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Lena Succar,1 Ross A Boadle,2 David C Harris,1,3 Gopala K Rangan1,3 1Centre for Transplant and Renal Research, The Westmead Institute for Medical Research, The University of Sydney, 2Electron Microscopy Laboratory, Institute of Clinical Pathology and Medical Research, Westmead Hospital, 3Department of Renal Medicine, Westmead Hospital, Western Sydney Local Health District, Westmead, Sydney, NSW, Australia Purpose: In crescentic glomerulonephritis (CGN), the development of cellular bridges between podocytes and parietal epithelial cells (PECs) triggers glomerular crescent formation. However, the sequential changes in glomerular ultrastructure in CGN are not well defined. This study investigated the time course of glomerular ultrastructure in experimental CGN. Methods: Transmission electron microscopy (TEM) was performed using kidney samples from rats with nephrotoxic serum nephritis (NSN) from day 1 to day 14. Morphometric analysis was conducted on randomly selected glomeruli captured on TEM digital images. Results: On day 1 of NSN, there was widespread formation of focal contacts between the cell bodies of neighboring podocytes, and tight junctions were evident at the site of cell-to-cell contact. This was confirmed by the increased expression of the tight junction molecule, zonula occludens-1 (ZO-1), which localized to the points of podocyte cell–cell body contact. On day 2, the interpodocyte distance decreased and the glomerular basement membrane thickness increased. Foot process effacement (FPE) was segmental on day 3 and diffuse by day 5, accompanied by the formation of podocyte cellular bridges with Bowman’s capsule, as confirmed by a decrease in podocyte-to-PEC distance. Fibrinoid necrosis and cellular crescents were evident in all glomeruli by days 7 and 14. In vitro, the exposure of podocytes to macrophage-conditioned media altered cellular morphology and caused an intracellular redistribution of ZO-1. Conclusion: The formation of tight junctions between podocytes is an early ultrastructural abnormality in CGN, preceding FPE and podocyte bridge formation and occurring in response to inflammatory injury. Podocyte-to-podocyte tight junction formation may be a compensatory mechanism to maintain the integrity of the glomerular filtration barrier following severe endocapillary injury. Keywords: glomerular, crescent, inflammation, zonula occludens

Explicit incorporation of patients' values and preferences is important in health care decision making. However, there are few data about this topic for patients with chronic kidney disease (CKD). We conducted 9 focus groups (3 each for CKD stages 1 to 5, CKD stage 5D, and CKD stages 1 to 5T). Five major themes were identified: (1) personal meaning of CKD, (2) managing and monitoring health, (3) lifestyle consequences, (4) family impact, and (5) informal support structures. Patients had to adjust to the disruptive and permanent implications of the illness on their physical health, identity, emotions, family, lifestyle, relationships, and employment. The overwhelming fatigue, complex treatment regimens, side effects, and liquid and diet restrictions constrained patients' lives. Patients appreciated specialist care, but described the health care system as nonintegrated and believed they received insufficient information and psychosocial support. Choice of treatments was based on lifestyle, family impact, and physical comfort, seldom on clinical outcomes. Time was needed to comprehend the diagnosis, cope with uncertainty, integrate their treatment regimen into their daily routine, and reestablish a sense of normality in their lives. Rather than focusing on clinical targets, greater attention may need to be given to providing information and psychosocial and practical support at a patient-level not organ-specific level, to maximize patient quality of life. Copyright © 2009 National Kidney Foundation, Inc. [ABSTRACT FROM AUTHOR]

Plasmacytoid dendritic cells play important roles in inducing immune tolerance, preventing allograft rejection, and regulating immune responses in both autoimmune disease and graft-versus-host disease. In order to evaluate a possible protective effect of plasmacytoid dendritic cells against renal inflammation and injury, we purified these cells from mouse spleens and adoptively transferred lipopolysaccharide (LPS)-treated cells, modified ex vivo, into mice with adriamycin nephropathy. These LPS-treated cells localized to the kidney cortex and the lymph nodes draining the kidney, and protected the kidney from injury during adriamycin nephropathy. Glomerulosclerosis, tubular atrophy, interstitial expansion, proteinuria, and creatinine clearance were significantly reduced in mice with adriamycin nephropathy subsequently treated with LPS-activated plasmacytoid dendritic cells as compared to the kidney injury in mice given naive plasmacytoid dendritic cells. In addition, LPS-pretreated cells, but not naive plasmacytoid dendritic cells, convert CD4+CD25- T cells into Foxp3+ regulatory T cells and suppress the proinflammatory cytokine production of endogenous renal macrophages. This may explain their ability to protect against renal injury in adriamycin nephropathy. [ABSTRACT FROM AUTHOR]

Objectives: Hearing loss is highly prevalent in older adults and is independently associated with accelerated cognitive decline. Cochlear implants are usually the only effective treatment for people with severe-profound hearing loss, who have the highest risk of cognitive decline and dementia, however, very few receive them. Current evidence of the effects of cochlear implant use on cognitive decline/dementia outcomes is limited and unclear. This study aimed to investigate the effect of cochlear implant use on longitudinal cognitive performance, as this intervention may be an effective method of modifying cognitive outcomes for older adults with significant hearing loss., Methods: This prospective longitudinal observational study investigated cognitive performance in a convenience sample of older adults (mean age 74 years) with cochlear implants over 4.5 years post-implantation, comparing this with that of community-living adults with untreated hearing loss/normal hearing over 3 years (Australian Imaging, Biomarker and Lifestyle Flagship Study of Ageing; AIBL). All participants were assessed at 18-month intervals from baseline using the same measures. Panel regression was used to compare cognitive trajectories., Results: Cochlear implant users demonstrated significantly improved performance in executive function and working memory, as well as stability in attention, psychomotor function, and visual learning at 4.5-year follow-up. Comparatively, AIBL participants showed significantly greater worsening performance per year in attention and psychomotor function, and stability in working memory and visual learning at 3-year follow-up., Conclusions: Cochlear implant use may delay cognitive decline and/or improve cognitive performance in older adults with severe-profound hearing loss, providing proof-of-concept evidence of the positive effects of hearing intervention on cognitive performance in older adults with hearing loss.

