Integration of estimated regional gene expression with neuroimaging and clinical phenotypes at biobank scale.

An understanding of human brain individuality requires the integration of data on brain organization across people and brain regions, molecular and systems scales, as well as healthy and clinical states. Here, we help advance this understanding by leveraging methods from computational genomics to integrate large-scale genomic, transcriptomic, neuroimaging, and electronic-health record data sets. We estimated genetically regulated gene expression (gr-expression) of 18,647 genes, across 10 cortical and subcortical regions of 45,549 people from the UK Biobank. First, we showed that patterns of estimated gr-expression reflect known genetic-ancestry relationships, regional identities, as well as inter-regional correlation structure of directly assayed gene expression. Second, we performed transcriptome-wide association studies (TWAS) to discover 1,065 associations between individual variation in gr-expression and gray-matter volumes across people and brain regions. We benchmarked these associations against results from genome-wide association studies (GWAS) of the same sample and found hundreds of novel associations relative to these GWAS. Third, we integrated our results with clinical associations of gr-expression from the Vanderbilt Biobank. This integration allowed us to link genes, via gr-expression, to neuroimaging and clinical phenotypes. Fourth, we identified associations of polygenic gr-expression with structural and functional MRI phenotypes in the Human Connectome Project (HCP), a small neuroimaging-genomic data set with high-quality functional imaging data. Finally, we showed that estimates of gr-expression and magnitudes of TWAS were generally replicable and that the p-values of TWAS were replicable in large samples. Collectively, our results provide a powerful new resource for integrating gr-expression with population genetics of brain organization and disease.

An economic evaluation on sub-optimal breastfeeding in Hong Kong: Infant health outcomes and costs.

AIM: This study estimated the healthcare cost savings for the government due to the prevention of gastroenteritis (GE) infections and lower respiratory tract infections (LRTI) in the first year of life, attributed to an increase in the exclusive breastfeeding rate at 4 months in Hong Kong. METHODS: The model used the best available data inputs, with uncertainty considered using probabilistic sensitivity analysis. We additionally assessed the impact of neonatal jaundice (NNJ) on the economic benefits of increasing exclusive breastfeeding rates. RESULTS: During 2010-2019, five admissions for GE and three admissions for LRTI per 1000 births would have been prevented in the first year of life if the exclusive breastfeeding rate at 4 months increased from the actual levels (~15-30%) to 50%, resulting in annual healthcare cost savings of USD1.05 (95% CI 1.03-1.07) million/year. The cost saving would reach USD1.89 (95% CI 1.86-1.92) million/year if the exclusive breastfeeding rate at 4 months increase to 70%. However, if higher NNJ admissions during 7-90 days related to more exclusive breastfeeding are considered, the cost saving would reduce by 60%. CONCLUSION: Our findings can guide policymakers in allocating budget and resources for breastfeeding promotion in Hong Kong. The prevention of unnecessary NNJ admissions would maximise the economic benefits of exclusive breastfeeding at 4 months.

Incidence of Strabismus Post-Plaque Brachytherapy in Patients With Uveal Melanoma.

PURPOSE: To determine the incidence and type of strabismus in patients with uveal melanoma treated with plaque brachytherapy. DESIGN: Multicenter, retrospective incidence estimation study. METHODS: A total of 438 eyes of 438 patients with uveal melanoma treated with plaque brachytherapy between October 2011 and May 2021. Intervention was Iodine 125, and Palladium 103 plaque brachytherapy. The variables reviewed included incidence of nonresolving strabismus post-plaque brachytherapy, type of strabismus developed, extraocular muscles operated, and modality of treatment received. RESULTS: A total of 438 patients underwent plaque brachytherapy treatment for uveal melanoma. Eleven patients developed strabismus post-plaque brachytherapy (2.5%, n = 11/438). Of these patients, 5 (1.1%, n = 5/438) developed strabismus immediately postoperation. Specifically, 2 patients (0.5%, n = 2/438) developed strabismus immediately postoperation due to slipped muscles, 2 patients (0.5%, n = 2/438) due to decompensated phorias, and 1 patient (0.5%, n = 1/438) due to a fibrotic muscle. Six patients (1.4%, n = 6/438) developed late-onset sensory strabismus. A total of 355 patients (81.1%, n = 355/438) had their extraocular muscles disinserted during surgery, with the lateral rectus being the most common, accounting for 45.4% (n = 161/355), followed by the superior rectus at 26.8% (n = 95/355). Strabismus surgery was the most common treatment modality, comprising 72.7% (n = 8/11) of patients. CONCLUSIONS: The incidence of strabismus after plaque brachytherapy treatment for uveal melanoma was low and primarily classified as late-onset sensory strabismus. Previous studies may underestimate the long-term incidence of strabismus after plaque brachytherapy by focusing primarily on strabismus present immediately postoperatively.

Extracellular matrices derived from different cell sources and their effect on macrophage behavior and wound healing.

A decellularized extracellular matrix (dECM) is an excellent biomaterial in regenerative medicine, due to its biomimetic nature in targeting tissues and organs. In this study, we prepared cell-derived ECMs (CDM) derived from four different cell sources, characterized them individually, and found that intrinsic properties of each CDM were substantially different in terms of the fibrous matrix, total protein, and biochemical factors. Based on such information, we selected two ECM candidates, the human lung fibroblast derived matrix (hFDM) and the umbilical cord-blood mesenchymal stem cell derived matrix (UMDM) for the study of ECM-macrophage interactions in vitro and in vivo. In fact, UMDM was the richer in both total protein and angiogenic-related cytokines than any other CDM. When THP-1 cell-derived macrophages (M0) were seeded onto the UMDM or the hFDM, it showed a mixed cell morphology of macrophage phenotype and the macrophages (M0) preconditioned on UMDM presented more diverse cytokine release profiles. The treatment of conditioned medium obtained from CDM-seeded macrophages showed that UMDM could yield significantly advanced wound closure in 24 h via the human dermal fibroblast scratch model. To investigate the role of ECM on macrophage polarization in vivo, we prepared an ECM hydrogel, a mixture of each CDM and Pluronic F127/hyaluronan, and applied them onto a full-thickness mouse skin wound model for 2 weeks. The therapeutic efficacy as assessed via histology and immunofluorescence staining (α-SMA and CD206) revealed that the UMDM-treated group showed more effective wound healing compared to the other groups, as proven via the thinner epidermal layer, significant recovery of skin appendage, better neovascularization, and higher recruitment of myofibroblasts and larger number of macrophages (M2) at 7 days. The difference between UMDM and hFDM was marginal. Taken together, among the CDMs, UMDM and hFDM are promising resources of ECM, showing a great potential for wound healing. Although the mechanism is not fully understood, bioactive innate factors in UMDM may contribute individually and/or collectively to advance wound healing.