craniopharyngeal canal with recurrent bacterial meningitis: case report and literature review.

BACKGROUND: A persistent craniopharyngeal canal (PCC) is a rare but treatable anatomical abnormality that causes recurrent meningitis and should be considered as a differential diagnosis. CASE REPORT: We report a case of an 8-year-old boy who presented with recurrent meningitis associated to his PCC. Surgical repair was performed, and no further episodes occurred.

Predictors of entering 24-h care for people with Alzheimer's disease: results from the LASER-AD study.

OBJECTIVES: Many studies have investigated predictors of people with dementia entering 24-h care but this is the first to consider a comprehensive range of carer and care recipient (CR) characteristics derived from a systematic review, in a longitudinal cohort study followed up for several years. METHODS: We interviewed 224 people with Alzheimer's disease (AD) and their carers, recruited to be representative in terms of their severity, sex and living situation as part of the LASER-AD study; and determined whether they entered 24-h care in the subsequent 4.5 years. We tested a comprehensive range of characteristics derived from a systematic review, and used Cox proportional hazard regression to determine whether they independently predicted entering 24-h care. RESULTS: The main independent predictors of shorter time to enter 24-h care were the patient being: more cognitively or functionally impaired (hazard ratio (HR) = 1.09; 95% CI = 1.06-1.12) and (HR = 1.04 95% CI = 1.03-1.05), having a paid versus a family carer (HR = 2.22; 95% CI = 1.39-3.57), the carer being less educated (HR = 1.43; 95% CI = 1.12-1.83) and spending less hours caring (HR = 1.01; 95% CI = 1.00-1.01). CONCLUSION: As having a family carer who spent more time caring (taking into account illness severity) delayed entry to 24-h care, future research should investigate how to enable carers to provide this. Other interventions to improve patients' impairment may not only have benefits for patients' health but also allow them to remain longer at home. This financial benefit could more than offset the treatment cost.

Improving teaching about medically unexplained symptoms for newly qualified doctors in the UK: findings from a questionnaire survey and expert workshop.

OBJECTIVES: Medically unexplained symptoms (MUS) present frequently in healthcare, can be complex and frustrating for clinicians and patients and are often associated with overinvestigation and significant costs. Doctors need to be aware of appropriate management strategies for such patients early in their training. A previous qualitative study with foundation year doctors (junior doctors in their first 2 years postqualification) indicated significant lack of knowledge about this topic and appropriate management strategies. This study reviewed whether, and in what format, UK foundation training programmes for newly qualified doctors include any teaching about MUS and sought recommendations for further development of such training. DESIGN: Mixed-methods design comprising a web-based questionnaire survey and an expert consultation workshop. SETTING: Nineteen foundation schools in England, Wales and Northern Ireland PARTICIPANTS: Questionnaire administered via email to 155 foundation training programme directors (FTPDs) attached to the 19 foundation schools, followed by an expert consultation workshop attended by 13 medical educationalists, FTPDs and junior doctors. RESULTS: The 53/155 (34.2%) FTPDs responding to the questionnaire represented 15 of the 19 foundation schools, but only 6/53 (11%) reported any current formal teaching about MUS within their programmes. However, most recognised the importance of providing such teaching, suggesting 2-3 hours per year. All those attending the expert consultation workshop recommended case-based discussions, role-play and the use of videos to illustrate positive and negative examples of doctor-patient interactions as educational methods of choice. Educational sessions should cover the skills needed to provide appropriate explanations for patients' symptoms as well as avoid unnecessary investigations, and providing information about suitable treatment options. CONCLUSIONS: There is an urgent need to improve foundation level training about MUS, as current provision is very limited. An interactive approach covering a range of topics is recommended, but must be delivered within a realistic time frame for the curriculum.