Mild traumatic brain injury (mTBI) or concussion is a substantial health problem globally, with up to 15% of patients experiencing persisting symptoms that can significantly impact quality of life. Currently, the diagnosis of mTBI relies on clinical presentation with ancillary neuroimaging to exclude more severe forms of injury. However, identifying patients at risk for a poor outcome or protracted recovery is challenging, in part due to the lack of early objective tests that reflect the relevant underlying pathology. While the pathophysiology of mTBI is poorly understood, axonal damage caused by rotational forces is now recognized as an important consequence of injury. Moreover, serum measurement of the neurofilament light (NfL) protein has emerged as a potentially promising biomarker of injury. Understanding the pathological processes that determine serum NfL dynamics over time, and the ability of NfL to reflect underlying pathology will be critical for future clinical research aimed at reducing the burden of disability after mild TBI. Using a gyrencephalic model of head rotational acceleration scaled to human concussion, we demonstrate significant elevations in serum NfL, with a peak at 3 days post-injury. Moreover, increased serum NfL was detectable out to 2 weeks post-injury, with some evidence it follows a biphasic course. Subsequent quantitative histological examinations demonstrate that axonal pathology, including in the absence of neuronal somatic degeneration, was the likely source of elevated serum NfL. However, the extent of axonal pathology quantified via multiple markers did not correlate strongly with the extent of serum NfL. Interestingly, the extent of blood-brain barrier (BBB) permeability offered more robust correlations with serum NfL measured at multiple time points, suggesting BBB disruption is an important determinant of serum biomarker dynamics after mTBI. These data provide novel insights to the temporal course and pathological basis of serum NfL measurements that inform its utility as a biomarker in mTBI., Competing Interests: Declarations. Ethics approval and consent to participate: All in vivo experiments were conducted in accordance with protocols approved by The University of Pennsylvania Institutional Animal Care and Use Committee. Consent for publication: Not applicable. Competing interests: Dr. Ramon Diaz-Arrastia has consulted with MesoScale Discoveries and BrainBox Solutions, Inc. Dr. Douglas Smith has consulted with Abbott Laboratories., (© 2024. The Author(s).)

Vaccines have historically played a pivotal role in controlling epidemics. Effective vaccines for viruses causing significant human disease, e.g. , Ebola, Lassa fever, or Crimean Congo hemorrhagic fever virus, would be invaluable to public health strategies and counter-measure development missions. Here, we propose coverage metrics to quantify vaccine-induced CD8 + T cell-mediated immune protection, as well as metrics to characterize immuno-dominant epitopes, in light of human genetic heterogeneity and viral evolution. Proof-of-principle of our approach and methods are demonstrated for Ebola virus, SARS-CoV-2, and Burkholderia pseudomallei (vaccine) proteins., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could beconstrued as a potential conflict of interest., (Copyright © 2024 Harris, Shanker, Montoya, Llewellyn, Matuszak, Lohar, Kubicek-Sutherland, Li, Wilding, Mcmahon, Gnanakaran, Ribeiro, Perelson and Molina-París.)

Background: The International Society of Nephrology proposes an acute kidney disease (AKD) management strategy that includes a risk score to aid AKD identification in low- and low-middle-income countries (LLMICs). We investigated the performance of the risk score and determined kidney and patient outcomes from AKD at multiple LLMIC sites., Methods and Findings: Adult patients presenting to healthcare facilities in Bolivia, Brazil, South Africa, and Nepal were screened using a symptom-based risk score and clinical judgment. Those at AKD risk underwent serum creatinine testing, predominantly with a point-of-care (POC) device. Clinical data were collected prospectively between September 2018 and November 2020. We analyzed risk score performance and determined AKD outcomes at discharge and over follow-up of 90 days. A total of 4,311 patients were at increased risk of AKD, and 2,922 (67.8%) had AKD confirmed. AKD prevalence was 80.2% in patients enrolled based on the risk score and 32.5% when enrolled on clinical judgment alone (p < 0.0001). The area under the receiver operating characteristic curve was 0.73 for the risk score to detect AKD. Death during admission occurred in 84 (2.9%) patients with AKD and 3 (0.2%) patients without kidney disease (p < 0.0001). Death after discharge occurred in 206 (9.7%) AKD patients, and 1865 AKD patients underwent reassessment of kidney function after discharge; 902 (48.4%) patients had persistent kidney disease including 740 (39.7%) patients reclassified with de novo or previously undiagnosed chronic kidney disease (CKD). The study was pragmatically designed to assess outcomes as part of routine healthcare, and there was heterogeneity in clinical practice and outcomes between sites, in addition to selection bias during cohort identification., Conclusions: The use of a risk score can aid AKD identification in LLMICs. High rates of persistent kidney disease and mortality after discharge highlight the importance of AKD follow-up in low-resource settings., Competing Interests: RE has received honoraria from Therakos. EB has received honoraria from Baxter and AstraZeneca. Other authors have no conflicts to declare., (Copyright: © 2024 Evans et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: With an aging population, the prevalence of hearing loss and dementia are increasing rapidly. Hearing loss is currently considered the largest potentially modifiable risk factor for dementia. The effect of hearing interventions on cognitive function should therefore be investigated, as if effective, these may be successfully implemented to modify cognitive outcomes for older adults with hearing loss., Methods: This prospective longitudinal observational cohort study compared outcomes of a convenience sample of prospectively recruited first-time hearing aid users without dementia from an audiology center with those of community-living older adults participating in a large prospective longitudinal cohort study with/without hearing loss and/or hearing aids. All participants were assessed at baseline, 18 months, and 36 months using the same measures., Results: Participants were 160 audiology clinic patients (48.8% female patient; mean age 73.5 years) with mild-severe hearing loss, fitted with hearing aids at baseline, and 102 participants of the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Aging (AIBL) (55.9% female patient; mean age 74.5 years). 18- and 36-month outcomes of subsets of the first participants to reach these points and complete the cognition assessment to date are compared. Primary comparative analysis showed cognitive stability for the hearing aid group while the AIBL group declined on working memory, visual attention, and psychomotor function. There was a non-significant trend for decline in visual learning for the AIBL group versus no decline for the hearing aid group. The hearing aid group showed significant decline on only 1 subtest and at a significantly slower rate than for the AIBL participants ( p  < 0.05). When education effects on cognitive trajectory were controlled, the HA group still performed significantly better on visual attention and psychomotor function (lower educated participants only) compared to the AIBL group but not on working memory or visual learning. Physical activity had no effect on cognitive performance trajectory., Conclusion: Hearing aid users demonstrated significantly better cognitive performance to 3 years post-fitting, suggesting that hearing intervention may delay cognitive decline/dementia onset in older adults. Further studies using appropriate measures of cognition, hearing, and device use, with longer follow-up, are required., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. JS declared that they were an editorial board member of Frontiers at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Sarant, Busby, Schembri, Fowler and Harris.)

