The presenilin 1 mutation P436S causes familial Alzheimer's disease with elevated Aß43 and atypical clinical manifestations.

INTRODUCTION: Familial Alzheimer's disease (fAD) is heterogeneous in terms of age at onset and clinical presentation. A greater understanding of the pathogenicity of fAD variants and how these contribute to heterogeneity will enhance our understanding of the mechanisms of AD more widely. METHODS: To determine the pathogenicity of the unclassified PSEN1 P436S mutation, we studied an expanded kindred of eight affected individuals, with magnetic resonance imaging (MRI) (two individuals), patient-derived induced pluripotent stem cell (iPSC) models (two donors), and post-mortem histology (one donor). RESULTS: An autosomal dominant pattern of inheritance of fAD was seen, with an average age at symptom onset of 46 years and atypical features. iPSC models and post-mortem tissue supported high production of amyloid beta 43 (Aß43). PSEN1 peptide maturation was unimpaired. DISCUSSION: We confirm that the P436S mutation in PSEN1 causes atypical fAD. The location of the mutation in the critical PSEN1 proline-alanine-leucine-proline (PALP) motif may explain the early age at onset despite appropriate protein maturation. HIGHLIGHTS: PSEN1 P436S mutations cause familial Alzheimer's disease. This mutation is associated with atypical clinical presentation. Induced pluripotent stem cells (iPSCs) and post-mortem studies support increased amyloid beta (Aß43) production. Early age at onset highlights the importance of the PALP motif in PSEN1 function.

Plasma amyloid-ß ratios in autosomal dominant Alzheimer's disease: the influence of genotype.

In vitro studies of autosomal dominant Alzheimer's disease implicate longer amyloid-ß peptides in disease pathogenesis; however, less is known about the behaviour of these mutations in vivo. In this cross-sectional cohort study, we used liquid chromatography-tandem mass spectrometry to analyse 66 plasma samples from individuals who were at risk of inheriting a mutation or were symptomatic. We tested for differences in amyloid-ß (Aß)42:38, Aß42:40 and Aß38:40 ratios between presenilin 1 (PSEN1) and amyloid precursor protein (APP) carriers. We examined the relationship between plasma and in vitro models of amyloid-ß processing and tested for associations with parental age at onset. Thirty-nine participants were mutation carriers (28 PSEN1 and 11 APP). Age- and sex-adjusted models showed marked differences in plasma amyloid-ß between genotypes: higher Aß42:38 in PSEN1 versus APP (P < 0.001) and non-carriers (P < 0.001); higher Aß38:40 in APP versus PSEN1 (P < 0.001) and non-carriers (P < 0.001); while Aß42:40 was higher in both mutation groups compared to non-carriers (both P < 0.001). Amyloid-ß profiles were reasonably consistent in plasma and cell lines. Within the PSEN1 group, models demonstrated associations between Aß42:38, Aß42:40 and Aß38:40 ratios and parental age at onset. In vivo differences in amyloid-ß processing between PSEN1 and APP carriers provide insights into disease pathophysiology, which can inform therapy development.

Efficacy of the oxime HI-6 dimethanesulphonate in the treatment of guinea-pigs exposed to the nerve agents GB and GD.

The bispyridinium oxime HI-6 DMS is in development as an improved therapy for the treatment of patients exposed to organophosphorus nerve agents. The aim of the work described in this paper was to provide non-clinical data to support regulatory approval of HI-6 DMS, by demonstrating efficacy against an oxime-sensitive agent, GB and an oxime-resistant agent, GD. We investigated the dose-dependent protection afforded by therapy including atropine, avizafone and HI-6 DMS in guinea-pigs challenged with GB or GD. We also compared the efficacy of 30 mg.kg-1 of HI-6 DMS to an equimolar dose of the current in-service oxime P2S and the dichloride salt of HI-6 (HI-6 Cl2). In the treatment of GB or GD poisoning there was no significant difference between the salt forms. The most effective dose of HI-6 DMS in preventing lethality following challenge with GB was 100 mg.kg-1; though protection ratios of at least 25 were obtained at 10 mg.kg-1. Protection against GD was lower, and there was no significant increase in effectiveness of HI-6 DMS doses of 30 or 100 mg.kg-1. For GD, the outcome was improved by the addition of pyridostigmine pre-treatment. These data demonstrate the benefits of HI-6 DMS as a component of nerve agent therapy. © Crown copyright (2023), Dstl.

