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Abstract MYCN oncogene amplification is frequently observed in aggressive childhood neuroblastoma. Using an unbiased large-scale mutagenesis screen in neuroblastoma-prone transgenic mice, we identify a single germline point mutation in the transcriptional corepressor Runx1t1, which abolishes MYCN-driven tumorigenesis. This loss-of-function mutation disrupts a highly conserved zinc finger domain within Runx1t1. Deletion of one Runx1t1 allele in an independent Runx1t1 knockout mouse model is also sufficient to prevent MYCN-driven neuroblastoma development, and reverse ganglia hyperplasia, a known pre-requisite for tumorigenesis. Silencing RUNX1T1 in human neuroblastoma cells decreases colony formation in vitro, and inhibits tumor growth in vivo. Moreover, RUNX1T1 knockdown inhibits the viability of PAX3-FOXO1 fusion-driven rhabdomyosarcoma and MYC-driven small cell lung cancer cells. Despite the role of Runx1t1 in MYCN-driven tumorigenesis neither gene directly regulates the other. We show RUNX1T1 forms part of a transcriptional LSD1-CoREST3-HDAC repressive complex recruited by HAND2 to enhancer regions to regulate chromatin accessibility and cell-fate pathway genes.

ABSTRACT The gold standard for measuring insulin sensitivity (IS) is the hyperinsulinemic–euglycemic clamp, a time, costly, and labor‐intensive research tool. A low insulin sensitivity is associated with a complication‐risk in type 1 diabetes. Various formulae using clinical data have been developed and correlated with measured IS in type 1 diabetes. We consolidated multiple formulae into an online calculator (bit.ly/estimated‐GDR), enabling comparison of IS and its probability of IS 6.50 mg/kg/min (high), as measured in a validation set of clamps in 104 adults with type 1 diabetes. Insulin sensitivity calculations using different formulae varied significantly, with correlations (R2) ranging 0.005–0.87 with agreement in detecting low and high glucose disposal rates in the range 49–93% and 89–100%, respectively. We demonstrate that although the calculated IS varies between formulae, their interpretation remains consistent. Our free online calculator offers a user‐friendly tool for individual IS calculations and also offers efficient batch processing of data for research.

Introduction. The emergence of new scientific and clinical evidence on the use of retrograde intrarenal surgery (RIRS) for the management of kidney stones has prompted periodic systematisation, analysis, and evaluation of outcomes to standardise its application and determine future directions for research and development.Objective. To present the Russian adaptation of a guideline on retrograde intrarenal surgery from the International Urolithiasis Alliance guideline series to provide a theoretical basis for urologists performing RIRS.Materials & Methods. A systematic review was conducted on the RIRS-associated publications available in the PubMed database to prepare a set of recommendations during the period from 1 January 1964 until 1 October 2021. The recommendations were evaluated using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) system, which classifies, evaluates, develops, and examines recommendations. The modified Oxford Centre for Evidence-Based Medicine's (OCEBM) system for categorising the level of evidence and relevant comments have been applied to assess the strength of the conclusions.Results. The research team conducted a comprehensive analysis of 36 published clinical guidelines on the following topics: 1. Indications and Contraindications 2. Preoperative Imaging 3. Preoperative Ureteral Stenting 4. Preoperative Medications 5. Perioperative Use of Antibiotics 6. Use of Antithrombotic Therapy 7. Anesthesia Issues 8. Intraoperative Positioning 9. Equipment 10. Complications.Conclusion. A series of recommendations for RIRS, offered here should help provide safe and effective performance of RIRS.