Glioblastoma (GBM) is an aggressive primary brain cancer that currently has minimally effective treatments. Like other cancers, immunosuppression by the PD-L1-PD-1 immune checkpoint complex is a prominent axis by which glioma cells evade the immune system. Myeloid-derived suppressor cells (MDSCs), which are recruited to the glioma microenviroment, also contribute to the immunosuppressed GBM microenvironment by suppressing T cell functions. In this paper, we propose a GBM-specific tumor-immune ordinary differential equations model of glioma cells, T cells, and MDSCs to provide theoretical insights into the interactions between these cells. Equilibrium and stability analysis indicates that there are unique tumorous and tumor-free equilibria which are locally stable under certain conditions. Further, the tumor-free equilibrium is globally stable when T cell activation and the tumor kill rate by T cells overcome tumor growth, T cell inhibition by PD-L1-PD-1 and MDSCs, and the T cell death rate. Bifurcation analysis suggests that a treatment plan that includes surgical resection and therapeutics targeting immune suppression caused by the PD-L1-PD1 complex and MDSCs results in the system tending to the tumor-free equilibrium. Using a set of preclinical experimental data, we implement the approximate Bayesian computation (ABC) rejection method to construct probability density distributions that estimate model parameters. These distributions inform an appropriate search curve for global sensitivity analysis using the extended fourier amplitude sensitivity test. Sensitivity results combined with the ABC method suggest that parameter interaction is occurring between the drivers of tumor burden, which are the tumor growth rate and carrying capacity as well as the tumor kill rate by T cells, and the two modeled forms of immunosuppression, PD-L1-PD-1 immune checkpoint and MDSC suppression of T cells. Thus, treatment with an immune checkpoint inhibitor in combination with a therapeutic targeting the inhibitory mechanisms of MDSCs should be explored., (© 2023. The Author(s).)

Background: In autosomal dominant polycystic kidney disease (ADPKD) impaired nitric oxide (NO) synthesis, in part, contributes to early-onset hypertension. Beetroot juice (BRJ) reduces blood pressure (BP) by increasing NO-mediated vasodilation. The aim of this double-blind, randomised, placebo-controlled study is to test the hypothesis that BRJ reduces systolic and diastolic clinic BP in hypertensive adults with ADPKD., Methods: Participants with ADPKD and treated hypertension (n = 60) will be randomly allocated (1:1) to receive a daily dose of either nitrate-replete (400 mg nitrate/day) or nitrate-deplete BRJ for 4 weeks. The co-primary outcomes are change in mean systolic and diastolic clinic BP before and after 4 weeks of treatment with daily BRJ. Secondary outcomes are changes in daily home BP, urinary albumin to creatinine ratio, serum and salivary nitrate/nitrite levels and serum asymmetric dimethylarginine levels before and after 4 weeks of BRJ., Discussion: The effect of BRJ in ADPKD has not been previously tested. BRJ is an accessible, natural dietary supplement that, if effective, will provide a novel adjunctive approach for treating hypertension in ADPKD., Trial Registration: ClinicalTrials.gov NCT05401409. Retrospectively registered on 27th May 2022., (© 2023. Crown.)

The bacterial colony is a powerful experimental platform for broad biological research, and reaction-diffusion models are widely used to study the mechanisms of its formation process. However, there are still some crucial factors that drastically affect the colony growth but are not considered in the current models, such as the non-homogeneously distributed nutrient within the colony and the substantially decreasing expansion rate caused by agar dehydration. In our study, we propose two plausible reaction-diffusion models (the VN and MVN models) based on the above two factors and validate them against experimental data. Both models provide a plausible description of the non-homogeneously distributed nutrient within the colony and outperform the classical Fisher-Kolmogorov equation and its variation in better describing experimental data. Moreover, by accounting for agar dehydration, the MVN model captures how a colony's expansion slows down and the change of a colony's height profile over time. Furthermore, we demonstrate the existence of a traveling wave solution for the VN model., (© 2023. The Author(s), under exclusive licence to Society for Mathematical Biology.)

