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Purpose Although Facebook addiction has been found to be a key motive for using Facebook, scant research has explored the association of Facebook addiction with social capital. While researchers addressed how Facebook use strengthened social capital, they did not address the resultant excessive and uncontrollable Facebook use, which is a key sign of Facebook addiction. Therefore, the authors develop this project to study this research gap.Design/methodology/approach This research explores the motive of Facebook addiction by using a questionnaire to examine the relationships between Facebook addiction and two types of social capital: cognitive and bonding social capital. The authors recruited Hong Kong youth through Facebook and peer groups to complete a set of questionnaires on Facebook addiction, cognitive social capital, bonding social capital and the degree of extraversion. Hierarchical regression is used for analyzing the data collected.Findings Hierarchical regression results indicated that the more addicted one was to Facebook, the lower the cognitive social capital one perceived. Such a negative relationship was particularly significant for female participants. A similar but marginally significant effect is also found for bonding social capital.Originality/value This research sheds light on the impact of Facebook addiction on how one perceives shared meanings and the sense of belongingness with other people on social networks.Peer reviewThe peer review history for this article is available at https://publons.com/publon/10.1108/OIR-06-2021-0300.

Accurately capturing cloud condensation nuclei (CCN) concentrations is key to understanding the aerosol–cloud interactions that continue to feature the highest uncertainty amongst numerous climate forcings. In situ CCN observations are sparse, and most non-polarimetric passive remote sensing techniques are limited to providing column-effective CCN proxies such as total aerosol optical depth (AOD). Lidar measurements, on the other hand, resolve profiles of aerosol extinction and/or backscatter coefficients that are better suited for constraining vertically resolved aerosol optical and microphysical properties. Here we present relationships between aerosol backscatter and extinction coefficients measured by the airborne High Spectral Resolution Lidar 2 (HSRL-2) and in situ measurements of CCN concentrations. The data were obtained during three deployments in the NASA ObseRvations of Aerosols above CLouds and their intEractionS (ORACLES) project, which took place over the southeast Atlantic (SEA) during September 2016, August 2017, and September–October 2018. Our analysis of spatiotemporally collocated in situ CCN concentrations and HSRL-2 measurements indicates strong linear relationships between both data sets. The correlation is strongest for supersaturations (S) greater than 0.25 % and dry ambient conditions above the stratocumulus deck, where relative humidity (RH) is less than 50 %. We find CCN–HSRL-2 Pearson correlation coefficients between 0.95–0.97 for different parts of the seasonal burning cycle that suggest fundamental similarities in biomass burning aerosol (BBA) microphysical properties. We find that ORACLES campaign-average values of in situ CCN and in situ extinction coefficients are qualitatively similar to those from other regions and aerosol types, demonstrating overall representativeness of our data set. We compute CCN–backscatter and CCN–extinction regressions that can be used to resolve vertical CCN concentrations across entire above-cloud lidar curtains. These lidar-derived CCN concentrations can be used to evaluate model performance, which we illustrate using an example CCN concentration curtain from the Weather Research and Forecasting Model coupled with physics packages from the Community Atmosphere Model version 5 (WRF-CAM5). These results demonstrate the utility of deriving vertically resolved CCN concentrations from lidar observations to expand the spatiotemporal coverage of limited or unavailable in situ observations.

PurposeThis paper investigates school library services in the digital age for students with dyslexia and explores the impact of current library services on students’ learning.Design/methodology/approachA qualitative study with semi-structured interviews was designed according to the LAFE (Look and listen, Assistance and accessibility, Format and fit, and Environment) framework for learners with dyslexia and the 5E instructional model and conducted with 11 school librarians.FindingsResults indicated that participants lacked knowledge of dyslexia for appropriate library services. Awareness, IT skills, school administration, funding and parental attitudes would influence the library’s tailored services to dyslexic children, despite the rich resources in these participants’ libraries, including paperbacks, digital resources and electronic devices. Adaptations are necessary to provide accessible services, especially by applying digital technologies, and school libraries can positively impact students’ reading interests, promote knowledge inquiry and strengthen information literacy skills.Originality/valueWhile students with dyslexia spend significant time in schools, limited studies focus on school library services in the digital age, especially in Asia. This study fills the gap by systematically exploring the issue with the 5E instructional model.

Background Neutropenic oncology patients often have mucosal barrier injury as a consequence of chemotherapy and are at risk of Viridans Group Streptococci (VGS) bacteremia. VGS is a commonly identified pathogen among oncology patients with neutropenic fever, however, limited data exists as to appropriate treatment duration. Methods The purpose of this study is to characterize the treatment duration and clinical course among neutropenic oncology patients with VGS bacteremia. A retrospective chart review of patients with VGS bacteremia from June 1, 2020 through January 31, 2022 at the University of Washington Medical Center (UWMC) and Seattle Cancer Care Alliance (SCCA). Eligible patients include adults ≥ 18 years with any cancer diagnosis, absolute neutrophil count ≤ 500 at time of blood culture collection, ≥ 1 positive blood culture for VGS, and treated with antibiotics for ≥ 48 hours. Polymicrobial infections were excluded. Results Among 86 patients identified with VGS bacteremia, 57 patients were included. Baseline characteristics are depicted in TABLE 1. Hematologic malignancy was present in a majority of patients. The mean duration of treatment was 12.4 (± 2.9) days. Mean time to defervescence was 3.7 days. The most common empiric regimen was cefepime + vancomycin (64.9%) with 78.9% of patients receiving ceftriaxone as definitive therapy. All VGS isolates were susceptible to at least one drug in their empiric regimen. Clinical outcomes are depicted in TABLE 2. There was 1 recurrence of VGS bacteremia and three deaths in the cohort. In TABLE 3, results are stratified by treatment duration. Conclusion There was significant heterogeneity in the duration of treatment of VGS bacteremia among neutropenic cancer patients utilizing levofloxacin prophylaxis, with > 50% treated in excess of 14 days. Fever persisted for several days despite active antimicrobials consistent with prior reports. The low rate of recurrence and death at any treatment duration suggests that a shorter duration of less than 14 days for VGS bacteremia may be feasible. A prospective evaluation is needed to confirm these findings. Disclosures All Authors: No reported disclosures.