Summary: Background: In the CALCIPHYX trial, we investigated hexasodium fytate, an inhibitor of vascular calcification, for the treatment of calcific uraemic arteriolopathy (calciphylaxis), a rare condition characterised by painful, non-healing skin lesions. Methods: In this international, phase 3, randomised, double-blind, placebo-controlled trial, adults with an ulcerated calciphylaxis lesion and pain visual analogue scale (VAS) score ≥50/100 were randomised 1:1 to hexasodium fytate 7 mg/kg or placebo intravenously during maintenance haemodialysis. Primary efficacy outcomes were an 8-item modification of the Bates-Jensen Wound Assessment Tool (BWAT-CUA) and Pain VAS in the intention-to-treat population. ClinicalTrials.gov number: NCT04195906. Findings: Overall, 34/37 patients randomised to hexasodium fytate and 26/34 patients randomised to placebo completed the 12-week randomised treatment period. At Week 12, both groups (hexasodium fytate versus placebo) showed similar improvements in BWAT-CUA (mean [standard deviation (SD)], −5.3 [5.2] versus −6.0 [6.2]; least squares mean difference, 0.3 [96% confidence interval (CI): −2.5, 3.0]; p = 0.88) and Pain VAS (mean [SD], −19.5 [26.9] versus −32.2 [38.5]; least squares mean difference, 11.5 [96% CI: −4.8, 27.8]; p = 0.15). One patient randomised to placebo briefly received hexasodium fytate in error. Serious adverse events through Week 12 included: calciphylaxis-related events leading to hospitalisation (2/38 [5%] versus 11/33 [33%]) and death (1/38 [3%] versus 5/33 [15%]). During the subsequent 12 weeks of open-label hexasodium fytate and 4 weeks of follow-up, there were no additional calciphylaxis-related events leading to hospitalisation. Over the course of the entire trial, deaths were 2/38 [5%] for the hexasodium fytate group and 7/33 [21%] for the placebo group. Interpretation: In patients with calciphylaxis, BWAT-CUA and Pain VAS improved similarly in hexasodium fytate- and placebo-treated patients; over the course of the entire trial, there were fewer deaths and calciphylaxis-related events leading to hospitalisation in the hexasodium fytate group. Funding: Funded by Sanifit, a CSL Vifor company.

Introduction: There remains an unmet need to reduce kidney and cardiovascular risk in patients with chronic kidney disease (CKD). This report is therefore intended to provide real-world clinical guidance to primary care providers on sodium-glucose co-transporter-2 (SGLT2) inhibitor use in patients with CKD, focusing on practical considerations. Initially developed as glucose-lowering drugs, SGLT2 inhibitors preserve kidney function and reduce risks of cardiovascular events and mortality. Clinical benefits of SGLT2 inhibitors in CKD have been demonstrated in multiple clinical trials, yet utilization in practice remains relatively low, likely due to the complexity of labeled indications (past and present) and misconceptions about SGLT2 inhibitors as a class. Methods: A panel of 8 US-based nephrologists convened in August 2022 to develop consensus guidance for the primary care community surrounding risk assessment as well as initiation and implementation of SGLT2 inhibitors in patients with CKD. Here, we provide an adapted version of the Kidney Disease: Improving Global Outcomes (KDIGO) heatmap and a treatment-decision algorithm. Conclusions: We advocate SGLT2 inhibitors as co-first-line therapy with renin-angiotensin-aldosterone system (RAAS) inhibitors, where RAAS inhibitor dose titration need not be completed before initiation of an SGLT2 inhibitor. In fact, SGLT2 inhibitor therapy may facilitate up-titration or maintenance of optimal RAAS inhibitor dosing. We describe potential strategies to aid implementation of an SGLT2 inhibitor in clinical practice, including improving education and awareness among care providers and patients and dispelling misconceptions about the safety of SGLT2 inhibitors. In summary, we support the use of SGLT2 inhibitors with RAAS inhibitors as co-first-line therapy in most patients with CKD.

Originally developed for use in type 2 diabetes mellitus (T2DM), sodium–glucose co-transporter-2 (SGLT2) inhibitors demonstrated diverse cardiovascular- and kidney-protective effects in large outcome trials. Their subsequent approval as a treatment for chronic kidney disease (CKD) marked a pivotal shift in the landscape of CKD management. Further to this, the approval of dapagliflozin and empagliflozin for use in patients with CKD with and without T2DM afforded new treatment opportunities for this population. SGLT2 inhibitors provide an effective treatment for CKD with a favorable safety profile. However, their uptake has been slow, especially among patients without T2DM, owing perhaps to a lack of certainty and familiarity among health care professionals. As the landscape of CKD management continues to evolve, health care professionals should remain knowledgeable about these changes, and implement new guideline recommendations promptly to avoid therapeutic inertia. SGLT2 inhibitors are recommended for patients with CKD with or without T2DM and are foundational agents to support cardiovascular, kidney, and metabolic health. In this review, we provide evidence-based answers to questions that may be asked in the clinic regarding the use of SGLT2 inhibitors to treat CKD.

