Evaluation of an emergency department Falls Pathway for older people: A patient chart review

The number of older adults presenting to EDs following a fall continues to rise, yet falls management often ignores opportunities for secondary falls risk reduction. Advanced Nurse Practitioners (ANPs) in EDs have an important clinical leadership role in improving outcomes for this group of patients. Aim: This study describes the development of an ANP led falls pathway in an ED to improve safe discharge. It evaluates compliance with the pathway and referrals to community falls prevention services. It also draws comparison with baseline practice as recorded in 2014. Methods: The Falls Pathway involves four steps: 1) screening at triage (3 questions), 2) risk stratification (low, medium, high), 3) risk assessment (lying and standing blood pressure (B/P), timed-up and go (TUG), 4-AT for delirium screening, polypharmacy), and 4) referral to community falls services. We undertook a 12-month chart review of all patients aged 65 years or older presenting following a fall to the ANP service in 2018. We compared data to a baseline audit in 2014; descriptive and Chi squared statistics were used to examine the data. Results: The 2018 audit involved 77 patients representing 27% of ANP caseload. A repeat fall occurred in 42% (32/77) of cases and 35% (22/77) reported a fear of falling. The Falls Pathway was initiated in nearly 80% (62/77) of patients and compliance with falls risk assessment ranged from 42% for lying and standing B/P to 75% for TUG. In 2014, a review of 59 patient charts showed 27% (16/59) experienced a repeat fall, but other risk factors such as fear of falling were not recorded. In 2018, the majority of patients (88%) discharged home were referred to community falls prevention services compared to 22% in 2014. Conclusion: The Falls Pathway improved falls risk assessment in the ED, identified opportunities for risk reduction and optimised referral to community falls services. The pathway continues to be a valuable tool but requires resources for ongoing implementation among the wider ED team

The Deubiquitylase MATH-33 Controls DAF-16 Stability and Function in Metabolism and Longevity

SummaryFOXO family transcription factors are downstream effectors of Insulin/IGF-1 signaling (IIS) and major determinants of aging in organisms ranging from worms to man. The molecular mechanisms that actively promote DAF16/FOXO stability and function are unknown. Here we identify the deubiquitylating enzyme MATH-33 as an essential DAF-16 regulator in IIS, which stabilizes active DAF-16 protein levels and, as a consequence, influences DAF-16 functions, such as metabolism, stress response, and longevity in C. elegans. MATH-33 associates with DAF-16 in cellulo and in vitro. MATH-33 functions as a deubiquitylase by actively removing ubiquitin moieties from DAF-16, thus counteracting the action of the RLE-1 E3-ubiquitin ligase. Our findings support a model in which MATH-33 promotes DAF-16 stability in response to decreased IIS by directly modulating its ubiquitylation state, suggesting that regulated oscillations in the stability of DAF-16 protein play an integral role in controlling processes such as metabolism and longevity

Receptors and Signalling Pathways that Regulate Thymocyte Development

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Paediatrics SHOs attending elective caesarean sections

Paediatrics SHOs attending elective caesarean section

Critical Role for Arginine Methylation in Adenovirus-Infected Cells▿

During the late stages of adenovirus infection, the 100K protein (100K) inhibits the translation of cellular messages in the cytoplasm and regulates hexon trimerization and assembly in the nucleus. However, it is not known how it switches between these two functions. Here we show that 100K is methylated on arginine residues at its C terminus during infection and that this region is necessary for binding PRMT1 methylase. Methylated 100K is exclusively nuclear. Mutation of the third RGG motif (amino acids 741 to 743) prevents localization to the nucleus during infection, suggesting that methylation of that sequence is important for 100K shuttling. Treatment of infected cells with methylation inhibitors inhibits expression of late structural proteins. These data suggest that arginine methylation of 100K is necessary for its localization to the nucleus and is a critical cellular function necessary for productive adenovirus infection

ChromEMT: Visualizing 3D chromatin structure and compaction in interphase and mitotic cells

The chromatin structure of DNA determines genome compaction and activity in the nucleus. On the basis of in vitro structures and electron microscopy (EM) studies, the hierarchical model is that 11-nanometer DNA-nucleosome polymers fold into 30- and subsequently into 120- and 300- to 700-nanometer fibers and mitotic chromosomes. To visualize chromatin in situ, we identified a fluorescent dye that stains DNA with an osmiophilic polymer and selectively enhances its contrast in EM. Using ChromEMT (ChromEM tomography), we reveal the ultrastructure and three-dimensional (3D) organization of individual chromatin polymers, megabase domains, and mitotic chromosomes. We show that chromatin is a disordered 5- to 24-nanometer-diameter curvilinear chain that is packed together at different 3D concentration distributions in interphase and mitosis. Chromatin chains have many different particle arrangements and bend at various lengths to achieve structural compaction and high packing densities

The 4D nucleome project.

The 4D Nucleome Network aims to develop and apply approaches to map the structure and dynamics of the human and mouse genomes in space and time with the goal of gaining deeper mechanistic insights into how the nucleus is organized and functions. The project will develop and benchmark experimental and computational approaches for measuring genome conformation and nuclear organization, and investigate how these contribute to gene regulation and other genome functions. Validated experimental technologies will be combined with biophysical approaches to generate quantitative models of spatial genome organization in different biological states, both in cell populations and in single cells

A Structural Basis for the Assembly and Functions of a Viral Polymer that Inactivates Multiple Tumor Suppressors

Evolution of minimal DNA tumor virus' genomes has selected for small viral oncoproteins that hijack critical cellular protein interaction networks. The structural basis for the multiple and dominant functions of adenovirus oncoproteins has remained elusive. E4-ORF3 forms a nuclear polymer and simultaneously inactivates p53, PML, TRIM24, and MRE11/RAD50/NBS1 (MRN) tumor suppressors. We identify oligomerization mutants and solve the crystal structure of E4-ORF3. E4-ORF3 forms a dimer with a central β core, and its structure is unrelated to known polymers or oncogenes. E4-ORF3 dimer units coassemble through reciprocal and nonreciprocal exchanges of their C-terminal tails. This results in linear and branched oligomer chains that further assemble in variable arrangements to form a polymer network that partitions the nuclear volume. E4-ORF3 assembly creates avidity-driven interactions with PML and an emergent MRN binding interface. This reveals an elegant structural solution whereby a small protein forms a multivalent matrix that traps disparate tumor suppressors