Despite recent calls to action and a heavy emphasis on timeliness of care in guidelines for common inborn errors of metabolism, there is a dearth of specific measurable quality metrics for these conditions and little to no electronic decision support for their management. We have developed a novel set of process-oriented metrics based on the aforementioned guidelines that can be calculated from data already contained in most major EHRs, which we believe are responsive to the needs of the metabolism community.

Plants demonstrate some of the greatest variation in genome size among eukaryotes, and their genome sizes can vary dramatically across individuals and populations within species. This genetic variation can have consequences for traits and fitness, but few studies have been able to attribute genome size differentiation to ecological and evolutionary processes. Biological invasions present particularly useful natural laboratories to infer selective agents that might drive genome size shifts across environments and population histories. Here, we test hypotheses for the evolutionary causes of genome size variation across 14 invading populations of yellow starthistle, Centaurea solstitialis, in California, USA. We use a survey of genome sizes and trait variation to ask: (1) Is variation in genome size associated with developmental trait variation? (2) Are genome sizes smaller toward the leading edge of the expansion, consistent with selection for ‘colonizer’ traits? Or alternatively, does genome size increase toward the leading edge of the expansion, consistent with predicted consequences of founder effects and drift? (3) Finally, are genome sizes smaller at higher elevations, consistent with selection for shorter development times? We found that 2C DNA content varied 1.21-fold among all samples, and was associated with flowering time variation, such that plants with larger genomes reproduced later, with lower lifetime capitula production. Genome sizes increased toward the leading edge of the invasion, but tended to decrease at higher elevations, consistent with genetic drift during range expansion but potentially strong selection for smaller genomes and faster development time at higher elevations.

Recent case reports suggest that coronavirus disease 2019 (COVID-19) is associated with collapsing glomerulopathy in African Americans with apolipoprotein L1 gene (APOL1) risk alleles; however, it is unclear whether disease pathogenesis is similar to HIV-associated nephropathy. RNA sequencing analysis of a kidney biopsy specimen from a patient with COVID-19–associated collapsing glomerulopathy and APOL1 risk alleles (G1/G1) revealed similar levels of APOL1 and angiotensin-converting enzyme 2 (ACE2) messenger RNA transcripts as compared with 12 control kidney samples downloaded from the GTEx (Genotype-Tissue Expression) Portal. Whole-genome sequencing of the COVID-19–associated collapsing glomerulopathy kidney sample identified 4 indel gene variants, 3 of which are of unknown significance with respect to chronic kidney disease and/or focal segmental glomerulosclerosis. Molecular profiling of the kidney demonstrated activation of COVID-19–associated cell injury pathways such as inflammation and coagulation. Evidence for direct severe acute respiratory syndrome coronavirus 2 infection of kidney cells was lacking, which is consistent with the findings of several recent studies. Interestingly, immunostaining of kidney biopsy sections revealed increased expression of phospho-STAT3 (signal transducer and activator of transcription 3) in both COVID-19–associated collapsing glomerulopathy and HIV-associated nephropathy as compared with control kidney tissue. Importantly, interleukin 6–induced activation of STAT3 may be a targetable mechanism driving COVID-19–associated acute kidney injury.

Background: Podocyte foot process effacement is a key histologic finding in proteinuric kidney disease. We previously showed that 3-week old CD2AP-deficient mice have significant proteinuria, glomerular hypertrophy and mesangial expansion. The goal of this study is to use morphometry to establish the temporal sequence of podocyte foot process effacement, glomerular volume expansion and albuminuria in Cd2ap−/− mice by measuring these parameters at the 2-week time point.Methods: Wild-type mice age 14 ± 1 days with the Cd2ap gene (WT, N = 5) and mice deficient for Cd2ap (Cd2ap KO, N = 5) were generated. Kidneys were harvested and fixed in 2.5% glutaraldehyde and processed for examination by light and electron microscopy. An average of 415.2 (range 268–716) grid points were counted for all the glomeruli, and quantification of glomerular volume from each kidney. Urine was collected the day prior to sacrifice for urine albumin-to-creatinine ratio (ACR) measurements.Results: There was no difference in albuminuria [median (range) mg/g] between WT [212.2 (177.6–388.4) mg/g] vs. Cd2ap KO mice [203.3 (164.7–910.2) mg/g], P = 0.89; or glomerular volume 68,307[10,931] vs. 66,844[13,022] μm3, p = 0.92. The volume densities of glomerular components of the podocyte, capillary lumen and mesangium were not different for the two groups, P = 0.14, 0.14 and 0.17 respectively. However, foot process width was increased in Cd2ap KO 1128[286] vs. WT [374 ± 42] nm, P = 0.02.Conclusion: Here we show that while 2-week old WT and Cd2ap KO mice have similar levels of albuminuria, glomerular and mesangial volume, Cd2ap KO mice have more extensive podocyte foot process effacement. The data suggests that podocyte injury is the initiating event leading to mesangial expansion and albuminuria in this model.

