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Background: Outcomes after relapse remain poor in pediatric patients with acute myeloid leukemia (AML), and new therapeutic approaches are needed. Lenalidomide has demonstrated activity in adults with lower risk myelodysplastic syndromes and older adults with relapsed or refractory (R/R) AML., Methods: In this phase 2 study (NCT02538965), pediatric patients with R/R AML who received two or more prior therapies were treated with lenalidomide (starting dose 2 mg/kg/day on days 1-21 of each 28-day cycle) for a maximum of 12 cycles. The primary endpoint was rate of complete response (CR) and CR with incomplete blood count recovery (CRi) within the first four cycles., Results: Seventeen patients enrolled and received one or more dose of lenalidomide. Median age was 12 years (range 5-18 years), median white blood cell count was 3.7 × 10 9 /L, and median peripheral blood blast count was 1.0 × 10 9 /L. One patient (5.9%) with a complex karyotype including del(5q) achieved CRi after two cycles of lenalidomide. This responder proceeded to a second hematopoietic stem cell transplantation and has remained without evidence of disease for 3 years. All patients experienced one or more of grades 3-4 treatment-emergent adverse event (TEAE). The most common grades 3-4 TEAEs were thrombocytopenia (58.8%), febrile neutropenia (47.1%), anemia (41.2%), and hypokalemia (41.2%)., Conclusions: In this population of pediatric patients with R/R AML, safety data were consistent with the known safety profile of lenalidomide. As only one patient responded, further evaluation of lenalidomide at the dose and schedule studied is not warranted in pediatric AML, with the possible exception of patients with del(5q)., (© 2021 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

The avibirnavirus infectious bursal disease virus (IBDV) is responsible for a highly contagious and sometimes lethal disease of chickens ( Gallus gallus ). IBDV genetic variation is well-described for both field and live-attenuated vaccine strains, however, the dynamics and selection pressures behind this genetic evolution remain poorly documented. Here, genetically homogeneous virus stocks were generated using reverse genetics for a very virulent strain, rvv, and a vaccine-related strain, rCu-1. These viruses were serially passaged at controlled multiplicities of infection in several biological systems, including primary chickens B cells, the main cell type targeted by IBDV in vivo . Passages were also performed in the absence or presence of a strong selective pressure using the antiviral nucleoside analog 7-deaza-2'-C-methyladenosine (7DMA). Next Generation Sequencing (NGS) of viral genomes after the last passage in each biological system revealed that (i) a higher viral diversity was generated in segment A than in segment B, regardless 7DMA treatment and viral strain, (ii) diversity in segment B was increased by 7DMA treatment in both viruses, (iii) passaging of IBDV in primary chicken B cells, regardless of 7DMA treatment, did not select cell-culture adapted variants of rvv, preserving its capsid protein (VP2) properties, (iv) mutations in coding and non-coding regions of rCu-1 segment A could potentially associate to higher viral fitness, and (v) a specific selection, upon 7DMA addition, of a Thr329Ala substitution occurred in the viral polymerase VP1. The latter change, together with Ala270Thr change in VP2, proved to be associated with viral attenuation in vivo . These results identify genome sequences that are important for IBDV evolution in response to selection pressures. Such information will help tailor better strategies for controlling IBDV infection in chickens., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Cubas-Gaona, Flageul, Courtillon, Briand, Contrant, Bougeard, Lucas, Quenault, Leroux, Keita, Amelot, Grasland, Blanchard, Eterradossi, Brown and Soubies.)

Introduction : Upfront treatment of pediatric patients with B-cell acute lymphoblastic leukemia (B-ALL) and T-cell acute lymphoblastic leukemia (T-ALL) results in cure rates of 60-95%, depending on risk factors. However, patients with refractory or relapsed B-ALL or T-ALL have much worse outcomes with conventional chemotherapy, hence treatment of these cohorts with novel agents is a priority. Areas Covered : This paper reviews early phase clinical trials in pediatric leukemia. Investigational antibody therapy, chimeric antigen receptor T-cell (CAR-T), and other targeted therapies are examined. The authors discuss the mechanisms of action, side effects, trial designs, and outcomes and reflect on potential research directions. PubMed and Clinicaltrials.gov were searched from 2010 to present, using keywords 'lymphoblastic leukemia' with filters for pediatric age, Phase 1 clinical trial and Phase 2 clinical trial. Expert Opinion : Pediatric patients with relapsed or refractory leukemia often do not derive additional benefit from intensified conventional chemotherapy approaches which have arguably been maximized in the upfront setting. Therefore, novel approaches, such as immunotherapy and targeted agents should be prioritized. Progress will require commitment from pharmaceutical companies regarding these orphan diagnoses and acknowledgment from regulatory bodies that outcomes are suboptimal with conventional chemotherapy.