Design and Selection of Heterodimerizing Helical Hairpins for Synthetic Biology.

Synthetic biology applications would benefit from protein modules of reduced complexity that function orthogonally to cellular components. As many subcellular processes depend on peptide-protein or protein-protein interactions, de novo designed polypeptides that can bring together other proteins controllably are particularly useful. Thanks to established sequence-to-structure relationships, helical bundles provide good starting points for such designs. Typically, however, such designs are tested in vitro and function in cells is not guaranteed. Here, we describe the design, characterization, and application of de novo helical hairpins that heterodimerize to form 4-helix bundles in cells. Starting from a rationally designed homodimer, we construct a library of helical hairpins and identify complementary pairs using bimolecular fluorescence complementation in E. coli. We characterize some of the pairs using biophysics and X-ray crystallography to confirm heterodimeric 4-helix bundles. Finally, we demonstrate the function of an exemplar pair in regulating transcription in both E. coli and mammalian cells.

CE: Original Research: Cognitive Behavioral Therapy for Symptom Management in Treatment-Resistant Schizophrenia.

BACKGROUND: Treatment-resistant schizophrenia (TRS) comes with significant medical comorbidities, including heart disease, liver disease, and diabetes-all of which contribute to higher mortality rates and shortened life expectancy. Second-generation antipsychotic medications do not consistently alleviate psychotic symptoms, especially among patients with TRS. Clozapine, the gold standard of pharmacological treatment for TRS, offers only partial relief for many patients. Additional treatment approaches, which include cognitive behavioral therapy (CBT), are often necessary. PURPOSE: The aim of this integrative review was to assess the efficacy of CBT as an adjunctive treatment for TRS in various study populations. METHODS: The Johns Hopkins Nursing Evidence-Based Practice Model and Guidelines were used to guide the review. A literature search of PubMed, CINAHL, Scopus, and PsycInfo was conducted, and a total of 66 articles were identified. Strong inclusion and exclusion criteria were applied to ensure that only high-quality studies were included for analysis. RESULTS: Of the eight studies that met the eligibility criteria, five indicated that CBT has statistically significant efficacy in reducing positive psychotic symptoms of TRS. There was also evidence that in implementing CBT, a follow-up period of at least six months helps to sustain improvements. CONCLUSIONS: CBT can be a safe and effective adjunctive treatment for patients with this illness. We recommend that nurses who work in psychiatric settings, EDs, and home health or community care settings obtain training in CBT.

Nanoparticle-induced enhancement of cholinesterase activity in the presence of malathion: A potential nerve agent therapeutic.

Organophosphate nerve agents are associated with assassination, terrorism and chemical warfare, but there has been slow progress in developing a broad-spectrum response to poisoning. For some nerve agents the oxime component of the therapy may not be effective, limiting the effectiveness of emergency treatment that is desperately needed. An alternative therapy may be possible based on accelerating enzyme (acetylcholinesterase) catalysis in unaffected adjacent enzymes. Herein we demonstrate a restoration of acetylcholinesterase activity in malathion-inhibited cell membrane preparations by the administration of functional nanoparticles. The molecularly imprinted polymer nanoparticles were designed to bind selectively to designated enzyme epitopes. Enzyme activity of membrane-bound acetylcholinesterase was measured in the presence of the organophosphate malathion and the selected nanoparticles. Enzymatic acceleration of the cholinesterase was observed at 162 ± 17 % the rate of erythrocyte ghosts without bound nanoparticles. This may restore sufficient acetylcholine hydrolysis to mitigate the effects of poisoning, offsetting the acetylcholine accumulation resulting from enzyme inhibition.

Working correlates of protection predict SchuS4-derived-vaccine candidates with improved efficacy against an intracellular bacterium, Francisella tularensis.

Francisella tularensis, the causative agent of tularemia, is classified as Tier 1 Select Agent with bioterrorism potential. The efficacy of the only available vaccine, LVS, is uncertain and it is not licensed in the U.S. Previously, by using an approach generally applicable to intracellular pathogens, we identified working correlates that predict successful vaccination in rodents. Here, we applied these correlates to evaluate a panel of SchuS4-derived live attenuated vaccines, namely SchuS4-ΔclpB, ΔclpB-ΔfupA, ΔclpB-ΔcapB, and ΔclpB-ΔwbtC. We combined in vitro co-cultures to quantify rodent T-cell functions and multivariate regression analyses to predict relative vaccine strength. The predictions were tested by rat vaccination and challenge studies, which demonstrated a clear relationship between the hierarchy of in vitro measurements and in vivo vaccine protection. Thus, these studies demonstrated the potential power a panel of correlates to screen and predict the efficacy of Francisella vaccine candidates, and in vivo studies in Fischer 344 rats confirmed that SchuS4-ΔclpB and ΔclpB-ΔcapB may be better vaccine candidates than LVS.