Children with Down syndrome (DS) are at increased risk of developing haematological malignancies, in particular acute megakaryoblastic leukaemia and acute lymphoblastic leukaemia. The microenvironment established by abnormal haematopoiesis driven by trisomy 21 is compounded by additional genetic and epigenetic changes that can drive leukaemogenesis in patients with DS. GATA-binding protein 1 ( GATA1 ) somatic mutations are implicated in the development of transient abnormal myelopoiesis and the progression to myeloid leukaemia of DS (ML-DS) and provide a model of the multi-step process of leukaemogenesis in DS. This review summarises key genetic drivers for the development of leukaemia in patients with DS, the biology and treatment of ML-DS and DS-associated acute lymphoblastic leukaemia, late effects of treatments for DS-leukaemias and the focus for future targeted therapy.

Rationale & Objective: In the wake of the coronavirus disease 2019 (COVID-19) pandemic, the United States federal government expanded originating telemedicine sites to include outpatient dialysis units. For the first time, nephrology practitioners across the United States could replace face-to-face visits with telemedicine for patients receiving in-center hemodialysis. This study describes patients’ perspectives on the use of telemedicine during in-center hemodialysis. Study Design: A qualitative study. Setting & Participants: Thirty-two patients from underserved populations (older, less educated, unemployed, persons of color) receiving in-center hemodialysis who used telemedicine with their nephrologist during the COVID-19 pandemic. Analytical Approach: Telephone semistructured interviews were conducted in English or Spanish. Transcripts were thematically analyzed. Results: We identified 6 themes with subthemes: adapting to telemedicine (gaining familiarity and confidence, overcoming and resolving technical difficulties, and relying on staff for communication); ensuring availability of the physician (enabling an immediate response to urgent medical needs, providing peace of mind, addressing patient needs adequately, and enhanced attention and contact from physicians); safeguarding against infection (limiting COVID-19 exposures and decreasing use); straining communication and physical interactions (loss of personalized touch, limited physical examination, and unable to reapproach physicians about forgotten issues); maintaining privacy (enhancing privacy and projecting voice enables others to hear); and supporting confidence in telemedicine (requiring established rapport with physicians, clinical stabilty of health, and ability to have in-person visits when necessary). Limitations: Interviews were conducted later in the pandemic when some nephrology care providers were using telemedicine infrequently. Conclusions: Patients receiving in-center hemodialysis adapted to telemedicine visits by their nephrologists in the context of the COVID-19 pandemic and observed its benefits. However, further considerations regarding communication, privacy, and physical assessments are necessary. Integrating telemedicine into future in-center hemodialysis care using a hybrid approach could potentially build trust, optimize communication, and augment care. Plain-Language Summary: This study describes patients’ perspectives on the use of telemedicine while receiving in-center hemodialysis during the coronavirus disease 2019 (COVID-19) pandemic. Data are derived from semistructured interviews with thirty-two patients from underserved populations (older, less educated, unemployed, persons of color). We identified 6 major themes including adapting to telemedicine, ensuring availability of the physicians, safeguarding against infection, straining communication and physical interactions, maintaining privacy, and supporting confidence in telemedicine. These findings suggest that patients receiving in-center hemodialysis adapted to telemedicine visits by their nephrologists in the context of the COVID-19 pandemic and observed its benefits. However, further considerations regarding communication, privacy, and physical assessments are necessary. Integrating telemedicine into future in-center hemodialysis care using a hybrid approach could potentially build trust, optimize communication, and augment care.

