Hearing Results after Transmastoid Superior Semicircular Canal Plugging for Superior Semicircular Canal Dehiscence: A Meta-Analysis.

OBJECTIVE The transmastoid plugging of a superior semicircular canal is considered a safe and effective technique for the management of superior semicircular canal dehiscence (SSCD). The aim of this meta-analysis is to assess the postoperative hearing outcomes after the transmastoid plugging of the superior semicircular canal. Search method and data sources: A systematic database search was performed on the following databases until 30 January 2023: MEDLINE, Embase, Cochrane Library, Web of Science, CINAHL, ICTRP, and clinicaltrials.gov. A systematic literature review and meta-analysis of the pooled data were conducted. We also included a consecutive case series with SCDS for those who underwent transmastoid plugging treatment at our clinic. RESULTS We identified 643 citations and examined 358 full abstracts and 88 full manuscripts. A total of 16 studies were eligible for the systematic review and 11 studies for the meta-analysis. Furthermore, 159 ears (152 patients) were included. The postoperative mean air conduction threshold remained unchanged (mean difference, 2.89 dB; 95% CI: -0.05, 5.84 dB, p = 0.58), while the mean bone conduction threshold was significantly worse (mean difference, -3.53 dB; 95% CI, -6.1, -0.95 dB, p = 0.9). CONCLUSION The transmastoid plugging technique for superior semicircular canal dehiscence syndrome, although minimally worsening the inner ear threshold, is a safe procedure in terms of hearing preservation and satisfactory symptom relief

Twin-shaped CFRP-sandwich pedestrian bridge

A concept of a nature-inspired pedestrian bridge which tries to merge architectural, structural and manufacturing aspects in an optimized way is presented. The 18.0-m-span bridge is designed as an overhead spatial frame of a complex double-curved shape, which is composed of twelve modules consisting of lightweight carbon fiber-reinforced polymer (CFRP) sandwich construction. The modules are fabricated with only one mould through vacuum assisted resin infusion. The aimed visible texture and black colour of the CFRP fabrics represents an essential architectonical element. The resulting benefits and required compromises of this multi-criteria approach are discussed

The immune receptor Tim-3 acts as a trafficker in a Tim-3/galectin-9 autocrine loop in human myeloid leukemia cells

The immune receptor Tim-3 is often highly expressed in human acute myeloid leukemia (AML) cells where it acts as a growth factor and inflammatory receptor. Recently, it has been demonstrated that Tim-3 forms an autocrine loop with its natural ligand galectin-9 in human AML cells. However, the pathophysiological functions of Tim-3 in human AML cells remain unclear. Here, we report for the first time that Tim-3 is required for galectin-9 secretion in human AML cells. However, this effect is cell-type specific and was found so far to be applicable only to myeloid (and not, for example, lymphoid) leukemia cells. We concluded that AML cells might use Tim-3 as a trafficker for the secretion of galectin-9 which can then be possibly used to impair the anticancer activities of cytotoxic T cells and natural killer (NK) cells

Dual roles of mTORC1-dependent activation of the ubiquitin-proteasome system in muscle proteostasis

Muscle size is controlled by the PI3K-PKB/Akt-mTORC1-FoxO pathway, which integrates signals from growth factors, energy and amino acids to activate protein synthesis and inhibit protein breakdown. While mTORC1 activity is necessary for PKB/Akt-induced muscle hypertrophy, its constant activation alone induces muscle atrophy. Here we show that this paradox is based on mTORC1 activity promoting protein breakdown through the ubiquitin-proteasome system (UPS) by simultaneously inducing ubiquitin E3 ligase expression via feedback inhibition of PKB/Akt and proteasome biogenesis via Nuclear Factor Erythroid 2-Like 1 (Nrf1). Muscle growth was restored by reactivation of PKB/Akt, but not by Nrf1 knockdown, implicating ubiquitination as the limiting step. However, both PKB/Akt activation and proteasome depletion by Nrf1 knockdown led to an immediate disruption of proteome integrity with rapid accumulation of damaged material. These data highlight the physiological importance of mTORC1-mediated PKB/Akt inhibition and point to juxtaposed roles of the UPS in atrophy and proteome integrity

Distinct and additive effects of calorie restriction and rapamycin in aging skeletal muscle

Preserving skeletal muscle function is essential to maintain life quality at high age. Calorie restriction (CR) potently extends health and lifespan, but is largely unachievable in humans, making "CR mimetics" of great interest. CR targets nutrient-sensing pathways centering on mTORC1. The mTORC1 inhibitor, rapamycin, is considered a potential CR mimetic and is proven to counteract age-related muscle loss. Therefore, we tested whether rapamycin acts via similar mechanisms as CR to slow muscle aging. Here we show that long-term CR and rapamycin unexpectedly display distinct gene expression profiles in geriatric mouse skeletal muscle, despite both benefiting aging muscles. Furthermore, CR improves muscle integrity in mice with nutrient-insensitive, sustained muscle mTORC1 activity and rapamycin provides additive benefits to CR in naturally aging mouse muscles. We conclude that rapamycin and CR exert distinct, compounding effects in aging skeletal muscle, thus opening the possibility of parallel interventions to counteract muscle aging

Distinct and additive effects of calorie restriction and rapamycin in aging skeletal muscle