Incorporating children's and their parents' perspectives into condition-specific quality-of-life instruments for children with cerebral palsy: a qualitative study.

OBJECTIVES: This study investigated the extent of agreement between children with cerebral palsy (CP) and their parents concerning their views on what contributed to the children's quality of life. It also investigated how well an Australian condition-specific health-related quality of life self-report measure for children with CP, the Cerebral Palsy Quality of Life Questionnaire for Children (CP QOL-Child), mapped to the views of UK children and parents. METHODS: UK children with CP aged 8 to 13 years and their parents participated in qualitative interviews about their perspectives on the child's quality of life. RESULTS: The interviews with 28 children and 35 parents showed considerable overlap but also some divergence. For example, both parties considered social relationships to be important, but children described how they enjoyed being on their own at times whereas parents tended not to value time spent alone for children. The CP QOL-Child covered most themes considered to be important to the children's quality of life. Omissions included relationships with extended family members, restful recreational activities and associated possessions, relaxing, tiredness, negative emotions, and safety. CONCLUSIONS: Both children's and parents' views are required for the development of child health-related quality of life instruments. The CP QOL-Child has good coverage of many aspects discussed in the interviews. Cultural differences may account for its omission of some topics considered important by UK children and parents. Rewording of many of the CP QOL-Child's items and further work on item content would optimize its suitability for UK children and possibly for children elsewhere.

Disease duration in autosomal dominant familial Alzheimer disease: A survival analysis.

OBJECTIVE: To use survival modeling to estimate disease duration in autosomal dominant familial Alzheimer disease (ADAD) and ascertain whether factors influencing age at onset also affect survival. METHODS: Symptomatic mutation carriers (201 presenilin 1 [PSEN1] and 55 amyloid precursor protein [APP]) from ADAD families referred to the Dementia Research Centre, between 1987 and 2019, were included. Survival was assessed with respect to age at onset, year of birth, APOE ε4 status, cognitive presentation, and sex using multilevel mixed-effects Weibull survival models. The contribution of mutation and family to variance in age at onset and duration was also assessed. RESULTS: Estimated mean survival was 11.6 (10.4-12.9) years and was similar for APP and PSEN1 mutations. Sixty-seven percent of the variance in age at onset was explained by mutation and 72% by mutation and family together. In contrast, only 6% of the variance in disease duration was explained by mutation specificity and 18% by family membership. Irrespective of gene, survival appeared longer for successive generations and in individuals with atypical presentations. Older age at onset was associated with longer duration within PSEN1 and shorter duration within APP mutation carriers. No differences in survival time were found between sexes or between mutations located before or beyond codon 200 within PSEN1. CONCLUSIONS: Survival is influenced by mutation to a much lesser extent than age at onset. Survival time has increased over time and is longer in atypical presentations. These insights may inform the interpretation of disease-modifying therapy trials in ADAD.

rM-CSF efficiently replaces L929 in generating mouse and rat bone marrow-derived macrophages for in vitro functional studies of immunity to intracellular bacteria.

Methods used to prepare bone marrow-derived macrophages (BMDMs) may influence the outcomes of immunological assays in which they are used. Supernatant conditioned by growth of L929 cells has often been used to generate mouse macrophages from bone marrow in vitro but is subject to lot-to-lot variability. To reduce experimental variability and to standardize techniques across laboratories, we investigated recombinant M-CSF (rM-CSF) as an alternative supplement for BMDM maturation in the context of macrophage infection, using the intracellular bacterium Live Vaccine Strain (LVS) of Francisella tularensis as a prototype. We compared rM-CSF with L929 supernatant in terms of their effects on mouse and rat macrophage growth, maturation patterns, surface marker expression, and the expression of selected genes. Further, we compared macrophage infectivity and bacterial replication using LVS. Finally, we compared the in vitro function of BMDMs co-cultured with splenocytes from vaccinated animals in terms of their control of intramacrophage bacterial replication, as well as production of cytokines and nitric oxide. We demonstrated that rM-CSF produced BMDMs with similar, or minimal, phenotypic and gene expression outcomes compared to those generated with media containing L929 supernatant. Most importantly, functional outcomes were similar. Taken together, our data support the use of the rM-CSF in cell culture media as an alternative to L929-supplemented media for functional bioassays that use C57BL/6J mouse or Fischer 344 rat BMDMs to study intracellular infections. This comparison therefore facilitates future protocol standardization.

