Neuroscience meets behavior: A systematic literature review on magnetic resonance imaging of the brain combined with real-world digital phenotyping.

A primary goal of neuroscience is to understand the relationship between the brain and behavior. While magnetic resonance imaging (MRI) examines brain structure and function under controlled conditions, digital phenotyping via portable automatic devices (PAD) quantifies behavior in real-world settings. Combining these two technologies may bridge the gap between brain imaging, physiology, and real-time behavior, enhancing the generalizability of laboratory and clinical findings. However, the use of MRI and data from PADs outside the MRI scanner remains underexplored. Herein, we present a Preferred Reporting Items for Systematic Reviews and Meta-Analysis systematic literature review that identifies and analyzes the current state of research on the integration of brain MRI and PADs. PubMed and Scopus were automatically searched using keywords covering various MRI techniques and PADs. Abstracts were screened to only include articles that collected MRI brain data and PAD data outside the laboratory environment. Full-text screening was then conducted to ensure included articles combined quantitative data from MRI with data from PADs, yielding 94 selected papers for a total of N = 14,778 subjects. Results were reported as cross-frequency tables between brain imaging and behavior sampling methods and patterns were identified through network analysis. Furthermore, brain maps reported in the studies were synthesized according to the measurement modalities that were used. Results demonstrate the feasibility of integrating MRI and PADs across various study designs, patient and control populations, and age groups. The majority of published literature combines functional, T1-weighted, and diffusion weighted MRI with physical activity sensors, ecological momentary assessment via PADs, and sleep. The literature further highlights specific brain regions frequently correlated with distinct MRI-PAD combinations. These combinations enable in-depth studies on how physiology, brain function and behavior influence each other. Our review highlights the potential for constructing brain-behavior models that extend beyond the scanner and into real-world contexts.

Iris melanoma in an Australian cohort.

BACKGROUND: To report the clinicopathological features and epidemiology of iris melanoma in Queensland, Australia. METHODS: This was a retrospective study of 86 patients with iris melanoma treated between 2001 and 2022 at the Queensland Ocular Oncology Service, Brisbane, Australia. Main outcome measures included demographics, clinical and phenotypic features, age-adjusted incidence and relative survival. RESULTS: Eighty-six patients (63% female) were included. Mean age was 54 years (range 17-82 years). The majority of patients (97%) were Caucasian, with blue eyes, fair skin and Fitzpatrick Skin Type I or II. Demographic features and clinical history showed a tendency for high ultraviolet radiation (UVR) exposure in the cohort. Histopathology was available in 69 cases (82%), and of these, 77% tumours were of spindle cell origin, with low-risk genetic profiles. Patients were followed for a mean of 8 years (median 7, range 1-21 years) after diagnosis, and only one case of metastasis was documented. CONCLUSIONS: The association of iris freckles, history of UVR exposure and dermatologic findings supports the role of UVR in iris melanoma. Occupation and avocation history, as well as evaluation of iris freckles may offer an easily accessible way of stratifying the risk of an individual for development of UVR-related uveal melanoma.

The ATM Ser49Cys Variant Effects ATM Function as a Regulator of Oncogene-Induced Senescence.

An apical component of the cell cycle checkpoint and DNA damage repair response is the ataxia-telangiectasia mutated (ATM) Ser/Thr protein kinase. A variant of ATM, Ser49Cys (rs1800054; minor allele frequency = 0.011), has been associated with an elevated risk of melanoma development; however, the functional consequence of this variant is not defined. ATM-dependent signalling in response to DNA damage has been assessed in a panel of patient-derived lymphoblastoid lines and primary human melanocytic cell strains heterozygous for the ATM Ser49Cys variant allele. The ATM Ser49Cys allele appears functional for acute p53-dependent signalling in response to DNA damage. Expression of the variant allele did reduce the efficacy of oncogene expression in inducing senescence. These findings demonstrate that the ATM 146C>G Ser49Cys allele has little discernible effect on the acute response to DNA damage but has reduced function observed in the chronic response to oncogene over-expression. Analysis of melanoma, naevus and skin colour genomics and GWAS analyses have demonstrated no association of this variant with any of these outcomes. The modest loss of function detected suggest that the variant may act as a modifier of other variants of ATM/p53-dependent signalling.

Exploring the Germline Genetics of In Situ and Invasive Cutaneous Melanoma: A Genome-Wide Association Study Meta-Analysis.

Importance: It is unknown whether germline genetic factors influence in situ melanoma risk differently than invasive melanoma risk. Objective: To determine whether differences in risk of in situ melanoma and invasive melanoma are heritable. Design, Setting, and Participants: Three genome-wide association study meta-analyses were conducted of in situ melanoma vs controls, invasive melanoma vs controls, and in situ vs invasive melanoma (case-case) using 4 population-based genetic cohorts: the UK Biobank, the FinnGen cohort, the QSkin Sun and Health Study, and the Queensland Study of Melanoma: Environmental and Genetic Associations (Q-MEGA). Melanoma status was determined using International Statistical Classification of Diseases and Related Health Problems codes from cancer registry data. Data were collected from 1987 to 2022, and data were analyzed from September 2022 to June 2023. Exposure: In situ and invasive cutaneous melanoma. Main Outcomes and Measures: To test whether in situ and invasive melanoma have independent heritable components, genetic effect estimates were calculated for single-nucleotide variants (SNV; formerly single-nucleotide polymorphisms) throughout the genome for each melanoma. Then, SNV-based heritability was estimated, the genetic correlation between melanoma subtypes was assessed, and polygenic risk scores (PRS) were generated for in situ vs invasive status in Q-MEGA participants. Results: A total of 6 genome-wide significant loci associated with in situ melanoma and 18 loci with invasive melanoma were identified. A strong genetic correlation (genetic r = 0.96; 95% CI, 0.76-1.15) was observed between the 2 classifications. Notably, loci near IRF4, KLF4, and HULC had significantly larger effects for in situ melanoma compared with invasive melanoma, while MC1R had a significantly larger effect on invasive melanoma compared with in situ melanoma. Heritability estimates were consistent for both, with in situ melanoma heritability of 6.7% (95% CI, 4.1-9.3) and invasive melanoma heritability of 4.9% (95% CI, 2.8-7.2). Finally, a PRS, derived from comparing invasive melanoma with in situ melanoma genetic risk, was on average significantly higher in participants with invasive melanoma (odds ratio per 1-SD increase in PRS, 1.43; 95% CI, 1.16-1.77). Conclusions and Relevance: There is much shared genetic architecture between in situ melanoma and invasive melanoma. Despite indistinguishable heritability estimates between the melanoma classifications, PRS suggest germline genetics may influence whether a person gets in situ melanoma or invasive melanoma. PRS could potentially help stratify populations based on invasive melanoma risk, informing future screening programs without exacerbating the current burden of melanoma overdiagnosis.