As global life expectancy continues to climb, maintaining skeletal muscle function is increasingly essential to ensure a good life quality for aging populations. Calorie restriction (CR) is the most potent and reproducible intervention to extend health and lifespan, but is largely unachievable in humans. Therefore, identification of "CR mimetics" has received much attention. CR targets nutrient-sensing pathways centering on mTORC1. The mTORC1 inhibitor, rapamycin, has been proposed as a potential CR mimetic and is proven to counteract age-related muscle loss. Therefore, we tested whether rapamycin acts via similar mechanisms as CR to slow muscle aging. Contrary to our expectation, long-term CR and rapamycin-treated geriatric mice display distinct skeletal muscle gene expression profiles despite both conferring benefits to aging skeletal muscle. Furthermore, CR improved muscle integrity in a mouse with nutrient-insensitive sustained muscle mTORC1 activity and rapamycin provided additive benefits to CR in aging mouse muscles. Therefore, RM and CR exert distinct, compounding effects in aging skeletal muscle, opening the possibility of parallel interventions to counteract muscle aging

Enabling transformative biodiversity governance in the Post-2020 era

While there are increasing calls for transformative change and transformative governance, what this means in the context of addressing biodiversity loss remains debated. The aim of this edited volume Transforming Biodiversity Governance is to open up this debate and identify ways forward in the context of the implementation of the Post-2020 Global Biodiversity Framework (GBF) of the Convention on Biological Diversity (CBD). To become transformative, biodiversity governance needs to be transformed: yet how and by whom? These questions are urgent, given the fact that around one million species are threatened with extinction (Díaz et al., 2019), despite over half a century of global efforts to avoid this tragedy. By bringing together insights from previous chapters, we here reflect on these questions

Targeting and Function of the Mitochondrial Fission Factor GDAP1 Are Dependent on Its Tail-Anchor

Proteins controlling mitochondrial dynamics are often targeted to and anchored into the mitochondrial outer membrane (MOM) by their carboxyl-terminal tail-anchor domain (TA). However, it is not known whether the TA modulates protein function. GDAP1 is a mitochondrial fission factor with two neighboring hydrophobic domains each flanked by basic amino acids (aa). Here we define GDAP1 as TA MOM protein. GDAP1 carries a single transmembrane domain (TMD) that is, together with the adjacent basic aa, critical for MOM targeting. The flanking N-terminal region containing the other hydrophobic domain is located in the cytoplasm. TMD sequence, length, and high hydrophobicity do not influence GDAP1 fission function if MOM targeting is maintained. The basic aa bordering the TMD in the cytoplasm, however, are required for both targeting of GDAP1 as part of the TA and GDAP1-mediated fission. Thus, this GDAP1 region contains critical overlapping motifs defining intracellular targeting by the TA concomitant with functional aspects

Fast, multiplexable and efficient somatic gene deletions in adult mouse skeletal muscle fibers using AAV-CRISPR/Cas9

Molecular screens comparing different disease states to identify candidate genes rely on the availability of fast, reliable and multiplexable systems to interrogate genes of interest. CRISPR/Cas9-based reverse genetics is a promising method to eventually achieve this. However, such methods are sorely lacking for multi-nucleated muscle fibers, since highly efficient nuclei editing is a requisite to robustly inactive candidate genes. Here, we couple Cre-mediated skeletal muscle fiber-specific Cas9 expression with myotropic adeno-associated virus-mediated sgRNA delivery to establish a system for highly effective somatic gene deletions in mice. Using well-characterized genes, we show that local or systemic inactivation of these genes copy the phenotype of traditional gene-knockout mouse models. Thus, this proof-of-principle study establishes a method to unravel the function of individual genes or entire signaling pathways in adult skeletal muscle fibers without the cumbersome requirement of generating knockout mice.ISSN:2041-172

Delirium in Meningitis and Encephalitis: Emergence and Prediction in a 6-Year Cohort

Data regarding delirium in patients presenting with infections of the central nervous system, such as meningitis and/or encephalitis (ME), are scarce. We aimed to determine the frequency and early predictors of delirium in the acute phase of ME.; We assessed clinical, radiologic, and laboratory data of patients with ME at a Swiss academic medical center from 2011 to 2017. The highest Intensive Care Delirium Screening Checklist (ICDSC) score was assessed within 24 hours around lumbar puncture. Multivariable logistic regression was performed to identify predictors of delirium (ICDSC ≥4).; Among 330 patients with ME, infectious pathogens were identified in 41%. An ICDSC >1 was found in 28% with and 19% without identified infectious pathogens. Delirium was diagnosed in 18% with and 14% without infectious pathogens and significantly associated with prolonged in-hospital treatment and mechanical ventilation, more frequent administration of neuroleptics and anesthetics (in 96% with delirium vs 35% without), complications, and less recovery to premorbid functional baseline. Low serum albumin at presentation was the only independent predictor of delirium (area under the receiver-operating curve [AUROC] = 0.792) in patients with pathogens. In patients with infections, the AUROC was smallest for encephalitis (AUROC = 0.641) and larger for patients with meningeal infections (meningitis AUROC = 0.807; meningoencephalitis AUROC = 0.896).; Delirium in the context of ME is seen in almost every fifth patient and linked to prolonged treatment, complications, and incomplete recovery. Among clinical, radiologic, and laboratory parameters, the good calibration and discrimination of low albumin serum concentrations for the prediction of delirium in patients with ME seem promising, especially if meninges are affected