Assessment of false transmitters as treatments for nerve agent poisoning.

Nerve agents inhibit acetylcholinesterase (AChE), leading to a build-up of acetylcholine (ACh) and overstimulation at cholinergic synapses. Current post-exposure nerve agent treatment includes atropine to treat overstimulation at muscarinic synapses, a benzodiazepine anti-convulsant, and an oxime to restore the function of AChE. Aside from the oxime, the components do not act directly to reduce the overstimulation at nicotinic synapses. The false transmitters acetylmonoethylcholine (AMECh) and acetyldiethylcholine (ADECh) are analogs of ACh, synthesised similarly at synapses. AMECh and ADECh are partial agonists, with reduced activity compared to ACh, so it was hypothesised the false transmitters could reduce overstimulation. Synthetic routes to AMECh and ADECh, and their precursors, monoethylcholine (MECh) and diethylcholine (DECh), were devised, allowing them to be produced easily on a laboratory-scale. The mechanism of action of the false transmitters was investigated in vitro. AMECh acted as a partial agonist at human muscarinic (M1 and M3) and muscle-type nicotinic receptors, and ADECh was a partial agonist only at certain muscarinic subtypes. Their precursors acted as antagonists at muscle-type nicotinic, but not muscarinic receptors. Administration of MECh and DECh improved neuromuscular function in the soman-exposed guinea-pig hemi-diaphragm preparation. False transmitters may therefore help reduce nerve agent induced overstimulation at cholinergic synapses.

3-Quinuclidinyl-α-methoxydiphenylacetate: A multi-targeted ligand with antimuscarinic and antinicotinic effects designed for the treatment of anticholinesterase poisoning.

Racemic 3-quinuclidinyl-α-methoxydiphenylacetate (MB266) was synthesised. Its activity at muscarinic acetylcholine receptors (mAChRs), and muscle and neuronal nicotinic acetylcholine receptors (nAChRs), was compared to that of atropine and racemic 3-quinucidinyl benzilate (QNB) using a functional assay based on agonist-induced elevation of intracellular calcium ion concentration in CN21, Chinese Hamster Ovary (CHO) and SHSY5Y human cell lines. MB266 acted as an antagonist at acetylcholine receptors, displaying 18-fold selectivity for mAChR versus nAChR (compared to the 15,200-fold selectivity observed for QNB). Thus O-methylation of QNB reduced the affinity for mAChR antagonism and increased the relative potency at both muscle and neuronal nAChRs. Despite MB266 having a pharmacological profile potentially useful for the treatment of anticholinesterase poisoning, its administration did not improve the neuromuscular function in a soman-poisoned guinea-pig diaphragm preparation pretreated with the organophosphorus nerve agent soman. Consideration should be given to exploring the potential of MB266 for possible anticonvulsant action in vitro as part of a multi-targeted ligand approach.

Barriers to self-management of chronic pain in primary care: a qualitative focus group study.

BACKGROUND: Supported self-management is a recommended intervention for chronic pain. Effective self-management should enable an individual to reduce the impact of pain on their everyday life. Clinical guidelines suggest primary care services have a role to play in supporting self-management of chronic pain. AIM: To examine the opinions of primary care healthcare professionals (HCPs) and people with chronic pain and their carers, in order to identify possible barriers to the facilitation and adoption of self-management. DESIGN AND SETTING: A qualitative study using focus groups in locations throughout Scotland. METHOD: Eighteen focus groups were held with patients and HCPs. Fifty-four patients, nine carers, and 38 HCPs attended the groups. RESULTS: Four categories of barriers were found. 1) Patient-HCP consultation: some patients felt a discussion about self-management came too late or not at all. Communication and building positive relations were sometimes challenging. 2) Patient experience: the emotional impact of pain was difficult and patients often felt unsupported by HCPs. 3) Limited treatment options: some participants felt there was a tendency for overmedicalisation. 4) Organisational constraints: short appointment times, long waiting lists, and a compartmentalised NHS created challenges. CONCLUSION: This study illustrates some of the barriers faced by HCPs and patients in the facilitation and adoption of self-management of chronic pain. If self-management is to be an important approach to chronic pain, primary care services need to be designed to address the barriers identified.