National strategies for addressing chronic kidney disease (CKD) are crucial to improving kidney health. We sought to describe country-level variations in non-communicable disease (NCD) strategies and CKD-specific policies across different regions and income levels worldwide. The International Society of Nephrology Global Kidney Health Atlas (GKHA) was a multinational cross-sectional survey conducted between July and October 2018. Responses from key opinion leaders in each country regarding national NCD strategies, the presence and scope of CKD-specific policies, and government recognition of CKD as a health priority were described overall and according to region and income level. 160 countries participated in the GKHA survey, comprising 97.8% of the world's population. Seventy-four (47%) countries had an established national NCD strategy, and 53 (34%) countries reported the existence of CKD-specific policies, with substantial variation across regions and income levels. Where CKD-specific policies existed, non-dialysis CKD care was variably addressed. 79 (51%) countries identified government recognition of CKD as a health priority. Low- and low-middle income countries were less likely to have strategies and policies for addressing CKD and have governments which recognise it as a health priority. The existence of CKD-specific policies, and a national NCD strategy more broadly, varied substantially across different regions around the world but was overall suboptimal, with major discrepancies between the burden of CKD in many countries and governmental recognition of CKD as a health priority. Greater recognition of CKD within national health policy is critical to improving kidney healthcare globally., Competing Interests: Outside the submitted work, BLN has received fees for advisory boards, scientific presentations, steering committee roles and travel support from AstraZeneca, Bayer, Boehringer and Ingelheim, and Janssen with all honoraria paid to his institution; AL and serves as a scientific advisor to Boehringer Ingelheim, AstraZeneca, and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); is on the data safety and monitoring board for the NIDDK, Kidney Precision Medicine, University of Washington Kidney Research Institute Scientific Advisory Committee; is funded by the Canadian Institute of Health Research and Kidney Foundation of Canada; PH reports grants from Chiesi Pharmaceuticals; VJ has research grants from Baxter, GSK and reports Consultancy and Advisory Board honoraria from Baxter Healthcare, and AstraZeneca; KK-Z has received honoraria and/or support from Abbott, Abbvie, ACI Clinical (Cara Therapeutics), Akebia, Alexion, Amgen, Ardelyx, ASN (American Society of Nephrology), Astra-Zeneca, Aveo, BBraun, Chugai, Cytokinetics, Daiichi, DaVita, Fresenius, Genentech, GSK, Haymarket Media, Hofstra Medical School, IFKF (International Federation of Kidney Foundations), ISH (International Society of Hemodialysis), International Society of Renal Nutrition & Metabolism (ISRNM), JSDT (Japanese Society of Dialysis Therapy), Hospira, Kabi, Keryx, Kissei, Novartis, Novo-Nordisk, OPKO, NIH (National Institutes of Health), NKF (National Kidney Foundations), Pfizer, Regulus, Relypsa, Resverlogix, Dr Schaer, Sandoz, Sanofi, Shire, VA (Veterans’ Affairs), Takeda, Vifor, UpToDate, ZS-Pharma; PGK reports conference attendance support from Amgen Australia and honorarium from Bayer Australia; SK is Director of the Real World Evidence Consortium that conducts investigator initiated industry funded projects (Allergan, Purdue, GSK, CSL, Lundbeck, NovoNordisk, Jansen, Bayer); CPK has received consulting fees from Abbott, Akebia, Astra-Zeneca, Bayer, Cara Therapeutics, CSL Behring, Rockwell and Vifor; JP reports grants and personal fees from Baxter Healthcare, Fresenius Medical Care, and Davita Healthcare partner; RTK reports personal fees from Baxter; AY-MW reports grants from Sanofi and Otsuka; MHZ has been a consultant or advisory committee member for GSK, AstraZeneca, Roche, and Bayer; KJJ reports personal fees from Fresenius Medical Care; VP has received fees for advisory boards, steering committee roles, or scientific presentations from AbbVie, Astellas, AstraZeneca, Bayer, Baxter, BMS, Boehringer Ingelheim, Dimerix, Durect, Eli Lilly, Gilead, GSK, Janssen, Merck, Mitsubishi Tanabe, Mundipharma, Novartis, Novo Nordisk, Pfizer, Pharmalink, Relypsa, Retrophin, Sanofi, Servier, Tricida, and Vifor. MT reports grants from the Canadian Institutes for Health Research during conduct of the study; DWJ has received consultancy fees, research grants, speaker’s honoraria and travel sponsorships from Baxter Healthcare and Fresenius Medical Care, consultancy fees from Astra Zeneca, Bayer, and AWAK, speaker’s honoraria from ONO and BI & Lilly, and travel sponsorships from Ono and Amgen. He is a current recipient of an Australian National Health and Medical Research Council Leadership Investigator Grant., (Copyright: © 2023 Neuen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The entomopathogenic fungi Batkoa major and Beauveria bassiana caused co-epizootics in populations of invasive spotted lanternflies, Lycorma delicatula, in 2018 in northeastern North America. Although first described from North America in 1888, the biology and ecology of Batkoa major had not been studied since that time. This entomophthoralean fungus found infecting L. delicatula in 2018 produces conidia and rhizoids similar in appearance to the original description. We conducted laboratory bioassays to investigate infection of different ages and sexes of these planthoppers, inoculating via showered conidia. All nymphs, and male and female adults were susceptible, dying in 4.3-6.7 days. Adult males died more quickly than adult females or fourth instars. Batkoa major grew out of cadavers of adult males more frequently than adult females or fourth instar nymphs. Rhizoids that provide attachment of cadavers to substrates were produced from adult cadavers more frequently than conidia. Resting spores were not observed in vivo or in vitro in the lab, or in the field., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Kidney transplantation (KT) is the optimal treatment for kidney failure and is associated with better quality of life and survival relative to dialysis. However, knowledge of the current capacity of countries to deliver KT is limited. This study reports on findings from the 2018 International Society of Nephrology Global Kidney Health Atlas survey, specifically addressing the availability, accessibility, and quality of KT across countries and regions., Methods: Data were collected from published online sources, and a survey was administered online to key stakeholders. All country-level data were analyzed by International Society of Nephrology region and World Bank income classification., Results: Data were collected via a survey in 182 countries, of which 155 answered questions pertaining to KT. Of these, 74% stated that KT was available, with a median incidence of 14 per million population (range: 0.04-70) and median prevalence of 255 per million population (range: 3-693). Accessibility of KT varied widely; even within high-income countries, it was disproportionately lower for ethnic minorities. Universal health coverage of all KT treatment costs was available in 31%, and 57% had a KT registry., Conclusions: There are substantial variations in KT incidence, prevalence, availability, accessibility, and quality worldwide, with the lowest rates evident in low- and lower-middle income countries. Understanding these disparities will inform efforts to increase awareness and the adoption of practices that will ensure high-quality KT care is provided around the world., Competing Interests: D.W.J. has received consultancy fees, research grants, speaker’s honoraria, and travel sponsorships from Baxter Healthcare and Fresenius Medical Care; consultancy fees from Astra Zeneca and AWAK, speaker’s honoraria and travel sponsorships from ONO; and travel sponsorships from Amgen. He is a current recipient of an Australian National Health and Medical Research Council Leadership Investigator Grant. V.J. has received grants, speaker honoraria, or consultancy fees from GlaxoSmithKline, Biocon, Baxter, Janssen, Medtronic, and NephroPlus. He has a policy of all funds being paid to his employer. A.K.B. has received consultancy fees from Janssen. The International Society of Nephrology provided administrative support for the design and implementation of the study and data collection activities. The authors were responsible for data management, analysis, and interpretation, as well as article preparation, review, and approval and the decision to submit the article for publication. The remaining authors have no conflicts of interest to declare., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

We describe a preliminary effort to model the growth and progression of glioblastoma multiforme, an aggressive form of primary brain cancer, in patients undergoing treatment for recurrence of tumor following initial surgery and chemoradiation. Two reaction-diffusion models are used: the Fisher-Kolmogorov equation and a 2-population model, developed by the authors, that divides the tumor into actively proliferating and quiescent (or necrotic) cells. The models are simulated on 3-dimensional brain geometries derived from magnetic resonance imaging (MRI) scans provided by the Barrow Neurological Institute. The study consists of 17 clinical time intervals across 10 patients that have been followed in detail, each of whom shows significant progression of tumor over a period of 1 to 3 months on sequential follow up scans. A Taguchi sampling design is implemented to estimate the variability of the predicted tumors to using 144 different choices of model parameters. In 9 cases, model parameters can be identified such that the simulated tumor, using both models, contains at least 40 percent of the volume of the observed tumor. We discuss some potential improvements that can be made to the parameterizations of the models and their initialization.

Background: Hearing loss is independently associated with a faster rate of cognitive decline in older adults and has been identified as a modifiable risk factor for dementia. The mechanism for this association is unknown, and there has been limited exploration of potential casual pathology., Objective: Our objective was to investigate whether there was an association between degree of audiometrically measured hearing loss (HL) and brain amyloid-β (Aβ) in a pre-clinical sample., Methods: Participants of the Australian Imaging and Biomarker Longitudinal Study (AIBL; n = 143) underwent positron emission tomography (PET) imaging and objective measurement of hearing thresholds within 5 years of imaging, as well as cognitive assessment within 2 years of imaging in this observational cohort study., Results: With one exception, study participants who had cognitive assessments within 2 years of their PET imaging (n = 113) were classified as having normal cognition. There was no association between cognitive scores and degree of hearing loss, or between cognitive scores and Aβ load. No association between HL and Aβ load was found once age was controlled for. As previously reported, positive Apolipoprotein E4 (APOE4) carrier status increased the risk of being Aβ positive (p = 0.002)., Conclusion: Degree of HL was not associated with positive Aβ status.

Background: Health information systems (HIS) are fundamental tools for the surveillance of health services, estimation of disease burden and prioritization of health resources. Several gaps in the availability of HIS for kidney disease were highlighted by the first iteration of the Global Kidney Health Atlas., Methods: As part of its second iteration, the International Society of Nephrology conducted a cross-sectional global survey between July and October 2018 to explore the coverage and scope of HIS for kidney disease, with a focus on kidney replacement therapy (KRT)., Results: Out of a total of 182 invited countries, 154 countries responded to questions on HIS (85% response rate). KRT registries were available in almost all high-income countries, but few low-income countries, while registries for non-dialysis chronic kidney disease (CKD) or acute kidney injury (AKI) were rare. Registries in high-income countries tended to be national, in contrast to registries in low-income countries, which often operated at local or regional levels. Although cause of end-stage kidney disease, modality of KRT and source of kidney transplant donors were frequently reported, few countries collected data on patient-reported outcome measures and only half of low-income countries recorded process-based measures. Almost no countries had programs to detect AKI and practices to identify CKD-targeted individuals with diabetes, hypertension and cardiovascular disease, rather than members of high-risk ethnic groups., Conclusions: These findings confirm significant heterogeneity in the global availability of HIS for kidney disease and highlight important gaps in their coverage and scope, especially in low-income countries and across the domains of AKI, non-dialysis CKD, patient-reported outcomes, process-based measures and quality indicators for KRT service delivery., (© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Objectives: The Global Kidney Health Atlas (GKHA) is a multinational, cross-sectional survey designed to assess the current capacity for kidney care across all world regions. The 2017 GKHA involved 125 countries and identified significant gaps in oversight, funding and infrastructure to support care for patients with kidney disease, especially in lower-middle-income countries. Here, we report results from the survey for the second iteration of the GKHA conducted in 2018, which included specific questions about health financing and oversight of end-stage kidney disease (ESKD) care worldwide., Setting: A cross-sectional global survey., Participants: Key stakeholders from 182 countries were invited to participate. Of those, stakeholders from 160 countries participated and were included., Primary Outcomes: Primary outcomes included cost of kidney replacement therapy (KRT), funding for dialysis and transplantation, funding for conservative kidney management, extent of universal health coverage, out-of-pocket costs for KRT, within-country variability in ESKD care delivery and oversight systems for ESKD care. Outcomes were determined from a combination of desk research and input from key stakeholders in participating countries., Results: 160 countries (covering 98% of the world's population) responded to the survey. Economic factors were identified as the top barrier to optimal ESKD care in 99 countries (64%). Full public funding for KRT was more common than for conservative kidney management (43% vs 28%). Among countries that provided at least some public coverage for KRT, 75% covered all citizens. Within-country variation in ESKD care delivery was reported in 40% of countries. Oversight of ESKD care was present in all high-income countries but was absent in 13% of low-income, 3% of lower-middle-income, and 10% of upper-middle-income countries., Conclusion: Significant gaps and variability exist in the public funding and oversight of ESKD care in many countries, particularly for those in low-income and lower-middle-income countries., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Fibrosis is characterized by progressively excessive deposition of matrix components and may lead to organ failure. Transforming growth factor-β (TGF-β) is a key cytokine involved in tissue repair and fibrosis. TGF-β's profibrotic signaling pathways converge at activation of β-catenin. β-Catenin is an important transcription cofactor whose function depends on its binding partner. Promoting β-catenin binding to forkhead box protein O (Foxo) via inhibition of its binding to T-cell factor (TCF) reduces kidney fibrosis in experimental murine models. Herein, we investigated whether β-catenin/Foxo diverts TGF-β signaling from profibrotic to physiological epithelial healing. In an in vitro model of wound healing (scratch assay), and in an in vivo model of kidney injury, unilateral renal ischemia reperfusion, TGF-β treatment in combination with either ICG-001 or iCRT3 (β-catenin/TCF inhibitors) increased β-catenin/Foxo interaction, increased scratch closure by increased cell proliferation and migration, reduced the TGF-β-induced mesenchymal differentiation, and healed the ischemia reperfusion injury with less fibrosis. In addition, administration of ICG-001 or iCRT3 reduced the contractile activity induced by TGF-β in C1.1 cells. Together, our results indicate that redirection of β-catenin binding from TCF to Foxo promotes β-catenin/Foxo-mediated epithelial repair. Targeting β-catenin/Foxo may rebuild normal structure of injured kidney., (Copyright © 2021 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Rationale & Objective: Approximately 11% of people with kidney failure worldwide are treated with peritoneal dialysis (PD). This study examined PD use and practice patterns across the globe., Study Design: A cross-sectional survey., Setting & Participants: Stakeholders including clinicians, policy makers, and patient representatives in 182 countries convened by the International Society of Nephrology between July and September 2018., Outcomes: PD use, availability, accessibility, affordability, delivery, and reporting of quality outcome measures., Analytical Approach: Descriptive statistics., Results: Responses were received from 88% (n=160) of countries and there were 313 participants (257 nephrologists [82%], 22 non-nephrologist physicians [7%], 6 other health professionals [2%], 17 administrators/policy makers/civil servants [5%], and 11 others [4%]). 85% (n=156) of countries responded to questions about PD. Median PD use was 38.1 per million population. PD was not available in 30 of the 156 (19%) countries responding to PD-related questions, particularly in countries in Africa (20/41) and low-income countries (15/22). In 69% of countries, PD was the initial dialysis modality for≤10% of patients with newly diagnosed kidney failure. Patients receiving PD were expected to pay 1% to 25% of treatment costs, and higher (>75%) copayments (out-of-pocket expenses incurred by patients) were more common in South Asia and low-income countries. Average exchange volumes were adequate (defined as 3-4 exchanges per day or the equivalent for automated PD) in 72% of countries. PD quality outcome monitoring and reporting were variable. Most countries did not measure patient-reported PD outcomes., Limitations: Low responses from policy makers; limited ability to provide more in-depth explanations underpinning outcomes from each country due to lack of granular data; lack of objective data., Conclusions: Large inter- and intraregional disparities exist in PD availability, accessibility, affordability, delivery, and reporting of quality outcome measures around the world, with the greatest gaps observed in Africa and South Asia., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)

Rationale & Objective: Hemodialysis (HD) is the most common form of kidney replacement therapy. This study aimed to examine the use, availability, accessibility, affordability, and quality of HD care worldwide., Study Design: A cross-sectional survey., Setting & Participants: Stakeholders (clinicians, policy makers, and consumer representatives) in 182 countries were convened by the International Society of Nephrology from July to September 2018., Outcomes: Use, availability, accessibility, affordability, and quality of HD care., Analytical Approach: Descriptive statistics., Results: Overall, representatives from 160 (88%) countries participated. Median country-specific use of maintenance HD was 298.4 (IQR, 80.5-599.4) per million population (pmp). Global median HD use among incident patients with kidney failure was 98.0 (IQR, 81.5-140.8) pmp and median number of HD centers was 4.5 (IQR, 1.2-9.9) pmp. Adequate HD services (3-4 hours 3 times weekly) were generally available in 27% of low-income countries. Home HD was generally available in 36% of high-income countries. 32% of countries performed monitoring of patient-reported outcomes; 61%, monitoring of small-solute clearance; 60%, monitoring of bone mineral markers; 51%, monitoring of technique survival; and 60%, monitoring of patient survival. At initiation of maintenance dialysis, only 5% of countries used an arteriovenous access in almost all patients. Vascular access education was suboptimal, funding for vascular access procedures was not uniform, and copayments were greater in countries with lower levels of income. Patients in 23% of the low-income countries had to pay >75% of HD costs compared with patients in only 4% of high-income countries., Limitations: A cross-sectional survey with possibility of response bias, social desirability bias, and limited data collection preventing in-depth analysis., Conclusions: In summary, findings reveal substantial variations in global HD use, availability, accessibility, quality, and affordability worldwide, with the lowest use evident in low- and lower-middle-income countries., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)

β-Catenin is an important co-factor which binds multiple transcriptional molecules and mediates fibrogenic signaling pathways. Its role in kidney transplantation is unknown. We quantified binding of β-catenin within renal tubular epithelial cells to transcription factors, TCF1 and FoxO1, using a proximity ligation assay in 240 transplanted kidneys, and evaluated their pathological and clinical outcomes. β-Catenin/FoxO1 binding in 1-month protocol biopsies inversely correlated with contemporaneous chronic fibrosis, subsequent inflammation. and inflammatory fibrosis (P < .001). The relative binding of β-catenin/TCF1 versus β-catenin/FoxO1 (TF ratio) was the optimal biomarker, and abnormal in diverse fibrotic transplant diseases. A high 1-month TF ratio was followed by greater tubular atrophy and interstitial fibrosis scores, cortical inflammation, renal impairment, and proteinuria at 1 year (n = 131, all P < .001). The TF ratio was associated with reduced eGFR (AUC 0.817), mild fibrosis (AUC 0.717), and moderate fibrosis (AUC 0.769) using receiver operating characteristic analysis. An independent validation cohort (n = 76) confirmed 1-month TF was associated with 12-month moderate fibrosis (15.8% vs. 2.6%, P = .047), however, not with other outcomes or 10-year graft survival, which limits generalizabilty of these findings. In summary, differential binding of β-catenin to TCF1 rather than FoxO1 in renal tubular cells was associated with the fibrogenic response in transplanted kidneys., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background and Objectives: People with kidney failure typically receive KRT in the form of dialysis or transplantation. However, studies have suggested that not all patients with kidney failure are best suited for KRT. Additionally, KRT is costly and not always accessible in resource-restricted settings. Conservative kidney management is an alternate kidney failure therapy that focuses on symptom management, psychologic health, spiritual care, and family and social support. Despite the importance of conservative kidney management in kidney failure care, several barriers exist that affect its uptake and quality., Design, Setting, Participants, & Measurements: The Global Kidney Health Atlas is an ongoing initiative of the International Society of Nephrology that aims to monitor and evaluate the status of global kidney care worldwide. This study reports on findings from the 2018 Global Kidney Health Atlas survey, specifically addressing the availability, accessibility, and quality of conservative kidney management., Results: Respondents from 160 countries completed the survey, and 154 answered questions pertaining to conservative kidney management. Of these, 124 (81%) stated that conservative kidney management was available. Accessibility was low worldwide, particularly in low-income countries. Less than half of countries utilized multidisciplinary teams (46%); utilized shared decision making (32%); or provided psychologic, cultural, or spiritual support (36%). One-quarter provided relevant health care providers with training on conservative kidney management delivery., Conclusions: Overall, conservative kidney management is available in most countries; however, it is not optimally accessible or of the highest quality., (Copyright © 2021 by the American Society of Nephrology.)

Background: Residual kidney function (RKF) is associated with improved survival and quality of life in dialysis patients. Previous studies have suggested that initiation of peritoneal dialysis (PD) may slow RKF decline compared to the pre-dialysis period. We sought to evaluate the association between PD initiation and RKF decline in the Initiating Dialysis Early And Late (IDEAL) trial., Methods: In this post hoc analysis of the IDEAL randomized controlled trial, PD participants were included if results from 24-hour urine collections had been recorded within 30 days of dialysis initiation, and at least one value pre- and one value post-dialysis commencement were available. The primary outcome was slope of RKF decline, calculated as mean of urinary creatinine and urea clearances. Secondary outcomes included slope of urine volume decline and time from PD initiation to anuria., Results: The study included 151 participants (79 early start, 72 late start). The slope of RKF decline was slower after PD initiation (-2.69±0.18mL/min/1.73m2/yr) compared to before PD (-4.09±0.33mL/min/1.73m2/yr; change in slope +1.19 mL/min/1.73m2/yr, 95%CI 0.48-1.90, p<0.001). In contrast, urine volume decline was faster after PD commencement (-0.74±0.05 L/yr) compared to beforehand (-0.57±0.06L/yr; change in slope -0.18L/yr, 95%CI -0.34--0.01, p = 0.04). No differences were observed between the early- and late-start groups with respect to RKF decline, urine volume decline or time to anuria., Conclusions: Initiation of PD was associated with a slower decline of RKF compared to the pre-dialysis period., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: YC reports personal fees from Baxter, outside the submitted work. CH reports personal fees from Janssen, GlaxoSmithKline and Osuka, and grant support from Baxter, Fresenius, Shire, PKD Aus and NHMRC, outside the submitted work. MGW has received honorarium for scientific lectures from AstraZeneca, Retrophin, Amgen and Baxter, outside the submitted work. His employer, the George Institute for Global Health, holds research contracts for trials in cardiovascular and/or kidney disease with a range of commercial organizations. DJ reports personal fees from AWAK, Astra-Zeneca, Baxter Healthcare and Fresenius Medical Care, and grant support from Baxter Extramural Grant and Baxter CEC Grant, outside the submitted work. The other authors declare no conflicts of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Type 2 innate lymphoid cells (ILC2s) are a subset of ILCs with critical roles in immunoregulation. However, the possible role of ILC2s as immunotherapy against allograft rejection remains unclear. Here, we show that IL-33 significantly prolonged islet allograft survival. IL-33-treated mice had elevated numbers of ILC2s and regulatory T cells (Tregs). Depletion of Tregs partially abolished the protective effect of IL-33 on allograft survival, and additional ILC2 depletion in Treg-depleted DEREG mice completely abolished the protective effects of IL-33, indicating that ILC2s play critical roles in IL-33-mediated islet graft protection. Two subsets of ILC2s were identified in islet allografts of IL-33-treated mice: IL-10 producing ILC2s (ILC2 10 ) and non-IL-10 producing ILC2s (non-ILC 10 ). Intravenous transfer of ILC2 10 cells, but not non-ILC 10 , prolonged islet allograft survival in an IL-10-dependent manner. Locally transferred ILC2 10 cells led to long-term islet graft survival, suggesting that ILC2 10 cells are required within the allograft for maximal suppressive effect and graft protection. This study has uncovered a major protective role of ILC2 10 in islet transplantation which could be potentiated as a therapeutic strategy., (© 2020 The Authors. Published under the terms of the CC BY 4.0 license.)

Background: Elevated serum urate levels are associated with progression of chronic kidney disease. Whether urate-lowering treatment with allopurinol can attenuate the decline of the estimated glomerular filtration rate (eGFR) in patients with chronic kidney disease who are at risk for progression is not known., Methods: In this randomized, controlled trial, we randomly assigned adults with stage 3 or 4 chronic kidney disease and no history of gout who had a urinary albumin:creatinine ratio of 265 or higher (with albumin measured in milligrams and creatinine in grams) or an eGFR decrease of at least 3.0 ml per minute per 1.73 m 2 of body-surface area in the preceding year to receive allopurinol (100 to 300 mg daily) or placebo. The primary outcome was the change in eGFR from randomization to week 104, calculated with the Chronic Kidney Disease Epidemiology Collaboration creatinine equation., Results: Enrollment was stopped because of slow recruitment after 369 of 620 intended patients were randomly assigned to receive allopurinol (185 patients) or placebo (184 patients). Three patients per group withdrew immediately after randomization. The remaining 363 patients (mean eGFR, 31.7 ml per minute per 1.73 m 2 ; median urine albumin:creatinine ratio, 716.9; mean serum urate level, 8.2 mg per deciliter) were included in the assessment of the primary outcome. The change in eGFR did not differ significantly between the allopurinol group and the placebo group (-3.33 ml per minute per 1.73 m 2 per year [95% confidence interval {CI}, -4.11 to -2.55] and -3.23 ml per minute per 1.73 m 2 per year [95% CI, -3.98 to -2.47], respectively; mean difference, -0.10 ml per minute per 1.73 m 2 per year [95% CI, -1.18 to 0.97]; P = 0.85). Serious adverse events were reported in 84 of 182 patients (46%) in the allopurinol group and in 79 of 181 patients (44%) in the placebo group., Conclusions: In patients with chronic kidney disease and a high risk of progression, urate-lowering treatment with allopurinol did not slow the decline in eGFR as compared with placebo. (Funded by the National Health and Medical Research Council of Australia and the Health Research Council of New Zealand; CKD-FIX Australian New Zealand Clinical Trials Registry number, ACTRN12611000791932.)., (Copyright © 2020 Massachusetts Medical Society.)

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic kidney disease and is caused by heterozygous germ-line mutations in either PKD1 (85%) or PKD2 (15%). It is characterised by the formation of numerous fluid-filled renal cysts and leads to adult-onset kidney failure in ~50% of patients by 60 years. Kidney cysts in ADPKD are focal and sporadic, arising from the clonal proliferation of collecting-duct principal cells, but in only 1-2% of nephrons for reasons that are not clear. Previous studies have demonstrated that further postnatal reductions in PKD1 (or PKD2) dose are required for kidney cyst formation, but the exact triggering factors are not clear. A growing body of evidence suggests that DNA damage, and activation of the DNA damage response pathway, are altered in ciliopathies. The aims of this review are to: (i) analyse the evidence linking DNA damage and renal cyst formation in ADPKD; (ii) evaluate the advantages and disadvantages of biomarkers to assess DNA damage in ADPKD and finally, (iii) evaluate the potential effects of current clinical treatments on modifying DNA damage in ADPKD. These studies will address the significance of DNA damage and may lead to a new therapeutic approach in ADPKD.

Transforming growth factor β (TGF-β) is the key cytokine involved in causing fibrosis through cross-talk with major profibrotic pathways. However, inhibition of TGF-β to prevent fibrosis would also abrogate its anti-inflammatory and wound-healing effects. β-catenin is a common co-factor in most TGF-β signaling pathways. β-catenin binds to T-cell factor (TCF) to activate profibrotic genes and binds to Forkhead box O (Foxo) to promote cell survival under oxidative stress. Using a proximity ligation assay in human kidney biopsies, we found that β-catenin/Foxo interactions were higher in kidney with little fibrosis, whereas β-catenin/TCF interactions were upregulated in the kidney of patients with fibrosis. We hypothesised that β-catenin/Foxo is protective against kidney fibrosis. We found that Foxo1 protected against rhTGF-β1-induced profibrotic protein expression using a CRISPR/cas9 knockout of Foxo1 or TCF1 in murine kidney tubular epithelial C1.1 cells. Co-administration of TGF-β with a small molecule inhibitor of β-catenin/TCF (ICG-001), protected against kidney fibrosis in unilateral ureteral obstruction. Collectively, our human, animal and in vitro findings suggest β-catenin/Foxo as a therapeutic target in kidney fibrosis.

