The major genetic risk for late onset Alzheimer's disease has been associated with the presence of APOE4 alleles. However, the impact of different APOE alleles on the brain aging trajectory, and how they interact with the brain local environment in a sex specific manner is not entirely clear. We sought to identify vulnerable brain circuits in novel mouse models with homozygous targeted replacement of the mouse ApoE gene with either human APOE3 or APOE4 gene alleles. These genes are expressed in mice that also model the human immune response to age and disease-associated challenges by expressing the human NOS2 gene in place of the mouse mNos2 gene. These mice had impaired learning and memory when assessed with the Morris water maze (MWM) and novel object recognition (NOR) tests. Ex vivo MRI-DTI analyses revealed global and local atrophy, and areas of reduced fractional anisotropy (FA). Using tensor network principal component analyses for structural connectomes, we inferred the pairwise connections which best separate APOE4 from APOE3 carriers. These involved primarily interhemispheric connections among regions of olfactory areas, the hippocampus, and the cerebellum. Our results also suggest that pairwise connections may be subdivided and clustered spatially to reveal local changes on a finer scale. These analyses revealed not just genotype, but also sex specific differences. Identifying vulnerable networks may provide targets for interventions, and a means to stratify patients.

BackgroundTendons and ligaments attach to bone are essential for joint mobility and stability in vertebrates. Tendon and ligament attachments (ie, entheses) are found at bony protrusions (ie, eminences), and the shape and size of these protrusions depend on both mechanical forces and cellular cues during growth. Tendon eminences also contribute to mechanical leverage for skeletal muscle. Fibroblast growth factor receptor (FGFR) signaling plays a critical role in bone development, and Fgfr1 and Fgfr2 are highly expressed in the perichondrium and periosteum of bone where entheses can be found.Results and ConclusionsWe used transgenic mice for combinatorial knockout of Fgfr1 and/or Fgfr2 in tendon/attachment progenitors (ScxCre) and measured eminence size and shape. Conditional deletion of both, but not individual, Fgfr1 and Fgfr2 in Scx progenitors led to enlarged eminences in the postnatal skeleton and shortening of long bones. In addition, Fgfr1/Fgfr2 double conditional knockout mice had more variation collagen fibril size in tendon, decreased tibial slope, and increased cell death at ligament attachments. These findings identify a role for FGFR signaling in regulating growth and maintenance of tendon/ligament attachments and the size and shape of bony eminences.

Telemedicine has seen widespread adoption during the COVID-19 pandemic. The implementation of telemedicine projects can be complex, with over 75% of telemedicine initiatives failing in the implementation phase. Health organizations that want to adopt telemedicine as part of their healthcare delivery programs struggle to plan and implement sustainable and scalable initiatives effectively. This paper presents the Telemedicine Program Design Canvas - a tool to guide health organizations in planning telemedicine interventions and drive intervention success. It was developed and validated through six workshops with users and stakeholders of telemedicine. Based on the workshops and the lessons learned from the subsequent interventions of these projects, we identified the fourteen key elements that must be addressed while planning and implementing a telemedicine project. We organized these into a simple visual tool that health organizations could use. The fourteen elements include - the Problem, Ecosystem, Patients, Patient Journey, Patient Engagement & Trust, Providers, Provider Training, Provider Engagement, Channels, Technology, Medicines & Diagnostics, Desired Outcomes, Costs, and Revenues. The tool was then tested and validated by applying it with a new group of six telemedicine projects. Overall, the perspectives of 108 users and stakeholders of telemedicine projects, including organizational leadership, doctors, nurses, midwives, community health workers, patients, policymakers, technologists, legal and finance experts, were included in the development of the tool. The Telemedicine Program Design Canvas provides a structured and straightforward method for the rapid prototyping and holistic planning of telemedicine interventions.

Tendons and ligaments are structural tissues that attach to bone and are essential for joint mobility and stability in vertebrates. Tendon and ligament attachments (i.e., entheses) are often found at bony protrusions (i.e., eminences), and the shape and size of these protrusions depends on both mechanical forces and cellular cues during growth and development. The formation of tendon eminences also contributes to mechanical leverage for skeletal muscle. Fibroblast growth factor receptor (FGFR) signaling plays a critical role in bone development, and Fgfr1 and Fgfr2 are highly expressed in the perichondrium and periosteum of bone where tendon and ligament attachments can be found. However, the role of FGFR signaling in attachment development and maintenance in the limb remains unknown. In this study, we used transgenic mouse models for combinatorial knockout of Fgfr1 and/or Fgfr2 in tendon/ligament and attachment progenitors using ScxCre and measured eminence size and bone shape in the appendicular skeleton. Conditional deletion of both, but not individual, Fgfr1 and Fgfr2 in Scx progenitors led to enlarged eminences in the postnatal appendicular skeleton and smaller secondary ossification centers in long bones. In addition, Fgfr1/Fgfr2 double conditional knockout mice had more variation in the size of collagen fibrils in tendon, narrowed synovial joint spacing, and increased cell death at sites of ligament attachments, as well as decreased plasticity of mature bone compared to age-matched wildtype littermates. These findings identify a role for FGFR signaling in regulating growth and maintenance of tendon/ligament attachments and the size and shape of bony eminences.