Background and study aims Small bowel capsule endoscopy [SBCE) has an established role in investigating suspected small bowel bleeding [SSBB). Identification of a biomarker to predict pathology would maximize utility of this valuable diagnostic modality. This study aimed to investigate if fecal immunochemical test [FIT) could predict likelihood of small bowel pathology on SBCE. Patients and methods Patients referred for SBCE to investigate anaemia or suspected small bowel bleeding were prospectively recruited. All patients had negative upper and lower endoscopy prior to referral. A FIT ≥ 45 ug Hb/g was considered positive. SBCE was positive if a potential source of SSBB was identified. The primary endpoint was correlation between FIT and positive SBCE. Secondary endpoints were correlation between anemia and SBCE and a combination of anemia plus FIT and SBCE. Results Fifty-one patients were included in the final study cohort. 29.4 % had a positive FIT, 33.3 % were anemic, and 25.5 % patients had significant SBCE findings. There was a statistically significant association between positive FIT and pathology on SBCE (OR 12, 95 % CI [2.8 – 51.9), P = 0.001). Sensitivity and specificity of positive FIT in predicting SBCE findings were 69 % and 84 %, respectively. A normal Hb had an NPV of 83 % (OR 0.30, P = 0.09). Combining Hb and FIT was statistically significant in predicting pathology on SBCE (OR 9.14, 67 % PPV, 82 % NPV, P = 0.025). Conclusion FIT ≥ 45 ug Hb/g is a useful tool in predicting small bowel pathology on SBCE. Use of this biomarker alone, or in combination with serum haemoglobin, has value as a screening tool and may help to better triage patients referred for SBCE.

The essential role of membrane associated guanylate kinase 2 (MAGI2) in podocytes is indicated by the phenotypes of severe glomerulosclerosis of both MAGI2 knockout mice and in patients with congenital nephrotic syndrome (CNS) caused by mutations in MAGI2. Here, we show that MAGI2 forms a complex with the Rap1 guanine nucleotide exchange factor, RapGEF2, and that this complex is lost when expressing MAGI2 CNS variants. Co-expression of RapGEF2 with wild-type MAGI2, but not MAGI2 CNS variants, enhanced activation of the small GTPase Rap1, a central signaling node in podocytes. In mice, podocyte-specific RapGEF2 deletion resulted in spontaneous glomerulosclerosis, with qualitative glomerular features comparable to MAGI2 knockout mice. Knockdown of RapGEF2 or MAGI2 in human podocytes caused similar reductions in levels of Rap1 activation and Rap1-mediated downstream signaling. Furthermore, human podocytes expressing MAGI2 CNS variants show severe abnormalities of cellular morphology and dramatic loss of actin cytoskeletal organization, features completely rescued by pharmacological activation of Rap1 via a non-MAGI2 dependent upstream pathway. Finally, immunostaining of kidney sections from patients with congenital nephrotic syndrome and MAGI2 mutations showed reduced podocyte Rap1-mediated signaling. Thus, MAGI2-RapGEF2-Rap1 signaling is essential for normal podocyte function. Hence, disruption of this pathway is an important cause of the renal phenotype induced by MAGI2 CNS mutations.

Nephrotoxicity is a critical adverse event that leads to discontinuation of kinase inhibitor (KI) treatment. Here we show, through meta-analyses of FDA Adverse Event Reporting System, that dasatinib is associated with high risk for glomerular toxicity that is uncoupled from hypertension, suggesting a direct link between dasatinib and podocytes. We further investigate the cellular effects of dasatinib and other comparable KIs with varying risks of nephrotoxicity. Dasatinib treated podocytes show significant changes in focal adhesions, actin cytoskeleton, and morphology that are not observed with other KIs. We use phosphoproteomics and kinome profiling to identify the molecular mechanisms of dasatinib-induced injury to the actin cytoskeleton, and atomic force microscopy to quantify impairment to cellular biomechanics. Furthermore, chronic administration of dasatinib in mice causes reversible glomerular dysfunction, loss of stress fibers, and foot process effacement. We conclude that dasatinib induces nephrotoxicity through altered podocyte actin cytoskeleton, leading to injurious cellular biomechanics., Kinase inhibitors used in chemotherapy are known for their adverse effects on kidney physiology. Here, Calizo et al. show that dasatinib is associated with a higher risk of glomerular toxicity compared to other kinase inhibitors, due to deleterious effects on cytoskeletal biomechanics in podocytes.

Evidence for perioperative methods to prevent persistent postsurgical pain (PPP) is uncertain, in part because few treatments have been directly compared. Here we have used component network meta-analysis (cNMA) to incorporate both direct and indirect evidence in the evaluation of the efficacy and tolerability of pharmacological and neural block treatments.We searched the Cochrane Central Registry of Controlled Trials, Embase, MEDLINE, ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry up to January 2021 for randomized, double-masked, controlled trials that reported the prevalence of PPP. We assessed trial quality with the Cochrane risk of bias tool (RoB 2.0). We analysed the results with frequentist cNMA models. The primary outcome was the relative risk (RR) of PPP. We assessed efficacy in relation to a clinically important effect size of RR = 0.9, which is a 10% improvement with treatment.The analysis included 107 trials (13,553 participants) of 13 treatments. The effects of complex interventions were the multiplicative effects of their components. Compared with placebo, serotonin-norepinephrine reuptake inhibitors (SNRIs), neural block alone, or in combination with NMDA receptor blockers or gabapentanoids were effective. Treatments with benefit in the immediate post-operative period predicted a reduced risk of PPP.Several treatments and treatment combinations effectively reduce PPP prevalence. Pain outcomes in the immediate postoperative period are an important mediator of PPP. Multimodal interventions can be analysed using cNMA.Systematic reviews of PPP prevention usually focus on the efficacy of specific treatments in comparison with control interventions. In this study we used component network meta-analysis to compare interventions to each other, including both pharmacological and neural block techniques, and multimodal interventions. Interventions that are not effective alone may improve the efficacy of multimodal interventions that include neural block techniques. Immediate postoperative benefit was an important mediator for reduction of PPP.PROSPERO: CRD42018085570 https://www.crd.york.ac.uk/prospero/.

