Highlights d 102 genes implicated in risk for autism spectrum disorder (ASD genes, FDR % 0.1) d Most are expressed and enriched early in excitatory and inhibitory neuronal lineages d Most affect synapses or regulate other genes; how these roles dovetail is unknown d Some ASD genes alter early development broadly, others appear more specific to ASD
SummaryWe present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n=35,584 total samples, 11,986 with ASD). Using an enhanced Bayesian framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate ≤ 0.1. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained for severe neurodevelopmental delay, while 53 show higher frequencies in individuals ascertained for ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most of the risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In human cortex single-cell gene expression data, expression of risk genes is enriched in both excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory/inhibitory imbalance underlying ASD.
Palliative care services have developed rapidly over the past 30 years, with little evaluation as to how needs have been met by these new services. As part of a systematic review of palliative care, evidence of the needs of patients and carers has been evaluated from the current literature. Of the total of 673 articles related to the 10 areas within the main review, 64 provided evidence on the need for palliative care services over the period from 1978 to 1997. A further nine articles were added in November 1998 after the end of the study of update the review with more recent research. Need can be assessed in one of two ways: either by adopting an epidemiological approach or by examining health service usage. In the former, evidence is provided on disease-specific mortality, and related to the duration of symptoms prior to the patient's death. As an example of this, it is suggested that services may need to provide pain control for 2800 patients per million (p/M) population dying from cancer each year and 3400 p/M with noncancer terminal illness. Using health service usage as an indicator of need, 700-1800 p/M with cancer and 350-1400 p/M with noncancer terminal illness would require a support team or specialist palliative home care nurse, with 400-700 cancer p/M and 200-700 noncancer p/M requiring inpatient terminal care. Studies indicate that at present usage, palliative care is being provided by 40-50 hospice beds/M. Despite this provision, there remains evidence that in certain areas of care such as pain control, there still remains a high degree of unmet need.
This study set out to systematically review the research evidence about the impact of alternative models of specialist palliative care on the quality of life of patients. Eighty-six relevant papers were identified and reviewed, including 22 descriptive and 27 comparative studies. We found few comparative trials of reasonable quality. There was some evidence that in-patient palliative care provided better pain control than home care of conventional hospital care, but this research was dated and open to criticism. Research on palliative home care teams and co-ordinating nurses has demonstrated limited impact on quality of life over conventional care for patients dying at home. These negative findings may be due to the limitations of the assessment tools used. There is a need for larger studies to provide clear evidence as to whether specialist palliative care services provide improvements in patients' quality of life. This review does not exclude the possibility that models of care might be justifiable on other grounds such as patient preference or cost-effectiveness.
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