The potential role of bioscavenger in the medical management of nerve-agent poisoned casualties.

The provision of effective Medical Countermeasures (MedCM) for all agents and routes of exposure is a strategic goal of defence research and development. In the case of military autoinjector-based therapies for nerve agent poisoning, current treatment effectiveness is limited by the oxime reactivator being effective against only certain agents, by rapid clearance times of the drugs and because the doses may not be optimal for treatment of severe poisoning. Prolonged poisoning by nerve agents entering the body through the skin is also challenging. Since casualty handling timelines have reduced significantly in recent years, it may be sufficient for first aid therapy to provide protection for only a few hours until further medical treatment is available. Therefore, the traditional evaluation of first aid therapy in animal models of survival at 24 h may not be appropriate. At various echelons of medical care, further therapeutic interventions are possible. The current basis for the medical management of nerve-agent poisoned casualties is derived mainly from clinical experience with pesticide poisoning. Adjunct therapy with a bioscavenger (such as human butyrylcholinesterase (huBChE)), could have utility as a delayed intervention by reducing the toxic load. It has previously been demonstrated that huBChE is an effective post-exposure therapy against percutaneous VX poisoning. It is recommended that the scope of animal models of nerve agent MedCM are extended to cover evaluation of both first aid MedCM over significantly reduced timescales, and subsequent supportive therapeutic and medical management strategies over longer timescales. In addition to bioscavengers, these strategies could include repeated combined and individual therapy drugs to alleviate symptoms, other classes of drugs or ventilatory support. Crown Copyright © [2016] Published by Elsevier Ireland Ltd. This is an open access article under the Open Government Licence (OGL) (http://www.nationalarchives.gov.uk/doc/open-government-licence/version/3/).

Pharmacokinetic profile and quantitation of protection against soman poisoning by the antinicotinic compound MB327 in the guinea-pig.

Current organophosphorus nerve agent medical countermeasures do not directly address the nicotinic effects of poisoning. A series of antinicotinic bispyridinium compounds has been synthesized in our laboratory and screened in vitro. Their actions can include open-channel block at the nicotinic receptor which may contribute to their efficacy. The current lead compound from these studies, MB327 1,1'-(propane-1,3-diyl)bis(4-tert-butylpyridinium) as either the diiodide (I2) or dimethanesulfonate (DMS) has been examined in vivo for efficacy against nerve agent poisoning. MB327 I2 (0-113mgkg(-1)) or the oxime HI-6 DMS (0-100mgkg(- 1)), in combination with atropine and avizafone (each at 3mgkg(-1)) was administered to guinea-pigs 1min following soman poisoning. Treatment increased the LD50 of soman in a dose-dependent manner. The increase was statistically significant (p<0.01) at the 33.9mgkg(-1) (MB327) or 30mgkg(-1) (HI-6) dose with a comparable degree of protection obtained for both compounds. Following administration of 10mgkg(-1) (i.m.), MB327 DMS reached plasma Cmax of 22µM at 12min with an elimination t1/2 of 22min. In an adverse effect study, in the absence of nerve agent poisoning, a dose of 100mgkg(-1) or higher of MB327 DMS was lethal to the guinea-pigs. A lower dose of MB327 DMS (30mgkg(-1)) caused flaccid paralysis accompanied by respiratory impairment. Respiration normalised by 30min, although the animals remained incapacitated to 4h. MB327 or related compounds may be of utility in treatment of nerve agent poisoning as a component of therapy with atropine, anticonvulsant and oxime, or alternatively as an infusion under medical supervision.

Toxicity and medical countermeasure studies on the organophosphorus nerve agents VM and VX.

To support the effort to eliminate the Syrian Arab Republic chemical weapons stockpile safely, there was a requirement to provide scientific advice based on experimentally derived information on both toxicity and medical countermeasures (MedCM) in the event of exposure to VM, VX or VM-VX mixtures. Complementary in vitro and in vivo studies were undertaken to inform that advice. The penetration rate of neat VM was not significantly different from that of neat VX, through either guinea pig or pig skin in vitro. The presence of VX did not affect the penetration rate of VM in mixtures of various proportions. A lethal dose of VM was approximately twice that of VX in guinea pigs poisoned via the percutaneous route. There was no interaction in mixed agent solutions which altered the in vivo toxicity of the agents. Percutaneous poisoning by VM responded to treatment with standard MedCM, although complete protection was not achieved.

