The price of nicotine dependence: A comparison of the cost of nicotine across products in Switzerland, Germany, USA, Sweden, France and the UK, in 2019 [short report].

INTRODUCTION Tobacco cigarette taxes aim at reducing smoking, but smokers are still dependent on nicotine and need safe and cheap alternatives. As the costs play a role in the product chosen, we compared standardized nicotine costs across products and countries. METHODS We gathered prices of tobacco cigarettes, heated tobacco products (HTP), pharmaceutical nicotine replacement therapy (pNRT) gums, snus, and open and closed electronic nicotine delivery systems (ENDS) in 6 countries (Switzerland, Germany, USA, Sweden, France, UK) in 2019. We compared the cost of a pack of cigarettes in Switzerland to the cost of equivalent doses of nicotine delivered by other products and across countries, normalizing to purchasing power GDP per capita to compute relative adjusted costs (RACs). RESULTS Adjusted tobacco cigarette cost was lowest in Switzerland, Germany, and Sweden; RAC for pNRT was 1.1 in Switzerland and 1.0 in Germany. In France and the UK, RACs for cigarettes were 1.5 and 2.1, while for pNRT they were cheaper (RAC: 0.04). In Switzerland, snus/nicotine pouches were the cheapest form of nicotine delivery (RAC: 0.2), open ENDS were a low-cost option for nicotine delivery in all countries (RAC: 0.2-0.3), and HTP cost more than regular tobacco products in most countries. CONCLUSIONS We found broad differences in costs of nicotine according to countries and products. This should be considered in future studies on smoking prevalence and in public health efforts

Prevalence and architecture of de novo mutations in developmental disorders.

The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year

Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy.

We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Hemispheric Processing of Sarcastic Text

Recent evidence suggests that certain types of figurative language, such as conventional metaphors or idioms, may have a left hemisphere processing advantage or are processed similarly in both hemispheres. Sarcasm, however, is likely processed differently than other types of figurative language in the hemispheres because readers often need to construct a novel interpretation of sarcastic text to successfully understand the text’s sarcastic meaning. To investigate how the hemispheres process sarcasm during text comprehension, participants in the current study read sarcastic, literal, and neutral texts and made lexical decisions to related target words presented to either the left visual field-right hemisphere or the right visual field-left hemisphere. Facilitation for sarcastic texts was greater in the right hemisphere than the left hemisphere. In addition, facilitation was greater for literal texts than sarcastic texts in the left hemisphere. These findings suggest that the right hemisphere may play a unique role when readers encounter sarcasm during text comprehension

Grundrechte im Alter. Ein Handbuch

Grundrechte gelten für alle Menschen, unabhängig von ihrem Alter. In der Praxis hingegen stossen ältere Menschen oft auf Hindernisse, die es ihnen erschweren, ihre Rechte wahrzunehmen. Häufig sind sie und ihr Umfeld sich nicht bewusst, dass sie Grund- und Menschenrechte einfordern können und Einschränkungen der Autonomie oder Benachteiligungen gegenüber jüngeren Menschen nicht einfach hinnehmen müssen. Das vorliegende Handbuch möchte das Bewusstsein für die Bedeutung der Grundrechte im Alter stärken. Es erklärt in verständlicher Sprache die wichtigsten Begriffe und Gesetze, welche in Bezug auf die Grundrechte von älteren Menschen relevant sind. Anhand konkreter Beispiele wird das theoretische Grundwissen in der Praxis erläutert. Die Fallbeispiele greifen Fragen aus den vier Themenfeldern «Arbeit», «Privatsphäre und Familie», «Wohnen und Heimalltag» und «Gesundheit» auf. Sie sollen Personen und Einrichtungen, welche beruflich oder im Rahmen eines freiwilligen Engagements mit älteren Menschen in Kontakt stehen, befähigen, grundrechtliche Fragestellungen in der Arbeit mit älteren Menschen zu erkennen und umzusetzen

Control of pulmonary surfactant secretion: an evolutionary perspective

Philip G. Wood , Olga V. Lopatko , Sandra Orgeig , Jean M. P. Joss , Allan W. Smits , Christopher B. Daniel