1. Introduction We are interested in systems where two phases coexist: a solid phase with a high effective viscosity, and a low-viscosity liquid phase which fills the porosity of the solid phase. Two-phase systems, or "mush", are common in planetary sciences: magma extraction, Earth's inner core, icy moons... On terrestrial or icy bodies, such biphasic layers can compact under their own weight, which leads to the extraction of the liquid phase from the solid phase, and compaction of this solid phase. We present here a new model of two-phase flows with phase change (melting or freezing), and focus on 2 applications: Earth's inner core compaction: Whether the inner core crystallises dendritically or by sedimentation, it is likely that some liquid iron is trapped within the inner core, which may explain its low rigidity [1]. We extend here the studies of Sumita et al., 1996 [2] and Lasbleis et al., 2019 [3] by taking into account phase change within the inner core. Transneptunian objects (TNOs): Ices may contain antifreezes like ammonia or methanol which could depress the melting point by up to 155 K [4]. Due to their presence, the melting temperature depends on their concentration. Then it is very likely that there would not be any clear border between solid and liquid if the melting point was reached, but rather a mushy layer. Several authors have studied the thermal evolution of TNOs without these considerations (for instance [5], [6], [7]). 2. Two-phase flow model The model is based on the two-phase formalism developed by Bercovici et al., 2001 [8] for a non-reacting two-phase medium, which we generalise to allow for non-congruent phase change. This requires solving equations of conservation of mass and momentum for each phases, energy, and solute, with appropriate boundary conditions. In our model, the solid and liquid phases are assumed to be in thermodynamic equilibrium, which allows to link temperature and composition through the phase diagram. To simplify the problem, the liquidus temperature is taken to be linear (Fig. 1), which implies that the temperature in the two-phase region is a linear function of solute concentration. We further assume that the solute is considered to be totally contained in the melt (solid/liquid partition coefficient equal to 0). The set of equations is written in 1D spherical geometry. These assumptions allow us to reduce the system of equations to a system of only three equations (conservation of momentum, energy, and solute), which we solve to obtain the temperature (directly connected to composition), radial velocity of liquid (linked to velocity of solid) and porosity (the proportion of liquid). The code solves equations in a 1D sphere, which size can evolve with time, either due to accretion (TNOs during their formation), or solidification (inner core). This is taken into account thanks to an adaptive grid. The code has been developed from the code written by Lasbleis et al., 2019 [3]. 3. Preliminary results Application to Earth's inner core In the inner core, 'light elements', and in particular oxygen, act as antifreezes [9]. Within the inner core, the effect of pressure on the liquidus temperature cannot be neglected, and we thus take this factor into account in the model. The temperature-composition relation thus depends on pressure, or radius; the slope of the liquidus with respect to solute concentration is take to be constant but TL decreases with decreasing pressure and increasing radius. At the inner core boundary, the temperature is set to TL(χ0, r). Fig. 2 and Fig. 3 show the evolution of porosity and temperature in the inner core as functions of time and radius. Application to TNOs When modeling the thermal evolution and differentiation of TNOs, our code has to be associated with an external icy diffusive spherical shell. If in addition we consider the formation of a rocky core, the mush (modeled by our code) is a spherical shell around a spherical rocky core. Our model takes into account the variations with temperature of ice thermal conductivity and heat capacity, which are far better known than for iron Earth's inner conditions [10] [11]. However, the pressure effect on TL is negligible. Acknowledgements This project has received funding from the European Research Council (ERC) under the European Unions Horizon 2020 research and innovation programme (grant agreements 802699 and 716429). References [1] Deguen, R. (2012). Earth and Planetary Science Letters, 333, 211-225. [2] Sumita, I., Yoshida, S., Kumazawa, M., & Hamano, Y. (1996). Geophysical Journal International, 124(2), 502-524. [3] Lasbleis, M., Kervazo, M., & Choblet, G. (2020). Geophysical Research Letters, 47(2), e2019GL085654. [4] McKinnon, W. B., Prialnik, D., Stern, S. A., & Coradini, A. (2008). The solar system beyond Neptune, 1, 213-241. [5] Bierson, C. J., Nimmo, F., & McKinnon, W. B. (2018). Icarus, 309, 207-219. [6] Desch, S. J., & Neveu, M. (2017). Icarus, 287, 175-186. [7] Malamud, U., & Prialnik, D. (2015). Icarus, 246, 21-36. [8] Bercovici, D., Ricard, Y., & Schubert, G. (2001). Journal of Geophysical Research: Solid Earth, 106(B5), 8887-8906. [9] Alfè, D., Gillan, M. J., & Price, G. D. (2002). Earth and Planetary Science Letters, 195(1-2), 91-98. [10] Klinger, J. (1980). Science, 209(4453), 271-272. [11] McCord, T. B., & Sotin, C. (2005). Journal of Geophysical Research: Planets, 110(E5).

