Association of variants in the SPTLC1 gene with juvenile amyotrophic lateral sclerosis

IMPORTANCE Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation.OBJECTIVE To identify the genetic variants associated with juvenile ALS.DESIGN, SETTING, AND PARTICIPANTS In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism.MAIN OUTCOMES AND MEASURES De novo variants present only in the index case and not in unaffected family members.RESULTS Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p. Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway.CONCLUSIONS AND RELEVANCE These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.Genetics of disease, diagnosis and treatmen

National and International Benefit Transfer Testing with a Rigorous Test Procedure

Benefit transfer, as a mean to transfer values from existing monetary valuation studies to new policy sites, has been in use for many years. This paper aims to analyze the forecasting quality of benefit transfer by applying a rigoroust-test – also referred to as Accuracy-t-test – that takes into account testing errors which were made in previous surveys. Beside the analysis of national benefit transfers based on two German contingent valuation studies additional efforts were made to investigate into the validity and accuracy of international benefit transfer by considering two Norwegian studies that employed a similar survey design. Copyright Kluwer Academic Publishers 2004benefit transfer, contingent valuation method, water quality,

Lack of association between classical HLA genes and asymptomatic SARS-CoV-2 infection.

Human genetic studies of critical COVID-19 pneumonia have revealed the essential role of type I interferon-dependent innate immunity to SARS-CoV-2 infection. Conversely, an association between the HLA-B*15:01 allele and asymptomatic SARS-CoV-2 infection in unvaccinated individuals was recently reported, suggesting a contribution of pre-existing T cell-dependent adaptive immunity. We report a lack of association of classical HLA alleles, including HLA-B*15:01, with pre-omicron asymptomatic SARS-CoV-2 infection in unvaccinated participants in a prospective population-based study in the US (191 asymptomatic vs. 945 symptomatic COVID-19 cases). Moreover, we found no such association in the international COVID Human Genetic Effort cohort (206 asymptomatic vs. 574 mild or moderate COVID-19 cases and 1,625 severe or critical COVID-19 cases). Finally, in the Human Challenge Characterisation study, the three HLA-B*15:01 individuals infected with SARS-CoV-2 developed symptoms. As with other acute primary infections studied, no classical HLA alleles favoring an asymptomatic course of SARS-CoV-2 infection were identified

A minimum income for healthy living

BACKGROUND—Half a century of research has provided consensual evidence of major personal requisites of adult health in nutrition, physical activity and psychosocial relations. Their minimal money costs, together with those of a home and other basic necessities, indicate disposable income that is now essential for health.
METHODS—In a first application we identified such representative minimal costs for healthy, single, working men aged 18-30, in the UK. Costs were derived from ad hoc survey, relevant figures in the national Family Expenditure Survey, and by pragmatic decision for the few minor items where survey data were not available.
RESULTS—Minimum costs were assessed at £131.86 per week (UK April 1999 prices). Component costs, especially those of housing (which represents around 40% of this total), depend on region and on several assumptions. By varying these a range of totals from £106.47 to £163.86 per week was detailed. These figures compare, 1999,( )with the new UK national minimum wage, after statutory deductions, of £105.84 at 18-21 years and £121.12 at 22+ years for a 38 hour working week. Corresponding basic social security rates are £40.70-£51.40 per week.
INTERPRETATION—Accumulating science means that absolute standards of living, "poverty", minimal official incomes and the like, can now be assessed by objective measurement of the personal capacity to meet the costs of major requisites of healthy living. A realistic assessment of these costs is presented as an impetus to public discussion. It is a historical role of public health as social medicine to lead in public advocacy of such a national agenda.


Keywords: income; public health; lifestyle; nutrition; housing; exercise; social exclusion; inequalitie

Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer’s disease and Parkinson’s disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition. © 2021, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply