Protocol for systematic review and network meta-analysis of comparative effectiveness of surgical interventions for primary congenital glaucoma.

INTRODUCTION: Primary congenital glaucoma (PCG), a type of childhood glaucoma, is primarily treated surgically to lower intraocular pressure (IOP). Failure to intervene could result in partial, or even total, blindness. Various surgical intervention types have been proposed for PCG, though the evidence on comparative effectiveness remains limited. The current protocol is an ongoing network meta-analysis enabling comparative investigation of surgical interventions for which randomised controlled trials (RCTs) are available. Our aim is to systematically compare the efficacy of various types of surgical intervention for patients with PCG. METHODS AND ANALYSIS: Studies of interest will assess the effects of those surgical interventions on surgery-naïve children (age <18 years) suffering PCG. RCTs regardless of language or publication date will be searched from three electronic databases (Cochrane Central Register of Controlled Trials, Embase and MEDLINE) from 4 April 2022. Two reviewers will screen, first, titles and abstracts, followed by full-text papers, for useful data that they will extract. The primary outcome measure will be the IOP-lowering effect of a given surgical intervention. The two reviewers also will assess the internal validity of studies using the relevant and domain-based risk-of-bias assessment tool. Overall evidence quality will be assessed according to the Confidence in Network Meta-Analysis approach and will be presented in summarised form with network diagrams. For enhanced visualisation of the included interventions' effects, forest plots will be constructed. Pairwise effect sizes also will be calculated based on the evidence that is available in the network. ETHICS AND DISSEMINATION: This work will synthesise evidence obtained from published studies, and as such, no ethics review or approval will be required. A paper presenting the findings will be submitted to a peer-reviewed scientific journal for publication. PROSPERO REGISTRATION NUMBER: CRD42022313954.

Kinase-independent role of nuclear RIPK1 in regulating parthanatos through physical interaction with PARP1 upon oxidative stress.

Regulated necrosis occurs in various pathophysiological conditions under oxidative stress. Here, we report that receptor-interacting protein kinase 1 (RIPK1), a key player in one type of regulated necrosis (necroptosis), also participates in another type of poly (ADP-ribose) polymerase 1 (PARP1)-dependent regulated necrosis (parthanatos). Various biological signatures of parthanatos were significantly attenuated in Ripk1-/- mouse embryonic fibroblasts, including PARylation, nuclear translocation of apoptosis-inducing factor, and PARP1-dependent cell death under H2O2 exposure. Hence, we investigated whether RIPK1 regulates the activity of PARP1. RIPK1 activated PARP1 via an interaction with the catalytic domain of PARP1 in the nucleus. Of note, both wild type and kinase-dead mutant RIPK1 induced PARP1 activation and led to PARP1-mediated cell death upon H2O2 insult, demonstrating the kinase-independent regulation of RIPK1 in PARP1 activation. Collectively, our results demonstrate the existence of a kinase-independent role of nuclear RIPK1 in the regulation of PARP1.

A New Instrument for Measuring Tibial Torsion in Pediatric Patients.

OBJECTIVE: To develop and test the validity and reliability of a new instrument for measuring the thigh-foot angle (TFA) for the patients with in-toeing and out-toeing gait. METHODS: The new instrument (Thigh-Foot Supporter [TFS]) was developed by measuring the TFA during regular examination of the tibial torsional status. The study included 40 children who presented with in-toeing and out-toeing gaits. We took a picture of each case to measure photographic-TFA (P-TFA) in the proper position and to establish a criterion. Study participants were examined by three independent physicians (A, B, and C) who had one, three and ten years of experience in the field, respectively. Each examiner conducted a separate classical physical examination (CPE) of every participant using a gait goniometer followed by a TFA assessment of each pediatric patient with or without the TFS. Thirty minutes later, repeated in the same way was measured. RESULTS: Less experienced examiner A showed significant differences between the TFA values depending on whether TFS used (left p=0.003 and right p=0.008). However, experienced examiners B and C did not show significant differences. Using TFS, less experienced examiner A showed a high validity and all examiner's inter-test and the inter-personal reliabilities increased. CONCLUSION: TFS may increase validity and reliability in measuring tibial torsion in patients who has a rotational problem in lower extremities. It would be more useful in less experienced examiners.

Development of elbow spasticity model for objective training of spasticity assessment of patients post stroke.

Reliable assessment is essential for the management of spasticity, one of the most frequent complication of various neurological diseases. For the spasticity assessment, several clinical tools have been developed and widely used in clinics. The most popular one is modified Ashworth scale (MAS). It has a simple protocol, but is subjective and qualitative. To improve its reliability, quantitative measurement and consistent training would be needed. This study presents an elbow spasticity simulator which mimics spastic response of adult post stroke survivors. First, spastic responses (i.e. resistance and joint motion) from patients with a stroke were measured during conventional MAS assessment. Each grade of MAS was quantified by using three parameters representing three characteristics of the spasticity. Based on the parameters, haptic models of MAS were developed for implementing repeatable and consistent haptic training of novice clinicians. Two experienced clinicians participated in preliminary evaluation of the models.

AIF-independent parthanatos in the pathogenesis of dry age-related macular degeneration.

Cell death of retinal pigment epithelium (RPE) is characterized as an essential late-stage phenomenon of dry age-related macular degeneration (AMD). The aim of this study was to elucidate the molecular mechanism underlying RPE cell death after exposure to oxidative stress, which occurs often because of the anatomical location of RPE cells. ARPE-19, an established RPE cell line, exhibited necrotic features involving poly (ADP-ribose) polymerase-1 (PARP-1) activation in response to hydrogen peroxide (H2O2). ARPE-19 cells were resistant to H2O2 when PARP-1 was depleted using siRNA or inhibited by a pharmacological inhibitor of PARP-1, olaparib. Our data suggest a causal relationship between PARP-1 activation and ARPE-19 cell death in response to H2O2. Next, we investigated downstream molecular events in PARP-1 activation. Increased mitochondrial depolarization, mitochondrial fission and alterations of the cellular energy dynamics with reduced NAD+ and ATP were observed in H2O2-treated ARPE-19 cells. H2O2-triggered mitochondrial dysfunction was inhibited by olaparib. Nevertheless, translocation of apoptosis-inducing factor (AIF), a biochemical signature for PARP-1-dependent cell death (parthanatos), was not observed in our study. Moreover, the depletion of AIF did not affect the amplitude of cell death, demonstrating the lack of a role for AIF in the death of ARPE-19 cells in response to H2O2. This feature distinguishes the type of death observed in this study from canonical parthanatos. Next, we examined the in vivo role of PARP-1 in a dry AMD animal model system. Histological analysis of the outer nuclear layer in the mouse retina revealed protection against sodium iodate (SI) following treatment with olaparib. Moreover, retina fundus and electroretinograms also confirmed such a protective effect in the SI-treated rabbit. Collectively, we report that AIF-independent PARP-1-dependent necrosis constitutes a major mechanism of RPE cell death leading to retinal degeneration in dry AMD.