Seismic observations of a slowdown in P wave velocity at the base of Earth's outer core suggest the presence of a stably-stratified region known as the F-layer. This raises an important question: how can light elements that drive the geodynamo pass through the stably-stratified layer without disturbing it? We consider the F-layer as a slurry containing solid particles dispersed within the liquid iron alloy that snow under gravity towards the inner core. We present a regime diagram showing how the dynamics of the slurry F-layer change upon varying the key parameters: P\'eclet number ($Pe$), the ratio between advection and chemical diffusion; Stefan number ($St$), the ratio between sensible and latent heat; and Lewis number ($Le$), the ratio between thermal and chemical diffusivity. We obtain four regimes corresponding to stable, partially stable, unstable and no slurries. No slurry is found when the heat flow at the base of the layer exceeds the heat flow at the top, while a stably-stratified slurry arises when advection overcomes thermal diffusion ($Pe \gtrsim Le$) that exists over a wide range of parameters relevant to the Earth's core. Our results estimate that a stably-stratified F-layer gives a maximum inner-core boundary (ICB) body wave density jump of $\Delta \rho_\textrm{bod} \leq 534 \ \mathrm{kg} \mathrm{m}^{-3}$ which is compatible with the lower end of the seismic observations where $280 \leq \Delta \rho_\textrm{bod} \leq 1,100 \ \mathrm{kg} \mathrm{m}^{-3}$ is reported in the literature. With high thermal conductivity the model predicts an inner core age between $0.6$ and $1.2 \ \mathrm{Ga}$, which is consistent with other core evolution models. Our results suggest that a slurry model with high core conductivity predicts geophysical properties of the F-layer and core that are consistent with independent seismic and geodynamic calculations.

Urinary plasminogen/plasmin, or plasmin (ogen) uria, has been demonstrated in proteinuric patients and exposure of cultured podocytes to plasminogen results in injury via oxidative stress pathways. A causative role for plasmin (ogen) as a "second hit" in kidney disease progression has yet to have been demonstrated in vivo. Additionally, association between plasmin (ogen) uria and kidney function in glomerular diseases remains unclear. We performed comparative studies in a puromycin aminonucleoside (PAN) nephropathy rat model treated with amiloride, an inhibitor of plasminogen activation, and measured changes in plasmin (ogen) uria. In a glomerular disease biorepository cohort (n = 128), we measured time-of-biopsy albuminuria, proteinuria, and plasmin (ogen) uria for correlations with kidney outcomes. In cultured human podocytes, plasminogen treatment was associated with decreased focal adhesion marker expression with rescue by amiloride. Increased glomerular plasmin (ogen) was found in PAN rats and focal segmental glomerulosclerosis (FSGS) patients. PAN nephropathy was associated with increases in plasmin (ogen) uria and proteinuria. Amiloride was protective against PAN-induced glomerular injury, reducing CD36 scavenger receptor expression and oxidative stress. In patients, we found associations between plasmin (ogen) uria and edema status as well as eGFR. Our study demonstrates a role for plasmin (ogen)-induced podocyte injury in the PAN nephropathy model, with amiloride having podocyte-protective properties. In one of the largest glomerular disease cohorts to study plasminogen, we validated previous findings while suggesting a potentially novel relationship between plasmin (ogen) uria and estimated glomerular filtration rate (eGFR). Together, these findings suggest a role for plasmin (ogen) in mediating glomerular injury and as a viable targetable biomarker for podocyte-sparing treatments.

Background We previously showed that the presence of a CKD-associated locus in SHROOM3 in a donor kidney results in increased expression of SHROOM3 (an F-actin–binding protein important for epithelial morphogenesis, via rho-kinase [ROCK] binding); this facilitates TGF-b signaling and allograft fibrosis. However, other evidence suggests Shroom3 may have a protective role in glomerular development. Methods We used human data, Shroom3 knockdown podocytes, and inducible shRNA-mediated knockdown mice to study the role of Shroom3 in adult glomeruli. Results Expression data from the Nephroseq database showed glomerular and nonglomerular SHROOM3 had opposing associations with renal function in CKD biopsy samples. In human allografts, homozygosity at rs17319721, the SHROOM3 locus linked with lower GFR, was associated with reduced albuminuria by 2 years after transplant. Although our previous data showed reduced renal fibrosis with tubular Shroom3 knockdown, this study found that glomerular but not tubular Shroom3 knockdown induced albuminuria. Electron microscopy revealed diffuse foot process effacement, and glomerular RNA-sequencing showed enrichment of tyrosine kinase signaling and podocyte actin cytoskeleton pathways in knockdown mice. Screening SHROOM3-interacting proteins identified FYN (a src-kinase) as a candidate.We confirmed the interaction of endogenous SHROOM3 with FYN in human podocytes via a critical Src homology 3–binding domain, distinct from its ROCK-binding domain. Shroom3-Fyn interaction was required in vitro and in vivo for activation of Fyn kinase and downstream nephrin phosphorylation in podocytes. SHROOM3 knockdown altered podocyte morphology, cytoskeleton, adhesion, and migration. Conclusions We demonstrate a novel mechanism that may explain SHROOM3’s dichotomous associations in glomerular versus nonglomerular compartments in CKD