Altruism and participation in longitudinal health research? Insights from the Whitehall II Study.

Research that follows people over a period of time (longitudinal or panel studies) is important in understanding the ageing process and changes over time in the lives of older people. Older people may choose to leave studies due to frailty, or illness and this may diminish the value of the study. However, people also drop out of studies for other reasons and understanding the motivation behind participation or drop out may prevent further loss of valuable longitudinal information and assist the continuation of longitudinal studies. This paper examines qualitative data from interviews and focus groups in 2003/2008 with participants of the Whitehall II Study (based at UCL), and investigates reasons participants give for participating in longitudinal health studies, and recommendations they give for encouraging continued participation as they grow older. A total of 28 participants and 14 staff were interviewed, and 17 participants took part in focus groups. Our findings are discussed in the light of the debate between of altruism and reciprocity. Rather than being wholly motivated by altruism, as research staff had assumed, participants were motivated by the benefits they perceived, particularly the information and care received during the medical examinations and the sense of loyalty and membership associated with being part of the study. Our findings support the view that far from being primarily motivated by altruism, research participation in studies such as this may also involve a degree of implicit and explicit reciprocity. However, participants disliked the obligation to complete the study questionnaires--which may have influenced the expectation of payment or reciprocation, as participation was not wholly pleasing. To try and maintain participation in longitudinal health studies this project recommended gathering information from exit interviews as a way of preventing further withdrawals and closer involvement of participants through a user panel.

An assessment of vascularity and flow intensity of the placenta in normal pregnancy and pre-eclampsia using three-dimensional ultrasound.

OBJECTIVE: To test the hypothesis that parameters of vascularity and flow intensity of the placenta as determined by three-dimensional (3D) ultrasound, (1) are different in normal pregnancy compared to pre-eclampsia (2) decrease from the basal plate towards the chorionic plate. METHODS: Twenty women with normal pregnancy and 17 women with pre-eclampisa were studied. 3D power Doppler ultrasound was used to acquire individual placental volumes. Rotational measurements of placental volumes were acquired using virtual organ computer aided analysis (VOCAL). The power Doppler signals were then semi-quantified within 'histogram facility', which generates three vascularity and flow intensity parameters: flow index (FI), vascular index (VI) and vascularisation flow index (VFI). RESULTS: FI, VI and VFI were lower in pre-eclampsia compared to normal pregnancy in all regions of the placenta. This difference was statistically significant in most regions of the placenta after accounting for gestational age, body mass index and placental site. We were not able to demonstrate a decreasing gradient of these parameters from basal plate to chorionic plate. CONCLUSION: 3D ultrasound to assess placental vascularity and flow intensity appears to be an interesting research tool. However, other indices derived from Power Doppler may be more relevant to obstetric practice.

A qualitative study of the health-related quality of life of disabled children.

This qualitative study investigated what disabled children thought most important in their lives and examined how well their priorities are represented in KIDSCREEN, a generic health-related quality of life (HRQoL) instrument. Participants were a subgroup of families who had previously taken part in a study of quality of life and participation in children with cerebral palsy (CP) using KIDSCREEN. This subgroup was sampled purposively, using children's scores on KIDSCREEN and demographic characteristics. Twenty-eight children (15 males, 13 females; age range 8y 3mo-13y 5mo) and 35 parents were interviewed. Ten children were at Gross Motor Function Classification System Level I, 15 were at Levels II or III, and three were at Levels IV or V. Eleven children had unilateral spastic CP, 16 had bilateral spastic C P, and one child had dyskinetic C P. Interviews were audio-recorded and transcribed verbatim. The analysis was based on the constant comparative method and focused largely on the children's data, though the parent data were drawn upon to illuminate the children's data. Four overarching areas of HRQoL were identified: social relationships; home and school environment; self and body; and recreational activities and resources. These generally mapped well to the dimensions and items in KIDSCREEN. The precedence children gave to environmental, social, interpersonal, health, and functional concerns corresponded well with the balance of these items in KIDSCREEN. However, children had some specific priority areas that were not represented in KIDSCREEN. These included: relationships with family members other than parents; inclusion and fairness; home life and neighbourhood; pain and discomfort; environmental accommodation of needs; and recreational resources other than finances and time. We recommend that further consideration be given to inclusion of these areas in the assessment of HRQoL of disabled children.