Despite a remarkable increase in the genomic profiling of cancer, integration of genomic discoveries into clinical care has lagged behind. We report the feasibility of rapid identification of targetable mutations in 153 pediatric patients with relapsed/refractory or high-risk leukemias enrolled on a prospective clinical trial conducted by the LEAP Consortium. Eighteen percent of patients had a high confidence Tier 1 or 2 recommendation. We describe clinical responses in the 14% of patients with relapsed/refractory leukemia who received the matched targeted therapy. Further, in order to inform future targeted therapy for patients, we validated variants of uncertain significance, performed ex vivo drug-sensitivity testing in patient leukemia samples, and identified new combinations of targeted therapies in cell lines and patient-derived xenograft models. These data and our collaborative approach should inform the design of future precision medicine trials. SIGNIFICANCE: Patients with relapsed/refractory leukemias face limited treatment options. Systematic integration of precision medicine efforts can inform therapy. We report the feasibility of identifying targetable mutations in children with leukemia and describe correlative biology studies validating therapeutic hypotheses and novel mutations. See related commentary by Bornhauser and Bourquin, p. 1322 . This article is highlighted in the In This Issue feature, p. 1307 ., (©2021 American Association for Cancer Research.)

Infants with KMT2A-rearranged acute lymphoblastic leukemia (KMT2A-r ALL) have a poor prognosis. KMT2A-r ALL overexpresses FLT3, and the FLT3 inhibitor (FLT3i) lestaurtinib potentiates chemotherapy-induced cytotoxicity in preclinical models. Children's Oncology Group (COG) AALL0631 tested whether adding lestaurtinib to post-induction chemotherapy improved event-free survival (EFS). After chemotherapy induction, KMT2A-r infants received either chemotherapy only or chemotherapy plus lestaurtinib. Correlative assays included FLT3i plasma pharmacodynamics (PD), which categorized patients as inhibited or uninhibited, and FLT3i ex vivo sensitivity (EVS), which categorized leukemic blasts as sensitive or resistant. There was no difference in 3-year EFS between patients treated with chemotherapy plus lestaurtinib (n = 67, 36 ± 6%) vs. chemotherapy only (n = 54, 39 ± 7%, p = 0.67). However, for the lestaurtinib-treated patients, FLT3i PD and FLT3i EVS significantly correlated with EFS. For FLT3i PD, EFS for inhibited/uninhibited was 59 ± 10%/28 ± 7% (p = 0.009) and for FLTi EVS, EFS for sensitive/resistant was 52 ± 8%/5 ± 5% (p < 0.001). Seventeen patients were both inhibited and sensitive, with an EFS of 88 ± 8%. Adding lestaurtinib did not improve EFS overall, but patients achieving potent FLT3 inhibition and those whose leukemia blasts were sensitive FLT3-inhibition ex vivo did benefit from the addition of lestaurtinib. Patient selection and PD-guided dose escalation may enhance the efficacy of FLT3 inhibition for KMT2A-r infant ALL.

Survival of infants with KMT2A-rearranged (R) acute lymphoblastic leukemia (ALL) remains dismal despite intensive chemotherapy. We observed constitutive phosphorylation of spleen tyrosine kinase (SYK) and associated signaling proteins in infant ALL patient-derived xenograft (PDX) model specimens and hypothesized that the SYK inhibitor entospletinib would inhibit signaling and cell growth in vitro and leukemia proliferation in vivo. We further predicted that combined entospletinib and chemotherapy could augment anti-leukemia effects. Basal kinase signaling activation and HOXA9/MEIS1 expression differed among KMT2A-R (KMT2A-AFF1 [n=4], KMT2A-MLLT3 [n=1], KMT2A-MLLT1 [n=4]) and non-KMT2A-R [n=3] ALL specimens and stratified by genetic subgroup. Incubation of KMT2A-R ALL cells in vitro with entospletinib inhibited methylcellulose colony formation and SYK pathway signaling in a dose-dependent manner. In vivo inhibition of leukemia proliferation with entospletinib monotherapy was observed in RAS-wild-type KMT2A-AFF1, KMT2A-MLLT3, and KMT2A-MLLT1 ALL PDX models with enhanced activity in combination with vincristine chemotherapy in several models. Surprisingly, entospletinib did not decrease leukemia burden in two KMT2A-AFF1 PDX models with NRAS/ or KRAS mutations, suggesting potential RAS-mediated resistance to SYK inhibition. As hypothesized, superior inhibition of ALL proliferation was observed in KMT2A-AFF1 PDX models treated with entospletinib and the MEK inhibitor selumetinib versus vehicle or inhibitor monotherapies (p.