Safety data for the multicomponent meningococcal group B vaccine (4CMenB) has so far been limited to experience from clinical trials and isolated local outbreaks. Since the UK is the first country to implement a nationwide routine immunisation programme with 4CMenB (at age 8 weeks, 16 weeks, and then 1 year), we aimed to assess the safety of 4CMenB in this setting.In this prospective surveillance study, we assessed suspected adverse reactions of 4CMenB in children up to age 18 months reported in the UK Yellow Card Scheme and primary care records extracted from the Clinical Practice Research Datalink (CPRD). We proactively assessed reports of fever, local reactions, Kawasaki disease, seizures, and sudden death, and compared the number of spontaneous reports with the expected number of events based on background incidence and the number of children vaccinated. We also identified any unexpected adverse reactions and estimated compliance with subsequent doses of routine vaccinations.From Sept 1, 2015, to May 31, 2017, approximately 1·29 million children aged 2-18 months received about a combined 3 million doses of 4CMenB. 902 reports of suspected adverse reactions were received through the UK Yellow Card Scheme, of which 366 (41%) were related to local reactions and 364 (40%) related to fever. The only unexpected finding was that 160 reports of local reactions described a persistent nodule at the site of injection, usually without other local symptoms. There were 55 (6%) reports of seizures, with an age-adjusted observed-to-expected ratio of 0·13 (95% CI 0·10-0·17). Ecological analyses found similar rates of seizures within 7 days of routine immunisation in the periods before and after 4CMenB introduction, with incidence rate ratios of 1·30 (95% CI 0·56-3·00) at age 2 months, 1·53 (0·49-4·74) at age 4 months, and 1·26 (0·69-2·32) at age 12 months. Of the 902 reports, three (1%) were of Kawasaki disease (observed-to-expected ratio 1·40, 95% CI 0·29-4·08) and three (1%) of sudden infant death syndrome within 3 days of vaccination in children aged 2-4 months (0·44, 0·12-1·14). Analysis of routine immunisations recorded in CPRD found that 11 602 (95·1%) of 12 199 children had received the second dose of 4CMenB by 26 weeks of age, 1793 (84·7%) of 2117 had received the third dose by 62 weeks of age, and 4CMenB introduction had not reduced compliance with doses of other routine vaccinations.We found no significant safety concerns after widespread use of 4CMenB in UK infants, and the vaccine appears to have been well accepted by parents. However, it is important to continue monitoring the safety and long-term effect of the immunisation programme in the UK to further characterise the reported suspected adverse reactions.None.

Objective: This study aimed to compare the effect of a Powerpoint lecture versus video presentation on the knowledge and attitude on HIV among grades 9 students in a public school in Manila. Methods: GRADE 9 public school students were randomly assigned into one of two groups, video presentation or PowerPoint presentation. Pre- and post-tests were administered to assess the efficacy of an intervention. Student t-test was used to compare knowledge on HIV/AIDS before and after the intervention, as well as compare the results between the 2 groups. Chi-square was used to compare scores on attitude before and after the intervention, with the level of significance at p=0.05. Results: Two hundred fourteen students participated in the study, and majority (57%) are females. The mean age of participants is 14.2 years. The difference in scores before and after the intervention was found to be statistically significant (p

The Rayleigh Ohnesorge Jetting Extensional Rheometer (ROJER) enables measurement of very short relaxation times of low viscosity complex fluids such as those encountered in ink-jet printing and spraying applications. This paper focuses on the design and operation of the ROJER. The performance of two nozzle designs are compared using Newtonian fluids alongside a study using computational fluid dynamics (CFD). Subsequently a disposable nozzle is developed that overcomes issues of blockage and cleaning. The operability of this design is subject to a focused study where low viscosity polymer solutions are characterised. The test fluid materials are ethyl hydroxy-ethyl cellulose (EHEC) and poly ethylene oxide (PEO) mixed with water/glycerol solutions. Results obtained by the disposable nozzle are encouraging, paving the way for a more cost-efficient and robust ROJER setup.

While glomerulosclerosis commonly progresses to kidney failure, its mechanisms are unclear. Using murine models and human samples, the authors show that progressive glomerulosclerosis results from loss of decay-accelerating factor (DAF/CD55) on podocytes, which in turn initiates complement C3aR signaling and downstream IL-1β/IL-1R1–mediated podocyte injury and loss., Kidney glomerulosclerosis commonly progresses to end-stage kidney failure, but pathogenic mechanisms are still poorly understood. Here, we show that podocyte expression of decay-accelerating factor (DAF/CD55), a complement C3 convertase regulator, crucially controls disease in murine models of adriamycin (ADR)-induced focal and segmental glomerulosclerosis (FSGS) and streptozotocin (STZ)-induced diabetic glomerulosclerosis. ADR induces enzymatic cleavage of DAF from podocyte surfaces, leading to complement activation. C3 deficiency or prevention of C3a receptor (C3aR) signaling abrogates disease despite DAF deficiency, confirming complement dependence. Mechanistic studies show that C3a/C3aR ligations on podocytes initiate an autocrine IL-1β/IL-1R1 signaling loop that reduces nephrin expression, causing actin cytoskeleton rearrangement. Uncoupling IL-1β/IL-1R1 signaling prevents disease, providing a causal link. Glomeruli of patients with FSGS lack DAF and stain positive for C3d, and urinary C3a positively correlates with the degree of proteinuria. Together, our data indicate that the development and progression of glomerulosclerosis involve loss of podocyte DAF, triggering local, complement-dependent, IL-1β–induced podocyte injury, potentially identifying new therapeutic targets., Graphical Abstract

