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BACKGROUND: An accurate, rapid estimate of glomerular filtration rate (GFR) in kidney transplant patients affords early detection of transplant deterioration and timely intervention. This study compared the performance of serum creatinine (Cr) and cystatin C (CysC)-based GFR equations to measured GFR (mGFR) using iohexol among pediatric kidney transplant recipients. METHODS: CysC, Cr, and mGFR were obtained from 45 kidney transplant patients, 1-18 years old. Cr- and CysC-estimated GFR (eGFR) was compared against mGFR using the Cr-based (Bedside Schwartz, U25-Cr), CysC-based (Gentian CysC, CAPA, U25-CysC), and Cr-CysC combination (CKiD Cr-CysC, U25 Cr-CysC) equations in terms of bias, precision, and accuracy. Bland-Altman plots assessed the agreement between eGFR and mGFR. Secondary analyses evaluated the formulas in patients with biopsy-proven histological changes, and K/DOQI CKD staging. RESULTS: Bias was small with Gentian CysC (0.1 ml/min/1.73 m2); 88.9% and 37.8% of U25-CysC estimations were within 30% and 10% of mGFR, respectively. In subjects with histological changes on biopsy, Gentian CysC had a small bias and U25-CysC were more accurate-both with 83.3% of and 41.7% of estimates within 30% and 10% mGFR, respectively. Precision was better with U25-CysC, CKiD Cr-CysC, and U25 Cr-CysC. Bland-Altman plots showed the Bedside Schwartz, Gentian CysC, CAPA, and U25-CysC tend to overestimate GFR when > 100 ml/min/1.72 m2. CAPA misclassified CKD stage the least (whole cohort 24.4%, histological changes on biopsy 33.3%). CONCLUSIONS: In this small cohort, CysC-based equations with or without Cr may have better bias, precision, and accuracy in predicting GFR.

Schwann cells (SCs) undergo phenotypic transformation and then orchestrate nerve repair following PNS injury. The ligands and receptors that activate and sustain SC transformation remain incompletely understood. Proteins released by injured axons represent important candidates for activating the SC Repair Program. The low-density lipoprotein receptor-related protein-1 (LRP1) is acutely up-regulated in SCs in response to injury, activating c-Jun, and promoting SC survival. To identify novel LRP1 ligands released in PNS injury, we applied a discovery-based approach in which extracellular proteins in the injured nerve were captured using Fc-fusion proteins containing the ligand-binding motifs of LRP1 (CCR2 and CCR4). An intracellular neuron-specific protein, Protein Kinase C and Casein Kinase Substrate in Neurons (PACSIN1) was identified and validated as an LRP1 ligand. Recombinant PACSIN1 activated c-Jun and ERK1/2 in cultured SCs. Silencing Lrp1 or inhibiting the LRP1 cell-signaling co-receptor, the NMDA-R, blocked the effects of PACSIN1 on c-Jun and ERK1/2 phosphorylation. Intraneural injection of PACSIN1 into crush-injured sciatic nerves activated c-Jun in wild-type mice, but not in mice in which Lrp1 is conditionally deleted in SCs. Transcriptome profiling of SCs revealed that PACSIN1 mediates gene expression events consistent with transformation to the repair phenotype. PACSIN1 promoted SC migration and viability following the TNFα challenge. When Src family kinases were pharmacologically inhibited or the receptor tyrosine kinase, TrkC, was genetically silenced or pharmacologically inhibited, PACSIN1 failed to induce cell signaling and prevent SC death. Collectively, these studies demonstrate that PACSIN1 is a novel axon-derived LRP1 ligand that activates SC repair signaling by transactivating TrkC.

Vincenza Bonfiglio, Michele Reibaldi, Matteo Fallico, Andrea Russo, Alessandra Pizzo, Stefano Fichera, Carlo Rapisarda, Iacopo Macchi, Teresio Avitabile, Antonio Longo Department of Ophthalmology, University of Catania, Catania, Italy Abstract: Sustained-release intravitreal 0.7 mg dexamethasone (DEX) implant is approved in Europe for the treatment of macular edema related to diabetic retinopathy, branch retinal vein occlusion, central retinal vein occlusion, and non-infectious uveitis. The implant is formulated in a biodegradable copolymer to release the active ingredient within the vitreous chamber for up to 6 months after an intravitreal injection, allowing a prolonged interval of efficacy between injections with a good safety profile. Various other ocular pathologies with inflammatory etiopathogeneses associated with macular edema have been treated by DEX implant, including neovascular age-related macular degeneration, Irvine–Gass syndrome, vasoproliferative retinal tumors, retinal telangiectasia, Coats’ disease, radiation maculopathy, retinitis pigmentosa, and macular edema secondary to scleral buckling and pars plana vitrectomy. We undertook a review to provide a comprehensive collection of all of the diseases that benefit from the use of the sustained-release DEX implant, alone or in combination with concomitant therapies. A MEDLINE search revealed lack of randomized controlled trials related to these indications. Therefore we included and analyzed all available studies (retrospective and prospective, comparative and non-comparative, randomized and nonrandomized, single center and multicenter, and case report). There are reports in the literature of the use of DEX implant across a range of macular edema-related pathologies, with their clinical experience supporting the use of DEX implant on a case-by-case basis with the aim of improving patient outcomes in many macular pathologies. As many of the reported macular pathologies are difficult to treat, a new treatment option that has a beneficial influence on the clinical course of the disease may be useful in clinical practice. Keywords: macular edema, dexamethasone, intravitreal, implant, corticosteroids