In cancer, linking epigenetic alterations to drivers of transformation has been difficult, in part because DNA methylation analyses must capture epigenetic variability, which is central to tumour heterogeneity and tumour plasticity. Here, by conducting a comprehensive analysis, based on information theory, of differences in methylation stochasticity in samples from patients with paediatric acute lymphoblastic leukaemia (ALL), we show that ALL epigenomes are stochastic and marked by increased methylation entropy at specific regulatory regions and genes. By integrating DNA methylation and single-cell gene-expression data, we arrived at a relationship between methylation entropy and gene-expression variability, and found that epigenetic changes in ALL converge on a shared set of genes that overlap with genetic drivers involved in chromosomal translocations across the disease spectrum. Our findings suggest that an epigenetically driven gene-regulation network, with UHRF1 (ubiquitin-like with PHD and RING finger domains 1) as a central node, links genetic drivers and epigenetic mediators in ALL.

Competing Interests: P.-A. Brown reports receiving grants from Otsuka Canada, personal fees from Otsuka Canada, and personal fees from Amgen outside the submitted work. All remaining authors have nothing to disclose.

Immunotherapies such as chimeric antigen receptor (CAR) T cells and bispecific antibodies redirect healthy T cells to kill cancer cells expressing the target antigen. The pan-B cell antigen-targeting immunotherapies have been remarkably successful in treating B cell malignancies. Such therapies also result in the near-complete loss of healthy B cells, but this depletion is well tolerated by patients. Although analogous targeting of pan-T cell markers could, in theory, help control T cell cancers, the concomitant healthy T cell depletion would result in severe and unacceptable immunosuppression. Thus, therapies directed against T cell cancers require more selective targeting. Here, we describe an approach to target T cell cancers through T cell receptor (TCR) antigens. Each T cell, normal or malignant, expresses a unique TCR β chain generated from 1 of 30 TCR β chain variable gene families (TRBV1 to TRBV30). We hypothesized that bispecific antibodies targeting a single TRBV family member expressed in malignant T cells could promote killing of these cancer cells, while preserving healthy T cells that express any of the other 29 possible TRBV family members. We addressed this hypothesis by demonstrating that bispecific antibodies targeting TRBV5-5 (α-V5) or TRBV12 (α-V12) specifically lyse relevant malignant T cell lines and patient-derived T cell leukemias in vitro. Treatment with these antibodies also resulted in major tumor regressions in mouse models of human T cell cancers. This approach provides an off-the-shelf, T cell cancer selective targeting approach that preserves enough healthy T cells to maintain cellular immunity., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Importance: Standard chemotherapy for first relapse of B-cell acute lymphoblastic leukemia (B-ALL) in children, adolescents, and young adults is associated with high rates of severe toxicities, subsequent relapse, and death, especially for patients with early relapse (high risk) or late relapse with residual disease after reinduction chemotherapy (intermediate risk). Blinatumomab, a bispecific CD3 to CD19 T cell-engaging antibody construct, is efficacious in relapsed/refractory B-ALL and has a favorable toxicity profile., Objective: To determine whether substituting blinatumomab for intensive chemotherapy in consolidation therapy would improve survival in children, adolescents, and young adults with high- and intermediate-risk first relapse of B-ALL., Design, Setting, and Participants: This trial was a randomized phase 3 clinical trial conducted by the Children's Oncology Group at 155 hospitals in the US, Canada, Australia, and New Zealand with enrollment from December 2014 to September 2019 and follow-up until September 30, 2020. Eligible patients included those aged 1 to 30 years with B-ALL first relapse, excluding those with Down syndrome, Philadelphia chromosome-positive ALL, prior hematopoietic stem cell transplant, or prior blinatumomab treatment (n = 669)., Interventions: All patients received a 4-week reinduction chemotherapy course, followed by randomized assignment to receive 2 cycles of blinatumomab (n = 105) or 2 cycles of multiagent chemotherapy (n = 103), each followed by transplant., Main Outcome and Measures: The primary end point was disease-free survival and the secondary end point was overall survival, both from the time of randomization. The threshold for statistical significance was set at a 1-sided P <.025., Results: Among 208 randomized patients (median age, 9 years; 97 [47%] females), 118 (57%) completed the randomized therapy. Randomization was terminated at the recommendation of the data and safety monitoring committee without meeting stopping rules for efficacy or futility; at that point, 80 of 131 planned events occurred. With 2.9 years of median follow-up, 2-year disease-free survival was 54.4% for the blinatumomab group vs 39.0% for the chemotherapy group (hazard ratio for disease progression or mortality, 0.70 [95% CI, 0.47-1.03]); 1-sided P = .03). Two-year overall survival was 71.3% for the blinatumomab group vs 58.4% for the chemotherapy group (hazard ratio for mortality, 0.62 [95% CI, 0.39-0.98]; 1-sided P = .02). Rates of notable serious adverse events included infection (15%), febrile neutropenia (5%), sepsis (2%), and mucositis (1%) for the blinatumomab group and infection (65%), febrile neutropenia (58%), sepsis (27%), and mucositis (28%) for the chemotherapy group., Conclusions and Relevance: Among children, adolescents, and young adults with high- and intermediate-risk first relapse of B-ALL, postreinduction treatment with blinatumomab compared with chemotherapy, followed by transplant, did not result in a statistically significant difference in disease-free survival. However, study interpretation is limited by early termination with possible underpowering for the primary end point., Trial Registration: ClinicalTrials.gov Identifier: NCT02101853.