Background Maintenance of the intricate interdigitating morphology of podocytes is crucial for glomerular filtration. One of the key aspects of specialized podocyte morphology is the segregation and organization of distinct cytoskeletal filaments into different subcellular components, for which the exact mechanisms remain poorly understood. Methods Cells from rats, mice, and humans were used to describe the cytoskeletal configuration underlying podocyte structure. Screening the time-dependent proteomic changes in the rat puromycin aminonucleoside-induced nephropathy model correlated the actin-binding protein LIM-nebulette strongly with glomerular function. Single-cell RNA sequencing and immunogold labeling were used to determine Nebl expression specificity in podocytes. Automated high-content imaging, super-resolution microscopy, atomic force microscopy (AFM), live-cell imaging of calcium, and measurement of motility and adhesion dynamics characterized the physiologic role of LIM-nebulette in podocytes. Results Nebl knockout mice have increased susceptibility to adriamycin-induced nephropathy and display morphologic, cytoskeletal, and focal adhesion abnormalities with altered calcium dynamics, motility, and Rho GTPase activity. LIM-nebulette expression is decreased in diabetic nephropathy and FSGS patients at both the transcript and protein level. In mice, rats, and humans, LIM-nebulette expression is localized to primary, secondary, and tertiary processes of podocytes, where it colocalizes with focal adhesions as well as with vimentin fibers. LIM-nebulette shRNA knockdown in immortalized human podocytes leads to dysregulation of vimentin filament organization and reduced cellular elasticity as measured by AFM indentation. Conclusions LIM-nebulette is a multifunctional cytoskeletal protein that is critical in the maintenance of podocyte structural integrity through active reorganization of focal adhesions, the actin cytoskeleton, and intermediate filaments.

Urinary plasminogen/plasmin, or plasmin(ogen)uria, has been demonstrated in proteinuric patients and exposure of cultured podocytes to plasminogen results in injury via oxidative stress pathways. A causative role for plasmin(ogen) as a “second hit” in kidney disease progression has yet to be demonstratedin vivo, and the association between plasmin(ogen)uria and kidney function in glomerular diseases remains unclear. We performed comparative studies in a puromycin aminonucleoside (PAN) nephropathy rat model treated with amiloride, an inhibitor of plasminogen activation, and measured changes in plasmin(ogen)uria and urinary endothelin-1 (ET1). In a glomerular disease biorepository cohort (n=128), we measured time-of-biopsy albuminuria, proteinuria, and plasmin(ogen)uria for correlations with renal outcomes. Increased glomerular plasmin(ogen) was found in PAN rats and FSGS patients. PAN nephropathy was associated with increases in plasmin(ogen)uria, proteinuria, and urinary ET1. Amiloride was protective against PAN-induced glomerular injury, reducing urinary ET1 and oxidative stress. In patients, we found associations between plasmin(ogen)uria and edema status as well as eGFR. Our study demonstrates a role for plasmin(ogen)-induced podocyte injury in the PAN nephropathy model, with amiloride having podocyte-protective properties. In one of largest glomerular disease cohorts to study plasminogen, we validated previous findings while suggesting a potentially novel relationship between plasmin(ogen)uria and eGFR. Together, these findings suggest a role for plasmin(ogen) in mediating glomerular injury and as a viable targetable biomarker for podocyte-sparing treatments.TRANSLATIONAL STATEMENTProteinuria is associated with CKD progression, and increased cardiovascular morbidity and mortality. The underlying mechanisms of podocyte injury, the hallmark of proteinuric kidney disease, are poorly understood with limited, non-specific therapeutic options. This study adds to the evidence that plasmin(ogen) in the urine of proteinuric patients is associated with podocyte injury, edema, and impaired renal function. Previously published results from us and others, taken together with our current rodent model and human data, suggest that urinary plasmin(ogen) is a potential targetable biomarker. Efforts to decrease plasmin(ogen)-mediated podocyte injury could be part of a novel therapeutic strategy for glomerular disease.

Bee orchids have long been an excellent example of how dishonest signal works in plant-animal interaction. Many studies compared the flower structures that resemble female bees, leading toward pseudo-copulation of the male bees on the flower. Using Machine Learning, we tested whether nature is capable of besting artificial intelligence. A total of 2000 images of related bees, wasps, and Ophrys sp. were collected from the Google Image Repository. Unsuitable images were later filtered out manually, leaving a total of 995 images in the final selection. 80% of these images were used to build a supervised model using Logistic Regression, while the model accuracy was tested using 20% of the remaining images. Based on our results using Wolfram Mathematica, the Ophrys is not capable of fooling artificial intelligence. The accuracy, accuracy baseline, mean cross-entropy, Area Under ROC (receiver operating characteristic curve) curve (AUC) and the confusion matrix gave excellent image classification. However, we can now show the key points and highlights of the images and how the structures closely resemble actual bees using the SURF method. Rather than just a descriptive method, ML learning has enabled a more quantitative approach. Since this is a simple test, we encourage other scientists to adopt our approach using a larger dataset and better database samples.

