Clinical information and guidance shared via a patient infotainment system can reduce hospital stay and maintain 2 medical quality for total knee arthroplasty: A single-blinded quasi-randomised controlled trial.

BACKGROUND: The demand for total knee arthroplasty is increasing worldwide. Optimising results and meeting patients' expectations are more challenging than before, because the length of hospitalisation has markedly reduced and the standard care processes have been accelerated. We incorporated an interactive patient infotainment system into the standard clinical pathway for total knee arthroplasty in the hope of improving patients' length of stay. OBJECTIVES: To analyse whether incorporation of an interactive infotainment system reduced the length of stay and improved the quality of medical care (in terms of number of medical orders and emergency room returns). DESIGN: A prospective, quasi-randomised controlled trial. PARTICIPANTS AND SETTING: Data of 86 patients hospitalised for a unilateral total knee arthroplasty at a medical centre in Taiwan were analysed. METHODS: From January 2017 to July 2017, 86 patients who underwent unilateral total knee arthroplasty and were cared for under a standard clinical pathway were included. The study group (41 patients) had access to electronic programs and video demonstrations related to health literacy, physical therapy, home care and precautions following total knee arthroplasty via a patient infotainment system, while the control group (45 patients) did not. Hospital course, quality indices, in-hospital medical costs, returns to the emergency room and readmission at 30 or 90 days were analysed and compared between the two groups of patients. RESULTS: The study group had a shorter length of stay (4.4 vs. 4.8 days, mean differences [MD] = -0.37, 95% CI -0.71 to -0.03, p = 0.026) and fewer medical orders (109 vs 111 orders, MD = -1.86, 95% confidence intervals (CI) -3.58 to -0.15, p = 0.047) as compared with the control group. The incidences of emergency room return and readmission to the hospital at 30 or 90 days were comparable between the two groups. No difference in the total medical cost was found between the two groups, with only the cost of laboratory tests in the study group being significantly lower than that in the control group ($144 vs. $163, MD = -21.7, 95% CI -41.0 to -2.25, p = 0.007). CONCLUSIONS: The incorporation of a patient infotainment system into the standard clinical pathway for total knee arthroplasty can efficiently reduce the length of hospital stay and maintain the quality of medical care. Further studies on improvement of patient medical literacy with the help of the infotainment system would be of interest in order to improve clinical practice and patient satisfaction. REGISTRATION NUMBER: NCT03788798 TWEETABLE ABSTRACT: A patient infotainment system can reduce hospital stay and maintain medical quality for total knee arthroplasty.

PINK1/Parkin Influences Cell Cycle by Sequestering TBK1 at Damaged Mitochondria, Inhibiting Mitosis.

PINK1 and Parkin are established mediators of mitophagy, the selective removal of damaged mitochondria by autophagy. PINK1 and Parkin have been proposed to act as tumor suppressors, as loss-of-function mutations are correlated with enhanced tumorigenesis. However, it is unclear how PINK1 and Parkin act in coordination during mitophagy to influence the cell cycle. Here we show that PINK1 and Parkin genetically interact with proteins involved in cell cycle regulation, and loss of PINK1 and Parkin accelerates cell growth. PINK1- and Parkin-mediated activation of TBK1 at the mitochondria during mitophagy leads to a block in mitosis due to the sequestration of TBK1 from its physiological role at centrosomes during mitosis. Our study supports a diverse role for the far-reaching, regulatory effects of mitochondrial quality control in cellular homeostasis and demonstrates that the PINK1/Parkin pathway genetically interacts with the cell cycle, providing a framework for understanding the molecular basis linking PINK1 and Parkin to mitosis.

Deleterious mitochondrial DNA point mutations are overrepresented in Drosophila expressing a proofreading-defective DNA polymerase γ.

Mitochondrial DNA (mtDNA) mutations cause severe maternally inherited syndromes and the accumulation of somatic mtDNA mutations is implicated in aging and common diseases. However, the mechanisms that influence the frequency and pathogenicity of mtDNA mutations are poorly understood. To address this matter, we created a Drosophila mtDNA mutator strain expressing a proofreading-deficient form of the mitochondrial DNA polymerase. Mutator flies have a dramatically increased somatic mtDNA mutation frequency that correlates with the dosage of the proofreading-deficient polymerase. Mutator flies also exhibit mitochondrial dysfunction, shortened lifespan, a progressive locomotor deficit, and loss of dopaminergic neurons. Surprisingly, the frequency of nonsynonymous, pathogenic, and conserved-site mutations in mutator flies exceeded predictions of a neutral mutational model, indicating the existence of a positive selection mechanism that favors deleterious mtDNA variants. We propose from these findings that deleterious mtDNA mutations are overrepresented because they selectively evade quality control surveillance or because they are amplified through compensatory mitochondrial biogenesis.

Endogenous Parkin Preserves Dopaminergic Substantia Nigral Neurons following Mitochondrial DNA Mutagenic Stress.

Parkinson's disease (PD) is a neurodegenerative disease caused by the loss of dopaminergic neurons in the substantia nigra. PARK2 mutations cause early-onset forms of PD. PARK2 encodes an E3 ubiquitin ligase, Parkin, that can selectively translocate to dysfunctional mitochondria to promote their removal by autophagy. However, Parkin knockout (KO) mice do not display signs of neurodegeneration. To assess Parkin function in vivo, we utilized a mouse model that accumulates dysfunctional mitochondria caused by an accelerated generation of mtDNA mutations (Mutator mice). In the absence of Parkin, dopaminergic neurons in Mutator mice degenerated causing an L-DOPA reversible motor deficit. Other neuronal populations were unaffected. Phosphorylated ubiquitin was increased in the brains of Mutator mice, indicating PINK1-Parkin activation. Parkin loss caused mitochondrial dysfunction and affected the pathogenicity but not the levels of mtDNA somatic mutations. A systemic loss of Parkin synergizes with mitochondrial dysfunction causing dopaminergic neuron death modeling PD pathogenic processes.