The NASA Atmospheric Tomography (ATom) mission built a photochemical climatology of air parcels based on in situ measurements with the NASA DC-8 aircraft along objectively planned profiling transects through the middle of the Pacific and Atlantic oceans. In this paper we present and analyze a data set of 10s (2km) merged and gap-filled observations of the key reactive species driving the chemical budgets of O3 and CH4 (O3, CH4, CO, H2O, HCHO, H2O2, CH3OOH, C2H6, higher alkanes, alkenes, aromatics, NOx, HNO3, HNO4, peroxyacetyl nitrate, and other organic nitrates), consisting of 146494 distinct air parcels from ATom deployments 1 through 4. Six models calculated the O3 and CH4 photochemical tendencies from this modeling data stream for ATom 1. We find that 80%-90% of the total reactivity lies in the top 50% of the parcels and 25%-35% in the top 10%, supporting previous model-only studies that tropospheric chemistry is driven by a fraction of all the air. Surprisingly, the probability densities of species and reactivities averaged on a model scale (100 km) differ only slightly from the 2km ATom 10s data, indicating that much of the heterogeneity in tropospheric chemistry can be captured with current global chemistry models. Comparing the ATom reactivities over the tropical oceans with climatological statistics from six global chemistry models, we find generally good agreement with the reactivity rates for O3 and CH4. Models distinctly underestimate O3 production below 2km relative to the mid-troposphere, and this can be traced to lower NOx levels than observed. Attaching photochemical reactivities to measurements of chemical species allows for a richer, yet more constrained-to-what-matters, set of metrics for model evaluation. This paper presents a corrected version of the paper published under the same authors and title (sans "corrected") as 10.5194/acp-21-13729-2021.

Introduction: Toxic gain-of-function Apolipoprotein L1 (APOL1) variants contribute to the development of proteinuric nephropathies collectively referred to as APOL1-mediated kidney disease (AMKD). Despite standard-of-care treatments, patients with AMKD experience accelerated progression to end-stage kidney disease. The identification of two APOL1 variants as the genetic cause of AMKD inspired development of inaxaplin, an inhibitor of APOL1 channel activity that reduces proteinuria in patients with AMKD. Methods: We conducted two phase 1 studies evaluating the safety, tolerability, and pharmacokinetics of single-ascending doses (SAD) and multiple-ascending doses (MAD) of inaxaplin in healthy participants. In the SAD cohorts, participants were randomized to receive inaxaplin as a single dose (range, 7.5 mg to 165 mg) or placebo. In the MAD cohorts, participants were randomized to receive multiple doses of inaxaplin (range, 15 to 120 mg daily) or placebo for 14 days. We assessed safety and tolerability based on adverse events (AEs), clinical laboratory values, electrocardiograms (ECGs), and vital signs. Results: A total of 178 participants were randomized in the SAD/MAD cohorts of both studies (mean age: 36.7 years; 94.9% male). The proportion of participants with any AEs was similar in the inaxaplin (24.6%) and placebo (22.7%) groups. All AEs were mild or moderate in severity; there were no serious AEs. Headache was the most common AE: 10.4% and 2.3% in the inaxaplin and placebo groups, respectively. There were no drug-related treatment discontinuations and no clinically relevant trends in laboratory values, ECGs, or vital signs. Discussion/Conclusion: Inaxaplin is safe and well tolerated at single doses up to 165 mg and multiple doses up to 120 mg daily for 14 days. These results are consistent with the favorable safety profile of inaxaplin in a completed phase 2a proof-of-concept study. Together, these findings support continued evaluation of inaxaplin in an ongoing phase 2/3 pivotal trial as a potential precision medicine for patients with AMKD.

Receiving a quality education is a constitutional right of every learner across the globe, regardless of the school's location. Its realization lies in the quality of teaching/learning under the management of the school head. In Buenavista District I, six (6) schools belonged to the last mile schools where learning resources are limited. This study determined the leadership practices of school heads in those schools. The self-made questionnaire was utilized to identify the perception of thirty (30) teachers and (6) school heads. The data collected were analyzed using frequency counting, percentage, weighted mean, and t-test to determine the significant difference between the two groups' perceptions and the significant difference between the problems encountered and the solutions offered. The study revealed a significant difference between the perception of teachers and school heads on the leadership practices but no significant difference in the problems encountered on leadership practices and the solution offered.