Podocytes are the key target for injury in proteinuric glomerular diseases that result in podocyte loss, progressive focal segmental glomerular sclerosis (FSGS), and renal failure. Current evidence suggests that the initiation of podocyte injury and associated proteinuria can be separated from factors that drive and maintain these pathogenic processes leading to FSGS. In nephrotic urine aberrant glomerular filtration of plasminogen (Plg) is activated to the biologically active serine protease plasmin by urokinase-type plasminogen activator (uPA). In vivo inhibition of uPA mitigates Plg activation and development of FSGS in several proteinuric models of renal disease including 5/6 nephrectomy. Here, we show that Plg is markedly increased in the urine in two murine models of proteinuric kidney disease associated with podocyte injury: Tg26 HIV-associated nephropathy and the Cd2ap−/−model of FSGS. We show that human podocytes express uPA and three Plg receptors: uPAR, tPA, and Plg-RKT. We demonstrate that Plg treatment of podocytes specifically upregulates NADPH oxidase isoforms NOX2/NOX4 and increases production of mitochondrial-dependent superoxide anion (O2−) that promotes endothelin-1 synthesis. Plg via O2−also promotes expression of the B scavenger receptor CD36 and subsequent increased intracellular cholesterol uptake resulting in podocyte apoptosis. Taken together, our findings suggest that following disruption of the glomerular filtration barrier at the onset of proteinuric disease, podocytes are exposed to Plg resulting in further injury mediated by oxidative stress. We suggest that chronic exposure to Plg could serve as a “second hit” in glomerular disease and that Plg is potentially an attractive target for therapeutic intervention.

No efficient treatment exists for nephrotic syndrome (NS), a frequent cause of chronic kidney disease. Here we show mutations in six different genes (MAGI2, TNS2, DLC1, CDK20, ITSN1, ITSN2) as causing NS in 17 families with partially treatment-sensitive NS (pTSNS). These proteins interact and we delineate their roles in Rho-like small GTPase (RLSG) activity, and demonstrate deficiency for mutants of pTSNS patients. We find that CDK20 regulates DLC1. Knockdown of MAGI2, DLC1, or CDK20 in cultured podocytes reduces migration rate. Treatment with dexamethasone abolishes RhoA activation by knockdown of DLC1 or CDK20 indicating that steroid treatment in patients with pTSNS and mutations in these genes is mediated by this RLSG module. Furthermore, we discover ITSN1 and ITSN2 as podocytic guanine nucleotide exchange factors for Cdc42. We generate Itsn2-L knockout mice that recapitulate the mild NS phenotype. We, thus, define a functional network of RhoA regulation, thereby revealing potential therapeutic targets., Nephrotic syndrome is the second most common chronic kidney disease but there are no targeted treatment strategies available. Here the authors identify mutations of six genes codifying for proteins involved in cytoskeleton remodelling and modulation of small GTPases in 17 families with nephrotic syndrome.

© 2016 by the American Society of Nephrology.FSGS is the most common primary glomerular disease underlying ESRD in the United States and is increasing in incidence globally. FSGS results from podocyte injury, yet the mechanistic details of disease pathogenesis remain unclear. This has resulted in an unmet clinical need for cell-specific therapy in the treatment of FSGS and other proteinuric kidney diseases.We previously identified Yes-associated protein (YAP) as a prosurvival signaling molecule, the in vitro silencing of which increases podocyte susceptibility to apoptotic stimulus. YAP is a potent oncogene that is a prominent target for chemotherapeutic drug development. In this study, we tested the hypothesis that podocyte-specific deletion of Yap leads to proteinuric kidney disease through increased podocyte apoptosis. Yap was selectively silenced in podocytes using Cre-mediated recombination controlled by the podocin promoter. Yap silencing in podocytes resulted in podocyte apoptosis, podocyte depletion, proteinuria, and an increase in serum creatinine. Histologically, features characteristic of FSGS, including mesangial sclerosis, podocyte foot process effacement, tubular atrophy, interstitial fibrosis, and casts, were observed. In human primary FSGS, we noted reduced glomerular expression of YAP. Taken together, these results suggest a role for YAP as a physiologic antagonist of podocyte apoptosis, the signaling of which is essential for maintaining the integrity of the glomerular filtration barrier. These data suggest potential nephrotoxicity with strategies directed toward inhibition of YAP function. Further studies should evaluate the role of YAP in proteinuric glomerular disease pathogenesis and its potential utility as a therapeutic target.

Podocyte loss is central to the progression of proteinuric kidney diseases leading to end-stage kidney disease (ESKD), requiring renal replacement therapy, such as dialysis. Despite modern tools and techniques, the 5-year mortality of some patients requiring dialysis remains at about 70% to 80%. Thus, there is a great unmet need for podocyte-specific treatments aimed at preventing podocyte loss and the ensuing development of ESKD. Here, we show that ablation of the podocyte death-promoting protein dendrin delays the onset of ESKD, thereby expanding the life span of mice lacking the adapter protein CD2AP. Ablation of dendrin delays onset and severity of proteinuria and podocyte loss. In addition, dendrin ablation ameliorates mesangial volume expansion and up-regulation of mesangial fibronectin expression, which is mediated by a podocyte-secreted factor. In conclusion, onset of ESKD and death can be markedly delayed by blocking the function of dendrin.

Large electronic health care databases can be used to evaluate the effectiveness of regulatory action. Designing and interpreting such studies can be challenging. We demonstrate using case studies on modafinil, benzodiazepines, dosulepin, and piroxicam that measuring the impact of regulatory action is possible and can be beneficial, particularly in determining the need for further action or communication. For each case study, we discuss difficulties that may arise when measuring the effectiveness of regulatory action, which include but are not limited to: the choice of denominator, changes in the patient population, the availability and selection of comparators, and the fact that the regulatory voice may be but one voice among many. The evaluation of regulatory action is possible, but not without its challenges, and a routine, one-size-fits all approach is unlikely to be possible.