Previous studies demonstrated that the 52-kDa FK506-binding protein (FKBP52) proline-rich loop is functionally relevant in the regulation of steroid hormone receptor activity. While zebra fish ( Danio rerio; Dr ) FKBP52 contains all of the analogous domains and residues previously identified as critical for FKBP52 potentiation of receptor activity, it fails to potentiate activity. Thus, we used a cross-species comparative approach to assess the residues that are functionally critical for FKBP52 function. Random selection of gain-of-function DrFKBP52 mutants in Saccharomyces cerevisiae identified two critical residues, alanine 111 (A111) and threonine 157 (T157), for activation of receptor potentiation by DrFKBP52. In silico homology modeling suggests that alanine to valine substitution at position 111 in DrFKBP52 induces an open conformation of the proline-rich loop surface similar to that observed on human FKBP52, which may allow for sufficient surface area and increased hydrophobicity for interactions within the receptor-chaperone complex. A second mutation in the FKBP12-like domain 2 (FK2), threonine 157 to arginine (T157R), also enhanced potentiation, and the DrFKBP52-A111V/T157R double mutant potentiated receptor activity similar to human FKBP52. Collectively, these results confirm the functional importance of the FKBP52 proline-rich loop, suggest that an open conformation on the proline-rich loop surface is a predictor of activity, and highlight the importance of an additional residue within the FK2 domain.

Escherichia coli strain 15 (ATCC 9723) formed robust biofilms of two distinct forms on glass tubes. In rich, low-osmolarity medium, the biofilms were restricted to the air/liquid interface, resulting in rings attached to the glass. As it was not evident that these biofilms extended across the liquid surface, we termed them 'ring' rather than 'pellicle' biofilms. In minimal medium supplemented with a non-fermentable substrate as the carbon/energy source, we observed either robust ring biofilms or little biofilm of any type, depending on the substrate. In contrast, fermentable substrates (sugars and sugar derivatives) supported robust biofilms covering most of the solid/liquid interface, which we termed 'tube-covering biofilms'. Maximal biofilm growth was observed when the sugar was a relatively poor substrate, supporting slow growth and known to cause minimal dephosphorylation of regulatory protein Enzyme IIA Glucose of the phosphotransferase system. Compounds found to be inhibitors of biofilm growth, such as lactate, caused a shift from tube-covering to ring form at low concentration and complete loss of biofilm growth at high when added to minimal medium supplemented with a fermentable substrate. Exogenous cAMP activated biofilm growth under all conditions tested, leading to more intense ring or tube-covering biofilms and/or to a shift from ring to tube-covering form.

The occurrence of a spontaneous nephropathy with intranuclear inclusions in laboratory mice has puzzled pathologists for over 4 decades, because its etiology remains elusive. The condition is more severe in immunodeficient animals, suggesting an infectious cause. Using metagenomics, we identify the causative agent as an atypical virus, termed "mouse kidney parvovirus" (MKPV), belonging to a divergent genus of Parvoviridae. MKPV was identified in animal facilities in Australia and North America, is transmitted via a fecal-oral or urinary-oral route, and is controlled by the adaptive immune system. Detailed analysis of the clinical course and histopathological features demonstrated a stepwise progression of pathology ranging from sporadic tubular inclusions to tubular degeneration and interstitial fibrosis and culminating in renal failure. In summary, we identify a widely distributed pathogen in laboratory mice and establish MKPV-induced nephropathy as a new tool for elucidating mechanisms of tubulointerstitial fibrosis that shares molecular features with chronic kidney disease in humans., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The decision about when to start dialysis for end-stage kidney disease (ESKD) is complex and is influenced by many factors. ESKD-related symptoms and signs are the most common indications for dialysis initiation. Creatinine-based formulae to estimate glomerular filtration rate (GFR) are inaccurate in patients with ESKD and, thus, the decision to start dialysis should not be based solely on estimated GFR (eGFR). Early dialysis initiation (ie, at an eGFR > 10 mL/min/1.73 m 2 ) is not associated with a morbidity and mortality benefit, as shown in the Initiating Dialysis Early and Late (IDEAL) study. This observation has been incorporated into the latest guidelines, which place greater emphasis on the assessment of patients' symptoms and signs rather than eGFR. It is suggested that in asymptomatic patients with stage 5 chronic kidney disease, dialysis may be safely delayed until the eGFR is at least as low as 5-7 mL/min/1.73 m 2 if there is careful clinical follow-up and adequate patient education. The decision on when to start dialysis is even more challenging in older patients. Due to their comorbidities and frailty, dialysis initiation may be associated with worse outcomes and quality of life. Therefore, the decision to start dialysis in these patients should be carefully weighed against its risks, and conservative care should be considered in appropriate cases. To optimise the decision-making process for dialysis initiation, patients need to be referred to a nephrologist in a timely fashion to allow adequate pre-dialysis care and planning. Dialysis initiation and its timing should be a shared decision between physician, patients and family members, and should be tailored to the individual patient's needs.

Objectives: There are mixed results regarding psychosocial development in children with cochlear implants (CIs) compared with children with normal hearing (NH), and the effect of bilateral CIs has not yet been investigated. This study aimed to investigate whether social development differed between NH children and those with early CIs, and to identify new predictors of psychosocial development in children with early CIs., Design: The psychosocial development, cognitive and language abilities of 159 children were measured as part of a longitudinal outcomes study of children with CIs. Parental involvement was also assessed., Results: The children in this study did not differ significantly from their peers with NH in terms of their psychosocial development, except with regard to Prosocial Behavior, with parents reporting significantly poorer development in this area. Having bilateral CIs predicted significantly fewer difficulties with psychosocial development, with earlier age at implantation increasing the effect size of the second CI for Emotional Symptoms and Peer Problems. Receptive language ability, higher parent education, later birth order, high parent involvement, and female gender predicted significantly fewer parent reports of psychosocial problems. Higher child cognitive ability and greater screen time predicted significantly greater reported psychosocial difficulties. Marginal effects modeling quantified the effects of changes in the predictive factors examined., Conclusions: Psychosocial development in these children with early CIs was found to be similar to that for peers with NH, with the exception of delayed Prosocial Behavior development. Having bilateral CIs predicted significantly better emotional outcomes. A number of new predictive factors were found for psychosocial development. The results of the marginal effects modeling should be shared with parents and professionals to increase their understanding of the impact of changes in predictive factors, particularly in terms of their own contribution to psychosocial outcomes for children with CIs.