This article examines the needs in New York State for public policy to address disparities in educational outcomes, opportunities to learn and appropriate evaluations that assess student readiness to advance in their education or work opportunities. Several proposals for educational public policy changes and practices are offered in the conclusion of this article.

Abstract The word ‘icon’ usually refers to a symbol, a famous person admired by all, or a religious image used for worship. Twentieth and twenty-first century icons are also sacred images of secular societies that help construct collective identities and delineate the zeitgeist. Places can also be considered icons if looked through social semiotic lenses. Through Kress and van Leeuwen (2006) and O’Toole’s (1990; 1994; 2004) re-conceptualisations of Halliday’s Systemic Functional Linguistics (1994) and the concept of Bonding Icons (Stenglin 2008a; 2008b; 2012), this paper investigates the ways in which the New York City DragCon 2019 became a rallying and bonding place that both abstractly, through its website, and concretely, through the actual event, gave people a sense of belonging. The main goal of the study is to underline the extent to which the rallying and bonding is money-driven and to highlight the ties between consumerism and the concept of ‘icons selling icons’.

Abstract Membrane contact sites (MCSs) are hubs allowing various cell organelles to coordinate their activities. The dynamic nature of these sites and their small size hinder analysis by current imaging techniques. To overcome these limitations, we here design a series of reversible chemogenetic reporters incorporating improved, low-affinity variants of splitFAST, and study the dynamics of different MCSs at high spatiotemporal resolution, both in vitro and in vivo. We demonstrate that these versatile reporters suit different experimental setups well, allowing one to address challenging biological questions. Using these probes, we identify a pathway in which calcium (Ca2+) signalling dynamically regulates endoplasmic reticulum-mitochondria juxtaposition, characterizing the underlying mechanism. Finally, by integrating Ca2+-sensing capabilities into the splitFAST technology, we introduce PRINCESS (PRobe for INterorganelle Ca2+-Exchange Sites based on SplitFAST), a class of reporters to simultaneously detect MCSs and measure the associated Ca2+ dynamics using a single biosensor.

Abstract Background This paper reports the results from a feasibility trial of an early parent-delivered social communication intervention for young children with Down syndrome (‘ASCEND’). The intervention focuses on developing children’s early social communication skills, in particular responding to shared attention. The aim was to inform the feasibility of running a full-scale trial through National Health Service (NHS) Speech and Language Therapy (SaLT) services, to assess whether the intervention is effective in improving language skills before children with Down syndrome start school. Methods This was a two-arm feasibility randomised controlled trial (RCT), with 1:1 randomisation stratified by trial site, comparing the intervention plus standard NHS SaLT provision with standard NHS SaLT alone. We recruited 20 children with Down syndrome aged between 11 and 36 months through 3 NHS SaLT services, 19 of whom were randomised (10 — intervention group, 9 —control group). Pre- and post-intervention and 6-month follow-up assessments included language, social communication skills, adaptive behaviour, quality of life (parents and children), parental anxiety and depression. The intervention was parent delivered with parents having access to SaLT services and the research team during the intervention. Data were collected on recruitment and retention, standard care, treatment fidelity, acceptability of the intervention by the parents and speech and language therapists, feasibility of collecting health economic measures and suitability of the primary outcome measure. Results The sample was sufficient for a feasibility study. The intervention (manual, support, materials) was positively received by the participating parents. Speech and language therapists also evaluated the acceptability of the intervention positively. Treatment fidelity which was measured by completion of weekly parent diaries and two adherence phone call was acceptable as 100% of the parent diaries were returned, over 90% of the parental diaries were completed correctly and 100% of adherence phone calls were completed. Retention was acceptable at 84% overall. The preliminary health economic data suggest that this intervention will be low cost. The sample size calculation suggests that 290 participants would need to be recruited, with 228 having a complete data set, for a full RCT. Conclusion Based on recruitment, retention and treatment fidelity, as well as the acceptability of the intervention to parents and speech and language therapists, a full-scale trial would be feasible in order to assess the effectiveness of the intervention. Trial registration ISRCTN13902755, registered on 25th August 2020, http://www.isrctn.com/ISRCTN13902755

