Hand grip strength (HGS) is a predictor of cognitive decline in aging. To understand the direct and indirect mechanisms underlying this association, we performed integrative analyses of genetic, cognitive, and autopsy data. A polygenic risk score for HGS (PRSHGS) was calculated in two independent studies of aging (total n = 25,227). Cross-sectional and longitudinal modeling, including mediation with physical activity, assessed the effects of PRSHGS on cognitive performance and postmortem neuropathology. In both cohorts, higher PRSHGS predicted better global cognitive performance (p = 7.77 × 10-4 and p = 0.025) and improved the predictive performance of an Alzheimer's disease PRS (likelihood ratio test p = 2.5 × 10-5 and p = 0.007). PRSHGS was not associated with levels of any postmortem neuropathology. PRSHGS effects on cognition were only partially and inconsistently mediated by physical activity. Genetic predisposition for greater HGS predicts better cognitive performance in late life, independent from Alzheimer's disease-related neuropathology.

Anhedonia, a core symptom of depression, is often resistant to conventional treatments and significantly impacts quality of life. This secondary analysis aimed to evaluate the effects of psilocybin-assisted psychotherapy (PAP) on anhedonia severity in individuals with treatment-resistant depression (TRD). Participants (n=30) with TRD and a primary diagnosis of Major Depressive Disorder or Bipolar II Disorder received at least one 25mg dose of oral psilocybin with psychotherapy as part of a randomized, waitlist-controlled trial (NCT05029466). The primary outcome of the present secondary analysis was changes in anhedonia, measured by the Snaith-Hamilton Pleasure Scale (SHAPS). Exploratory analysis examined whether changes in anhedonia were mediated through changes in overall depression severity, measured by the Montgomery-Asberg Depression Rating Scale (MADRS). A mixed ANOVA, adjusted for sex and age, revealed a statistically significant reduction in SHAPS scores following PAP at the 2-week primary endpoint (F(8, 143.48)=3.43, p=0.001, n=29) with clinically significant improvements observed at 3-month and 6-month secondary endpoints. Our findings from this preliminary analysis suggest that PAP may offer a promising intervention for addressing anhedonia in TRD, but further research with larger, placebo-controlled trials are needed to confirm these effects and elucidate potential mediators. This study adds to a growing body of evidence supporting the therapeutic potential of PAP.

• Heat accumulation with build height is geometry-dependent. • Samples wider than ∼4 mm can be treated as “bulk” components. • Conduction losses between the melt pool and the surrounding materials are strongly non-linear with wall thicknesses. • Convection and radiation contribute up to 35% of heat losses in the melt pool during the fabrication of thin walls by DED. • Minimum heat losses in the melt pool occur at 2.1 mm wall thickness, increasing by 39% in narrower walls. Heat flow conditions vary significantly in Directed Energy Deposition (DED), such as during the repair of structures with varying cross sections. While classical thermal analyses emphasize conduction, heat losses through convection and radiation can be consequential in thin-wall geometries. This can lead to certain geometries experiencing heat accumulation with build height, while in other geometries, the temperature decreases as the build height increases. To quantify how heat flow mechanisms vary with wall thickness, in this study, in-situ coaxial monitoring was combined with a finite element (FE) model that accounts for conduction, convection, and radiation. Measured melt pool thermal intensities during the deposition of 9 Inconel 718 walls with thicknesses ranging from thin- to thick-wall regimes are compared with FE-based predictions. The results show that conduction is the dominant heat transfer mechanism between the melt pool and the surrounding materials in all cases during deposition; however, convective and radiative losses of the melt pool are non-negligible in thin-wall regimes, being responsible for up to 35 % of the total heat losses. Meanwhile, the relative importance of convection/radiation of the melt pool was found to increase as sections narrow. In addition, the minimum heat loss of the melt pool (and the maximum thermal intensity) was observed at an intermediate wall thickness (2.1 mm), while the total heat losses of the melt pool increased by 39 % in a 1.1 mm wall thickness and by 17 % in a 9.1 mm wall thickness. These strongly non-linear thermal relationships lead to the conclusion that samples wider than 4 mm can be treated as “bulk”, for which conduction-dominated assumptions are adequate in thermal analysis; sections with a thickness less than 4 mm require convection and radiation to be considered. These findings could provide guidance in the selection of deposition parameters and modeling assumptions to ensure consistent DED repairs across highly variable cross-sections.

<h2>Abstract</h2> Primary central nervous system lymphoma (PCNSL) is a rare and aggressive neoplasm usually of B-cell origin. Its occurrence is associated with age, with PCNSL affecting more often elderly patients. In adults, PCNSL is a non-germinal center B-cell lymphoma characterized by C5/MCD/MYD88 gene signature, and HLA I/II expression alterations. The disease behaviour differs in children, adolescent, and young adults (CAYA) or in those with an inborn or acquired immune dysregulation/dysfunction, with greater variety of histologic subtypes. Also, different genetic signatures are observed in younger patients (<i>MYD88</i> wildtype) or in those with EBV+ tumours, including higher frequency of abnormalities in checkpoint inhibitor axes, suggesting different tumour microenvironment compositions and immune escape mechanisms. Children, adolescents and young adults (CAYA) with PCNSL demonstrate more favourable outcomes, likely reflecting a superior response to therapy, whereas outcomes in adult patients remain comparatively poor. Focused research that specifically includes CAYA PCNSL is necessary to uncover additional unique molecular features and association with the immune system in an "immune-privileged" site such as the CNS. These efforts will likely lead to better diagnostic methods, prognostication and optimization of treatment protocols in children, and adolescents with PCNSL.