Cerebral palsy (CP), a neurodevelopmental disorder characterized by irreversible, nonprogressive central motor dysfunction, is commonly associated with prematurity or perinatal brain injury. However, accumulating evidence suggests deleterious genomic variants may contribute to CP in addition to environmental insults. To identify genes contributing to risk for CP, we performed whole-exome sequencing on 250 parent-offspring CP trios. We identified a significant contribution of damaging de novo mutations (DNMs), especially in genes that are intolerant to loss of function mutations. Eight genes had multiple, independently-arising damaging DNMs, including two novel CP-associated genes, FBXO31 and RHOB, and four genes previously implicated in cerebral palsy phenotypes, TUBA1A, CTNNB1, SPAST, and ATL1. Functional experiments, including molecular and biochemical assays and patient fibroblast studies indicate that the recurrent RHOB mutation identified in patients enhances Rho effector binding in the active state and that the FBXO31 mutation leads to elevated levels of cyclin D. Analysis of candidate CP risk genes highlighted genetic overlap with hereditary spastic paraplegia as well as intellectual disability, autism, and epilepsy, converging with epidemiologic findings. Computational network analysis of risk genes identified significant enrichment of Rho GTPase, extracellular matrix, focal adhesions, cytoskeleton, and cell projection pathways. CP risk genes in Rho GTPase, cytoskeleton and cell projection pathways were found to play an important role in neuromotor development via a Drosophila reverse genetics screen. Based on enrichment analysis, we estimate that an excess of damaging de novo and inherited recessive variants collectively account for ~14% of the cases in our cohort, whereas perinatal asphyxia is currently estimated to occur in 8-10% of CP cases. Together, these findings provide evidence for the role of genetically-mediated dysregulation of early brain connectivity in CP.

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Patients on certain waiting lists in the UK National Health Service (NHS) are now offered the choice of persevering with their home hospital or switching to another hospital where they will be treated on a guaranteed date. Such decisions require knowledge of performance. We used facilitated focus groups to investigate the views of patients and members of the public on publication of information about the performance of healthcare providers. Six groups with a total of 50 participants met in six different locations in England. Participants felt that independent monitoring of healthcare performance is necessary, but they were ambivalent about the value of performance indicators and hospital rankings. They tended to distrust government information and preferred the presentational style of 'Dr Foster', a commercial information provider, because it gave more detailed locally relevant information. Many participants felt the NHS did not offer much scope for choice of provider. If public access to performance information is to succeed in informing referral decisions and raising quality standards, the public and general practitioners will need education on how to interpret and use the data.

Patients on certain waiting lists in the UK National Health Service (NHS) are now offered the choice of persevering with their home hospital or switching to another hospital where they will be treated on a guaranteed date. Such decisions require knowledge of performance. We used facilitated focus groups to investigate the views of patients and members of the public on publication of information about the performance of healthcare providers. Six groups with a total of 50 participants met in six different locations in England. Participants felt that independent monitoring of healthcare performance is necessary, but they were ambivalent about the value of performance indicators and hospital rankings. They tended to distrust government information and preferred the presentational style of 'Dr Foster', a commercial information provider, because it gave more detailed locally relevant information. Many participants felt the NHS did not offer much scope for choice of provider. If public access to performance information is to succeed in informing referral decisions and raising quality standards, the public and general practitioners will need education on how to interpret and use the data.

Objective To develop a questionnaire to assess patientsÕ views of clinical trials, and to report the results from the questionnaire in two patient groups: asthma and cancer.Design A 43 item questionnaire asking patients about their views to clinical trials was developed on the basis of interviews with trialists and focus groups with patients. The questionnaire was mailed to patients with a diagnosis of either asthma or cancer. A set of items was then selected, via statistical analyses, to form the core of the questionnaire.Participants Patients with a diagnosis of cancer in one NHS Hospital Trust, and patients with a diagnosis of asthma in two NHS Hospital Trusts.Results Completed questionnaires were received from 353 cancer patients and 578 asthma patients. Factor analyses of the data indicated that 22 items contributed to five dimensions: Ôpositive beliefsÕ, ÔsafetyÕ, Ôinformation needsÕ, Ônegative expectationsÕ and Ôpatient involvementÕ. Differences between asthma and cancer patients on these dimensions were small. A regression of these dimension scores against a variable asking if patients would be willing to take part in trials found that ÔsafetyÕ and Ôinformation needsÕ did not contribute significantly to the model for either asthma or cancer patients.Conclusions A questionnaire has been developed for use in assessing patientsÕ views towards clinical trials. Results from the surveys reported here suggest that patient views about the importance of trials and beliefs about the value of patient involvement are likely to be predictive of whether or not patients will agree to take part in a study.