IntroductionMortality from preeclampsia (PE) and PE-associated morbidities are 3-to 5-fold higher in persons of African ancestry than in those of Asian and European ancestries.MethodsTo elucidate placental contribution to worse PE outcomes in African ancestry pregnancies, we performed bulk RNA sequencing on 50 placentas from persons with severe PE (sPE) of African (n = 9), Asian (n = 18) and European (n = 23) ancestries and 73 normotensive controls of African (n = 10), Asian (n = 15) and European (n = 48) ancestries.ResultsPreviously described canonical preeclampsia genes, involved in metabolism and hypoxia/angiogenesis including: LEP, HK2, FSTL3, FLT1, ENG, TMEM45A, ARHGEF4 and HTRA1 were upregulated sPE versus normotensive placentas across ancestries. LTF, NPR3 and PHYHIP were higher in African vs. Asian ancestry sPE placentas. Allograft rejection/adaptive immune response genes were upregulated in placentas from African but not in Asian or European ancestry sPE patients; IL3RA was of particular interest because the patient with the highest placental IL3RA expression, a person of African ancestry with sPE, developed postpartum cardiomyopathy, and was the only patient out of 123, that developed this condition. Interestingly, the sPE patients with the highest IL3RA expression among persons of Asian and European ancestries developed unexplained tachycardia peripartum, necessitating echocardiography in the European ancestry patient. The association between elevated placental IL3RA levels and unexplained tachycardia or peripartum cardiomyopathy was found to be significant in the 50 sPE patients (p = .0005).DiscussionHigh placental upregulation of both canonical preeclampsia and allograft rejection/adaptive immune response genes may contribute to worse PE outcomes in African ancestry sPE patients.

Abstract Cellular senescence is characterized by a permanent growth arrest and is associated with tissue aging and cancer. Senescent cells secrete a number of different cytokines referred to as the senescence-associated secretory phenotype (SASP), which impacts the surrounding tissue and immune response. Here, we find that senescent cells exhibit higher rates of protein synthesis compared to proliferating cells and identify eIF5A as a crucial regulator of this process. Polyamine metabolism and hypusination of eIF5A play a pivotal role in sustaining elevated levels of protein synthesis in senescent cells. Mechanistically, we identify a p53-dependent program in senescent cells that maintains hypusination levels of eIF5A. Finally, we demonstrate that functional eIF5A is required for synthesizing mitochondrial ribosomal proteins and monitoring the immune clearance of premalignant senescent cells in vivo. Our findings establish an important role of protein synthesis during cellular senescence and suggest a link between eIF5A, polyamine metabolism, and senescence immune surveillance.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive head trauma. Brain pathology in CTE is characterized by neuronal loss, gliosis, and a distinctive pattern of neuronal accumulation of hyper-phosphorylated tau (p-tau) and phospho-TDP43 (p-TDP43). Visual anomalies have been reported by patients with CTE, but the ocular pathology underlying these symptoms is unknown. We evaluated retinal pathology in post-mortem eyes collected from 8 contact sport athletes with brain autopsy-confirmed stage IV CTE and compared their findings to retinas from 8 control patients without CTE and with no known history of head injury. Pupil-optic nerve cross sections were prepared and stained with hematoxylin and eosin (H&E), p-tau, p-TDP43, and total TDP43 by immunohistochemistry. No significant retinal degeneration was observed in CTE eyes compared to control eyes by H&E. Strong cytoplasmic p-TDP43 and total TDP43 staining was found in 6/8 CTE eyes in a subset of inner nuclear layer interneurons (INL) of the retina, while only 1/8 control eyes showed similar p-TDP43 pathology. The morphology and location of these inner nuclear layer interneurons were most compatible with retinal horizontal cells, although other retinal cell types present in INL could not be ruled out. No p-tau pathology was observed in CTE or control retinas. These findings identify novel retinal TDP43 pathology in CTE retinas and support further investigation into the role of p-TDP43 in producing visual deficits in patients with CTE.

