A Guide for the Godless: The Secular Path to Meaning

This book aims to apply recent thinking in philosophy to the age-old problem of the meaning of life, and to do so in a way that is useful to atheists, agnostics, and humanists. The book reorients the search for meaning away from a search for purpose and toward a search for what truly matters, and criticizes our society's prevailing theory of value, the preference satisfaction theory of the economists. It next argues that emotions are our best guides to what matters in life, and shows how emotional judgments about what matters can be true. Finally it discusses how a meaningful life can be lived, describes the role of justice, freedom, identity, and culture in its construction, and compares the meaningful with the happy life. Andrew Kernohan has a Ph.D in philosophy from the University of Toronto and is an Adjunct Professor at Dalhousie University. He is the author of Liberalism, Equality, and Cultural Oppression (Cambridge University Press, 1998) and various articles in professional philosophy journals

HMG co-reductase expression and response to intravesical Bacillus Calmette-Guérin in patients with high grade non-muscle invasive urinary bladder cancer receiving statins

BackgroundCardiovascular disease affects over 7 million people in the UK and statins are often prescribed to mitigate cardiovascular risks. The effect of statins on a number of cancers is debated and their effect on Bacillus Calmette-Guérin (BCG) responsiveness in non-muscle invasive urinary bladder cancer (NMIBC) is not fully understood.AimsThis study aims to explore the difference in HMG Co-A reductase (HMGCR) expression in NMIBC on immunochemistry in BCG responders and non-responders while on statins.MethodThree hundred and thirty-two cases of intravesical BCG treatment for high-risk NMIBC between November 2003 and December 2017 were identified. Patients taking statins for at least 12 months before the diagnosis of NIMBC and with a follow-up of at least 5 years were included. They were divided into BCG responders and non-responders. Tumour tissue from these patients was immunohistochemically stained and quantitative image analysis carried out to assess and compare HMGCR expression in the groups.Results & ConclusionThis study showed a differential expression of HMGCR in responders vs. non-responders to BCG for high-risk NMIBC on statins. This data should form the basis of a further research and multi-centre study in a larger cohort, using HMGCR as a biomarker of response in patients on statins

Diagnosis and treatment of anti-insulin antibody-mediated labile glycaemia in insulin-treated diabetes.

Funder: Diabetes Research & Wellness Foundation; doi: http://dx.doi.org/10.13039/501100000273Funder: United Kingdom National Institute for Health Research (NIHR) Cambridge Biomedical Research CentreAIMS: Anti-insulin antibodies in insulin-treated diabetes can derange glycaemia, but are under-recognised. Detection of significant antibodies is complicated by antigenically distinct insulin analogues. We evaluated a pragmatic biochemical approach to identifying actionable antibodies, and assessed its utility in therapeutic decision making. METHODS: Forty people with insulin-treated diabetes and combinations of insulin resistance, nocturnal/matutinal hypoglycaemia, and unexplained ketoacidosis were studied using broad-specificity insulin immunoassays, polyethylene glycol (PEG) precipitation and gel filtration chromatography (GFC) with or without ex vivo insulin preincubation. RESULTS: Twenty-seven people had insulin immunoreactivity (IIR) below 3000 pmol/L that fell less than 50% after PEG precipitation. Insulin binding by antibodies in this group was low and judged insignificant. In 8 people IIR was above 3000 pmol/L and fell by more than 50% after PEG precipitation. GFC demonstrated substantial high molecular weight (HMW) IIR in 7 of these 8. In this group antibodies were judged likely significant. In 2 people immunosuppression was introduced, with a good clinical result in one but only a biochemical response in another. In 6 people adjustment of insulin delivery was subsequently informed by knowledge of underlying antibody. In a final group of 5 participants IIR was below 3000 pmol/L but fell by more than 50% after PEG precipitation. In 4 of these GFC demonstrated low levels of HMW IIR and antibody significance was judged indeterminate. CONCLUSIONS: Anti-insulin antibodies should be considered in insulin-treated diabetes with unexplained glycaemic lability. Combining immunoassays with PEG precipitation can stratify their significance. Antibody depletion may be beneficial, but conservative measures often suffice

Early infantile epileptic encephalopathy due to biallelic pathogenic variants in PIGQ : Report of seven new subjects and review of the literature

We investigated seven children from six families to expand the phenotypic spectrum associated with an early infantile epileptic encephalopathy caused by biallelic pathogenic variants in the phosphatidylinositol glycan anchor biosynthesis class Q (PIGQ) gene. The affected children were all identified by clinical or research exome sequencing. Clinical data, including EEGs and MRIs, was comprehensively reviewed and flow cytometry and transfection experiments were performed to investigate PIGQ function. Pathogenic biallelic PIGQ variants were associated with increased mortality. Epileptic seizures, axial hypotonia, developmental delay and multiple congenital anomalies were consistently observed. Seizure onset occurred between 2.5 months and 7 months of age and varied from treatable seizures to recurrent episodes of status epilepticus. Gastrointestinal issues were common and severe, two affected individuals had midgut volvulus requiring surgical correction. Cardiac anomalies including arrythmias were observed. Flow cytometry using granulocytes and fibroblasts from affected individuals showed reduced expression of glycosylphosphatidylinositol (GPI)-anchored proteins. Transfection of wildtype PIGQ cDNA into patient fibroblasts rescued this phenotype. We expand the phenotypic spectrum of PIGQ-related disease and provide the first functional evidence in human cells of defective GPI-anchoring due to pathogenic variants in PIGQ

Early infantile epileptic encephalopathy due to biallelic pathogenic variants inPIGQ: Report of seven new subjects and review of the literature

We investigated seven children from six families to expand the phenotypic spectrum associated with an early infantile epileptic encephalopathy caused by biallelic pathogenic variants in the phosphatidylinositol glycan anchor biosynthesis class Q (PIGQ) gene. The affected children were all identified by clinical or research exome sequencing. Clinical data, including EEGs and MRIs, was comprehensively reviewed and flow cytometry and transfection experiments were performed to investigate PIGQ function. Pathogenic biallelicPIGQvariants were associated with increased mortality. Epileptic seizures, axial hypotonia, developmental delay and multiple congenital anomalies were consistently observed. Seizure onset occurred between 2.5 months and 7 months of age and varied from treatable seizures to recurrent episodes of status epilepticus. Gastrointestinal issues were common and severe, two affected individuals had midgut volvulus requiring surgical correction. Cardiac anomalies including arrythmias were observed. Flow cytometry using granulocytes and fibroblasts from affected individuals showed reduced expression of glycosylphosphatidylinositol (GPI)-anchored proteins. Transfection of wildtypePIGQcDNA into patient fibroblasts rescued this phenotype. We expand the phenotypic spectrum ofPIGQ-related disease and provide the first functional evidence in human cells of defective GPI-anchoring due to pathogenic variants inPIGQ