High-content genome-wide RNAi screens identify regulators of parkin upstream of mitophagy.

An increasing body of evidence points to mitochondrial dysfunction as a contributor to the molecular pathogenesis of neurodegenerative diseases such as Parkinson's disease. Recent studies of the Parkinson's disease associated genes PINK1 (ref. 2) and parkin (PARK2, ref. 3) indicate that they may act in a quality control pathway preventing the accumulation of dysfunctional mitochondria. Here we elucidate regulators that have an impact on parkin translocation to damaged mitochondria with genome-wide small interfering RNA (siRNA) screens coupled to high-content microscopy. Screening yielded gene candidates involved in diverse cellular processes that were subsequently validated in low-throughput assays. This led to characterization of TOMM7 as essential for stabilizing PINK1 on the outer mitochondrial membrane following mitochondrial damage. We also discovered that HSPA1L (HSP70 family member) and BAG4 have mutually opposing roles in the regulation of parkin translocation. The screens revealed that SIAH3, found to localize to mitochondria, inhibits PINK1 accumulation after mitochondrial insult, reducing parkin translocation. Overall, our screens provide a rich resource to understand mitochondrial quality control.

Abi plays an opposing role to Abl in Drosophila axonogenesis and synaptogenesis.

Abl tyrosine kinase (Abl) regulates axon guidance by modulating actin dynamics. Abelson interacting protein (Abi), originally identified as a kinase substrate of Abl, also plays a key role in actin dynamics, yet its role with respect to Abl in the developing nervous system remains unclear. Here we show that mutations in abi disrupt axonal patterning in the developing Drosophila central nervous system (CNS). However, reducing abi gene dosage by half substantially rescues Abl mutant phenotypes in pupal lethality, axonal guidance defects and locomotion deficits. Moreover, we show that mutations in Abl increase synaptic growth and spontaneous synaptic transmission frequency at the neuromuscular junction. Double heterozygosity for abi and enabled (ena) also suppresses the synaptic overgrowth phenotypes of Abl mutants, suggesting that Abi acts cooperatively with Ena to antagonize Abl function in synaptogenesis. Intriguingly, overexpressing Abi or Ena alone in cultured cells dramatically redistributed peripheral F-actin to the cytoplasm, with aggregates colocalizing with Abi and/or Ena, and resulted in a reduction in neurite extension. However, co-expressing Abl with Abi or Ena redistributed cytoplasmic F-actin back to the cell periphery and restored bipolar cell morphology. These data suggest that abi and Abl have an antagonistic interaction in Drosophila axonogenesis and synaptogenesis, which possibly occurs through the modulation of F-actin reorganization.

The involvement of Abl and PTP61F in the regulation of Abi protein localization and stability and lamella formation in Drosophila S2 cells.

Most aspects of cellular events are regulated by a series of protein phosphorylation and dephosphorylation processes. Abi (Abl interactor protein) functions as a substrate adaptor protein for Abl and a core member of the WAVE complex, relaying signals from Rac to Arp2/3 complex and regulating actin dynamics. It is known that the recruitment of Abi into the lamella promotes polymerization of actin, although how it does this is unclear. In this study, we found PTP61F, a Drosophila homolog of mammalian PTP1B, can reverse the Abl phosphorylation of Abi and colocalizes with Abi in Drosophila S2 cells. Abi can be translocalized from the cytosol to the cell membrane by either increasing Abl or reducing endogenous PTP61F. This reciprocal regulation of Abi phosphorylation is also involved in modulating Abi protein level, which is thought to affect the stability of the WAVE complex. Using mass spectrometry, we identified several important tyrosine phosphorylation sites in Abi. We compared the translocalization and protein half-life of wild type (wt) and phosphomutant Abi and their abilities to restore the lamellipodia structure of the Abi-reduced cells. We found the phosphomutant to have reduced ability to translocalize and to have a protein half-life shorter than that of wt Abi. We also found that although the wt Abi could fully restore the lamellipodia structure, the phosphomutant could not. Together, these findings suggest that the reciprocal regulation of Abi phosphorylation by Abl and PTP61F may regulate the localization and stability of Abi and may regulate the formation of lamella.

Abi enhances Abl-mediated CDC2 phosphorylation and inactivation.

Abelson tyrosine kinase (Abl) is a non-receptor tyrosine kinase which is frequently coupled with adaptor proteins to interact with its substrates for the regulation of cytoskeleton rearrangement, cell growth and apoptosis in response to a variety of biological stimuli. The Abl interactor (Abi) family members were first identified as adaptor proteins of Abl for regulating Abl transforming and kinase activity. In the present study, we used a yeast two-hybrid screen to identify Cdc2 as a novel Abi-binding protein. This finding led us to investigate the role of Abi in linking Abl and Cdc2. These three proteins formed a trimeric complex in Drosophila and mammalian cells. The expression of Abi in cells greatly enhanced the formation of the Abl-Cdc2 complex, suggesting that Abi functions as an adaptor protein facilitating the binding between Abl and Cdc2. We show that Abi promotes Abl-mediated phosphorylation of Cdc2 at tyrosine 15 and inactivation of Cdc2 kinase activity. Furthermore, coexpression of Abl and Abi in Drosophila S2 cells led to suppression of cell growth. These data suggest that Abl signaling may be involved in the downregulation of Cdc2 kinase in cell cycle control.