Introduction: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and its subtypes, granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic GPA (EGPA), frequently present with acute kidney injury and can often lead to kidney failure, even with successful induction therapy. Few contemporary, nationally representative studies have described hospital complications of AAV. Methods: Using data from the 2016–2020 National Inpatient Sample, a nationally representative database, we identified hospitalizations from adults with a new diagnosis of AAV (subtype or unspecified) and an inpatient kidney biopsy during the index hospitalization. We described baseline characteristics, associated inpatient procedures and complications, and compared lengths of stay and costs by geographic region, hospital characteristics, and AAV subtype. Results: We identified an average of 1,329 cases of hospitalized AAV with a concurrent kidney biopsy per year over the 5-year period. More than 50% were not designated as having a specific subtype, likely owing to delays in documentation of histopathology. Kidney involvement was severe as the majority of patients developed acute kidney injury, and the proportion of patients who required inpatient dialysis was approximately 24%. Approximately 20% of patients developed hypoxia. Inpatient plasmapheresis was delivered to 20.4% and 20.6% of patients with GPA and MPA, respectively. There were no clinically meaningful or statistically significant differences in adjusted length of stay or inpatient costs among AAV subtypes. Admission in the Midwest region was associated with shorter hospital stays and lower costs than that in the Northeast, South, or West regions of the USA (adjusted p = 0.007 and

The period March 2020-March 2021 marks the time reference for this theoretical study as it denotes the initial surge of the Pandemic, where whole societies were destabilized by the ferocity of COVID-19. Within this context, I posit COVID-19 as a transforming event: one that exhausts "worlds." Drawing from Jan Masschelein's works on Arendt and the architecture of public education, the question at hand is how does COVID-19, as a transforming event, affect and change the very essence of education? I begin by comparing two definitions of crisis, Arendt's notion of "krisis," with philosopher Peter Pal Pelbart's thinking around crisis, illness, and 'exhaustion.' I conclude by identifying an 'inconsequential' architectural space, a 'spandrel.' This spatial by-product, revealed during the Pandemic, is located within the very design of the 'perfect' public school, "schole": the Arendtian 'table.' This spandrel aligns with Fernand Deligny's 'primordial communism.'

Introduction Despite the provision of renin-angiotensin-aldosterone-system inhibitors and immunosuppressive therapies, membranous nephropathy often progresses to end-stage kidney disease (ESKD). The objective of this prespecified analysis was to assess the safety and efficacy of dapagliflozin in patients with membranous nephropathy enrolled in the DAPA-CKD trial. Methods Patients with an estimated glomerular filtration rate (eGFR) of 25–75 mL/min/1.73m2 and urinary albumin-to-creatinine ratio (UACR) 200–5000 mg/g were randomized to dapagliflozin 10 mg once daily or placebo, along with standard-of-care and followed for median 2.4 years. The primary endpoint was a composite of ≥50% sustained decline in eGFR, ESKD, or kidney or cardiovascular death. Exploratory efficacy endpoints included eGFR slope and UACR. Results Among DAPA-CKD participants with membranous nephropathy, 19 were randomized to dapagliflozin and 24 to placebo. Mean (SD) age was 59.9 ± 12.1 years; mean eGFR 45.7 ± 12.1 mL/min/1.73m2, and median UACR 1694.5 (25%, 75% range 891–2582.5) mg/g. Two of 19 (11%) patients randomized to dapagliflozin, and five of 24 (21%) randomized to placebo experienced the primary composite endpoint. Total and chronic mean eGFR slopes for dapagliflozin and placebo were −3.87 and −4.29 and −2.66 and −4.22 mL/min/1.73m2/year, respectively; corresponding between-group mean differences were 0.42 and 1.57 mL/min/1.73m2/year. Dapagliflozin reduced geometric mean (SEM) UACR relative to placebo (−29.3% ± 1.2% versus −3.6% ± 1.1%; between-group mean difference [95% CI] −26.7 [−50.4, 8.3]). Four (21%) patients randomized to dapagliflozin and seven (29%) randomized to placebo experienced a serious adverse event. Conclusions In membranous nephropathy, effects of dapagliflozin on kidney disease progression and albuminuria were generally favourable; there was insufficient power to justify formal inference testing.