Alzheimer's disease (AD) is the most prevalent cause of dementia; microglia have been implicated in AD pathogenesis, but their role is still matter of debate. Our study showed that single systemic wild-type (WT) hematopoietic stem and progenitor cell (HSPC) transplantation rescued the AD phenotype in 5xFAD mice and that transplantation may prevent microglia activation. Indeed, complete prevention of memory loss and neurocognitive impairment and decrease of β-amyloid plaques in the hippocampus and cortex were observed in the WT HSPC-transplanted 5xFAD mice compared with untreated 5xFAD mice and with mice transplanted with 5xFAD HSPCs. Neuroinflammation was also significantly reduced. Transcriptomic analysis revealed a significant decrease in gene expression related to "disease-associated microglia" in the cortex and "neurodegeneration-associated endothelial cells" in the hippocampus of the WT HSPC-transplanted 5xFAD mice compared with diseased controls. This work shows that HSPC transplant has the potential to prevent AD-associated complications and represents a promising therapeutic avenue for this disease.

ObjectiveThis study aims to evaluate the efficacy and safety of deep brain stimulation (DBS) of the medial pulvinar nucleus (PuM) in reducing seizure frequency and addressing comorbidities in patients with drug and vagal nerve-resistant focal epilepsy.MethodsThis is an open-label prospective treatment trial with a planned enrollment of 12 patients suffering from medically refractory epilepsy (Clinical trial gov NCT04692701), for which the interim 12-month post-implantation results for the first 6 patients are being reported. Inclusion criteria were focal epilepsy not suitable for or after failed surgical intervention and previous failure of neurostimulation therapies (vagus nerve stimulation or anterior thalamic nucleus DBS). Evaluations included seizure diaries, neuropsychological assessments, and scales for depression, anxiety, quality of life, and seizure severity. PuM DBS was performed using ROSA robotic assistance, with follow-ups every 3 months for 1 year.ResultsOut of six patients, five completed 1-year follow-up (one patient died prematurely). A non-significant trend toward seizure reduction was observed at 6 months, becoming more pronounced at 1 year (mean reduction: 45%; responders: 2/5). Seizure severity significantly improved (p = 0.02), with a reduction in the NHS3 scale scores. Quality of life improved significantly at 1 year (p = 0.03). Psychiatric assessments indicated a non-significant trend toward improvement in depression (mean improvement: 26%) and anxiety (mean improvement: 20%) scores. Neuropsychological testing showed stable or improved cognitive performance in three out of five patients. Adverse events included one case of cerebral hemorrhage, one infection leading to device removal, and one possible SUDEP.SignificancePreliminary results suggest that PuM DBS may offer a promising therapeutic option for reducing seizure severity and improving quality of life and cognitive functions in patients with drug-resistant epilepsy. Despite the small sample size and the presence of serious adverse events, the findings warrant further investigation with larger cohorts to confirm these trends and optimize the treatment protocol.

Not available.

The coronavirus disease 2019 (COVID-19) pandemic rapidly boosted the introduction of certain changes in mental healthcare services, consequently driving up the adoption of remote care delivery options. We conducted an online Italian survey to evaluate telepsychology use, attitudes, acceptance, and training needs, as well as to understand patient-professional interactions in video-consultations, aiming to inform future mental healthcare practices and policies. The current study's survey responses were collected using an anonymous, self-reported questionnaire on the ‘REDCap’ platform from 25 October 2022 to 26 July 2023. In total, 128 mental health professionals and 113 patients completed the survey. In our sample, 69 % of patients and 79.7 % of mental health professionals reported having used telepsychology during COVID-19 pandemic; in particular, 84.6 % of patients and 95.1 % of professionals selected video-consultation modality. Data showed that participants expressed high satisfaction with this communication tool. The increase in satisfaction was directly proportional to increase in the quality of interactions and in relation to the quality of the experiences. The critical factors influencing the video-consultation experience include communication style, information completeness, patient-centredness, and the comfort underscoring the central role of the professional-patient relationship, which, substantially, remains a key element in the psychological treatment process. These findings reinforce the need for continued refinement and expansion of telepsychology services, thus highlighting the potential for integrating innovative technologies into mental health practise.

Abstract Following a request from the European Commission, the Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on the safety of a feed additive consisting of vitamin B2/riboflavin produced with Eremothecium ashbyi CCTCCM 2019833 intended for use as a nutritional additive (functional group: vitamins, pro‐vitamins and chemically well‐defined substances having similar effects) for all animal species. The characterisation, safety and efficacy of the additive have been already assessed previously; however, the FEEDAP Panel could not conclude on the safety of the additive for the target species, consumers and the users due to lack of reliable toxicological data. In the present assessment, the applicant submitted new genotoxicity and repeated dose oral toxicity studies. After the assessment of the data newly submitted, the FEEDAP Panel concluded that the use of the feed additive in animal nutrition under the conditions of use proposed is of no safety concern for the target species and the consumer. The additive is not a skin/eye irritant nor a skin sensitiser, but it is considered a respiratory sensitiser.