A single copy of klotho allele KL-VS is associated with longevity, better health, increased cognition, and bigger regional brain volume. However, its longitudinal effects on cognition and brain volumes, both global and regional, in late life are unclear. In this study we show that, relative to noncarriers, KL-VS heterozygotes had (1) shorter survival; (2) smaller white matter volumes; (3) slower cognitive decline; and (4) greater right frontal lobe volumes. The KL-VS heterozygote survival and white matter volume disadvantages were unexpected. A possible explanation for these results in the context of the literature is a potential interaction between the environment and/or age of the participants, leading to a heterozygote disadvantage. The longitudinal cognitive trajectories indicate that heterozygotes would have an advantage in very late life. Collectively these results suggest that the genotype-survival advantage of the KL-VS allele is age-dependent and possibly mediated through differential cognition and brain volume.

Variation in the klotho gene is linked to differences in health outcomes: klotho allele KL-VS heterozygosity is associated with longevity, better cognition and greater right frontal grey matter volume in late life. Contradicting reports, however, suggest that KL-VS's effect on health might be age-dependent. Here we examine the relationship between KL-VS genotype, cognition and brain structure in childhood and adolescence. We hypothesized that KL-VS has early influences on cognitive and brain development. We investigated the associations of KL-VS carrier status with cognition and brain morphology in a cohort of 1387 children and adolescents aged 3-21 years, examining main effects and interactions between age, sex and socioeconomic circumstance. KL-VS had no main effect on either cognition or brain structure, though there was a significant KL-VS × age interaction for cognition (specifically executive function, attention, episodic memory, and general cognition), total grey matter and total brain volume. KL-VS heterozygotes had better cognition than non-carriers before age 11, but lower cognition after age 11. Heterozygotes had smaller brains than non-carriers did in early childhood. Sex moderated the association between KL-VS and white matter volume. Among girls, KL-VS heterozygotes had smaller white matter volumes than non-carriers. Among boys, heterozygotes had greater white matter volumes than non-carriers. However, a replication in a cohort of 2306 children aged 6-12 years showed no significant associations. In contrast to findings in late life, these results show that KL-VS does not have a main effect on cognition and brain structure. Furthermore, KL-VS's influence may depend on age and sex.

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A recent U.K. National Screening Committee review (1,2) concluded that evidence was insufficient to support the implementation of artificial intelligence (AI) in routine breast cancer screening. The review identified limited evidence on sources of variability, impact on interval cancers (ICs) detected between screening cycles, and performance of a preset threshold to classify recall or no recall. In addition, evidence for the transferability of AI models is inconsistent (3-5).We evaluated commercial AI software (6) by using data from a U.K. screening program to determine whether its performance transferred to an external dataset generated with different mammography equipment. The AI software is Conformité Européenne marked, indicating compliance with applicable European Union regulations. This study evaluates the generalizability of the AI tool by using consecutively acquired clinical data, comparing stand-alone performance to the dual reporting system in the U.K. screening service. Materials and Methods SampleThe Proportionate Review Subcommittee of the London-Bloomsbury Research Ethics Committee approved this retrospective study (reference no. 20/LO/0563). Secondary use of de-identified data negated the requirement for individual consent. Public Benefit and Privacy Panel approval was obtained (reference no. 1920-0258).National Health Service (NHS) Grampian clinical data and mammograms were collected from the Scottish Breast Screening Service (SBSS) (February 12, 2016-March 31, 2020. Full-field digital mammograms were acquired with five mammography units of the same make and model (Selenia Dimensions; Hologic) with no known differences at study commencement. All units conform to NHS breast cancer screening quality standards (7). The standard imaging protocol consisted of two views per breast (craniocaudal and mediolateral oblique). As part of routine screening,