Persimmon Fiber-Rich Ingredients Promote Anti-Inflammatory Responses and the Growth of Beneficial Anti-Inflammatory Firmicutes Species from the Human Colon.

Persimmon fruit processing-derived waste and by-products, such as peels and pomace, are important sources of dietary fiber and phytochemicals. Revalorizing these by-products could help promote circular nutrition and agricultural sustainability while tackling dietary deficiencies and chronic diseases. In this study, fiber-rich fractions were prepared from the by-products of Sharoni and Brilliant Red persimmon varieties. These fractions were quantified for their phenolic composition and assessed for their ability to promote the growth of beneficial human colonic Firmicutes species and for their in vitro anti-inflammatory potential. Gallic and protocatechuic acids, delphinidin, and cyanidin were the main phenolics identified. Faecalibacterium prausnitzii strains showed significantly higher growth rates in the presence of the Brilliant Red fraction, generating more than double butyrate as a proportion of the total short-chain fatty acids (39.5% vs. 17.8%) when compared to glucose. The fiber-rich fractions significantly decreased the inflammatory effect of interleukin-1ß in Caco-2 cells, and the fermented fractions (both from Sharoni and Brilliant Red) significantly decreased the inflammatory effect of interleukin-6 and tumor necrosis factor-α in the RAW 264.7 cells. Therefore, fiber-rich fractions from persimmon by-products could be part of nutritional therapies as they reduce systemic inflammation, promote the growth of beneficial human gut bacteria, and increase the production of beneficial microbial metabolites such as butyrate.

A day in the life of a GP.

Nick Hayward, who has been a GP for 19 years and is now clinical director for a large primary care network, outlines a typical day in his professional life and reflects on his experiences.

Estimating CDKN2A mutation carrier probability among global familial melanoma cases using GenoMELPREDICT

BACKGROUND:Although rare in the general population, highly penetrant germline mutations in CDKN2A are responsible for 5%-40% of melanoma cases reported in melanoma-prone families. We sought to determine whether MELPREDICT was generalizable to a global series of families with melanoma and whether performance improvements can be achieved.METHODS:In total, 2116 familial melanoma cases were ascertained by the international GenoMEL Consortium. We recapitulated the MELPREDICT model within our data (GenoMELPREDICT) to assess performance improvements by adding phenotypic risk factors and history of pancreatic cancer. We report areas under the curve (AUC) with 95% confidence intervals (CIs) along with net reclassification indices (NRIs) as performance metrics.RESULTS:MELPREDICT performed well (AUC 0.752, 95% CI 0.730-0.775), and GenoMELPREDICT performance was similar (AUC 0.748, 95% CI 0.726-0.771). Adding a reported history of pancreatic cancer yielded discriminatory improvement (P < .0001) in GenoMELPREDICT (AUC 0.772, 95% CI 0.750-0.793, NRI 0.40). Including phenotypic risk factors did not improve performance.CONCLUSION:The MELPREDICT model functioned well in a global data set of familial melanoma cases. Adding pancreatic cancer history improved model prediction. GenoMELPREDICT is a simple tool for predicting CDKN2A mutational status among melanoma patients from melanoma-prone families and can aid in directing these patients to receive genetic testing or cancer risk counseling(AU)

Germline Variation at CDKN2A and Associations with Nevus Phenotypes among Members of Melanoma Families

Germline mutations in CDKN2A are frequently identified among melanoma kindreds and are associated with increased atypical nevus counts. However, a clear relationship between pathogenic CDKN2A mutation carriage and other nevus phenotypes including counts of common acquired nevi has not yet been established. Using data from GenoMEL, we investigated the relationships between CDKN2A mutation carriage and 2-mm, 5-mm, and atypical nevus counts among blood-related members of melanoma families. Compared with individuals without a pathogenic mutation, those who carried one had an overall higher prevalence of atypical (odds ratio = 1.64; 95% confidence interval = 1.18-2.28) nevi but not 2-mm nevi (odds ratio = 1.06; 95% confidence interval = 0.92-1.21) or 5-mm nevi (odds ratio = 1.26; 95% confidence interval = 0.94-1.70). Stratification by case status showed more pronounced positive associations among non-case family members, who were nearly three times (odds ratio = 2.91; 95% confidence interval = 1.75-4.82) as likely to exhibit nevus counts at or above the median in all three nevus categories simultaneously when harboring a pathogenic mutation (vs. not harboring one). Our results support the hypothesis that unidentified nevogenic genes are co-inherited with CDKN2A and may influence carcinogenesis(AU)