Rationale & Objective: Because of coronavirus disease 2019 (COVID-19), the US government issued emergency waivers in March 2020 that removed regulatory barriers around the use of telemedicine. For the first time, nephrologists were reimbursed for telemedicine care delivered during in-center hemodialysis. We examined the use of telemedicine for in-center hemodialysis during the first 16 months of the pandemic. Study Design: We ascertained telemedicine modifiers on nephrologist claims. We used multivariable regression to examine time trends and patient, dialysis facility, and geographic correlates of telemedicine use. We also examined whether the estimated effects of predictors of telemedicine use changed over time. Setting & Participants: US Medicare beneficiaries receiving in-center hemodialysis between March 1, 2020, and June 30, 2021. Exposures: Patient, geographic, and dialysis facility characteristics. Outcomes: The use of telehealth for in-center hemodialysis care. Analytic Approach: Retrospective cohort analysis. Results: Among 267,434 Medicare beneficiaries identified, the reported use of telemedicine peaked at 9% of patient-months in April 2020 and declined to 2% of patient-months by June 2021. Telemedicine use varied geographically and was more common in areas that were remote and socioeconomically disadvantaged. Patients were more likely to receive care by telemedicine in areas with higher incidence of COVID-19, although the predictive value of COVID-19 diminished later in the pandemic. Patients were more likely to receive care using telemedicine if they were at facilities with more staff, and the use of telemedicine varied by facility ownership type. Limitations: Limited reporting of telemedicine on claims could lead to underestimation of its use. Reported telemedicine use was higher in an analysis designed to address this limitation by focusing on patients whose physicians used telemedicine at least once during the pandemic. Conclusions: Some US nephrologists continued to use telemedicine for in-center hemodialysis throughout the pandemic, even as the association between COVID-19 incidence and telemedicine use diminished over time. These findings highlight unique challenges and opportunities to the future use of telemedicine in dialysis care. Plain-Language Summary: Emergency waivers issued during the coronavirus disease 2019 pandemic enabled reimbursement to US nephrologists for telemedicine care delivered during in-center hemodialysis. Using modifiers from Medicare claims, we examined telemedicine use in the first 16 months of the pandemic. Reported telemedicine use peaked early in the pandemic and declined subsequently. Telemedicine use was more common in areas that were remote and socioeconomically disadvantaged and at facilities with more staff. Telemedicine use also varied by facility ownership type. Some nephrologists continued to use telemedicine for in-center hemodialysis throughout the pandemic, even as the association between coronavirus disease 2019 incidence and telemedicine use diminished over time. These findings highlight unique challenges and opportunities to the future use of telemedicine in dialysis care.

Patients with chronic kidney disease (CKD) develop anemia largely because of inappropriately low erythropoietin (EPO) production and insufficient iron available to erythroid precursors. In four phase 3, randomized, open-label, clinical trials in dialysis-dependent and non-dialysis-dependent patients with CKD and anemia, the hypoxia-inducible factor prolyl hydroxylase inhibitor, vadadustat, was noninferior to the erythropoiesis-stimulating agent, darbepoetin alfa, in increasing and maintaining target hemoglobin concentrations. In these trials, vadadustat increased the concentrations of serum EPO, the numbers of circulating erythrocytes, and the numbers of circulating reticulocytes. Achieved hemoglobin concentrations were similar in patients treated with either vadadustat or darbepoetin alfa, but compared with patients receiving darbepoetin alfa, those receiving vadadustat had erythrocytes with increased mean corpuscular volume and mean corpuscular hemoglobin, while the red cell distribution width was decreased. Increased serum transferrin concentrations, as measured by total iron-binding capacity, combined with stable serum iron concentrations, resulted in decreased transferrin saturation in patients randomized to vadadustat compared with patients randomized to darbepoetin alfa. The decreases in transferrin saturation were associated with relatively greater declines in serum hepcidin and ferritin in patients receiving vadadustat compared with those receiving darbepoetin alfa. These results for serum transferrin saturation, hepcidin, ferritin, and erythrocyte indices were consistent with improved iron availability in the patients receiving vadadustat. Thus, overall, vadadustat had beneficial effects on three aspects of erythropoiesis in patients with anemia associated with CKD: increased endogenous EPO production, improved iron availability to erythroid cells, and increased reticulocytes in the circulation.