Objective: Carboplatin is a cytotoxic chemotherapy drug developed in the 1980s which is still widely used today across various tumour types. Despite its common application, there remains a significant controversy and practice variation on its unique method of dosing by area under the curve (AUC). One potential reason for this variability stems from the reliance of using an estimated glomerular filtration rate (eGFR) as an extrapolation of the measured GFR (mGFR) which the commonly used Calvert equation was originally validated for. This review takes a novel and collaborative nephro-oncology approach to highlight the historical evolution of carboplatin dosing, methods for estimating GFR and its relative performance in the application of carboplatin dosing for adult patients., Data Sources: We reviewed all pertinent publications comparing carboplatin AUC-based dosing in adult patients based on the various methods of GFR measurements or estimations in order to provide a comprehensive description of each method's advantages and risks., Data Summary and Conclusions: The Cockcroft-Gault equation has been widely studied but newer eGFR equations, such as the CKD-Epidemiology Collaboration (CKD-EPI) or Janowitz-Williams equation have outperformed the Cockcroft-Gault in recent studies.

Neonates are at risk for 3 major forms of leukemia in the first year of life: acute leukemia, juvenile myelomonocytic leukemia, and transient abnormal myelopoiesis associated with Down syndrome. These disorders are rare but generate interest due to aggressive clinical presentation, suboptimal response to current therapies, and fascinating biology. Each can arise as a result of unique constitutional and acquired genetic events. Genetic insights are pointing the way toward novel therapeutic approaches. This article reviews key epidemiologic, clinical, and molecular features of neonatal leukemias, focusing on risk stratification, treatment, and strategies for developing novel molecularly targeted approaches to improve future outcomes., Competing Interests: Disclosures No relevant conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Based on biology and pre-clinical data, bromodomain and extra-terminal (BET) inhibitors have at least three potential roles in paediatric malignancies: NUT (nuclear protein in testis) carcinomas, MYC/MYCN-driven cancers and fusion-driven malignancies. However, there are now at least 10 BET inhibitors in development, with a limited relevant paediatric population in which to evaluate these medicinal products. Therefore, a meeting was convened with the specific aim to develop a consensus among relevant biopharmaceutical companies, academic researchers, as well as patient and family advocates, about the development of BET inhibitors, including prioritisation and their specific roles in children. Although BET inhibitors have been in clinical trials in adults since 2012, the first-in-child study (BMS-986158) only opened in 2019. In the future, when there is strong mechanistic rationale or pre-clinical activity of a class of medicinal product in paediatrics, early clinical evaluation with embedded correlative studies of a member of the class should be prioritised and rapidly executed in paediatric populations. There is a strong mechanistic and biological rationale to evaluate BET inhibitors in paediatrics, underpinned by substantial, but not universal, pre-clinical data. However, most pan-BET inhibitors have been challenging to administer in adults, since monotherapy results in only modest anti-tumour activity and provides a narrow therapeutic index due to thrombocytopenia. It was concluded that it is neither scientifically justified nor feasible to undertake simultaneously early clinical trials in paediatrics of all pan-BET inhibitors. However, there is a clinical need for global access to BET inhibitors for patients with NUT carcinoma, a very rare malignancy driven by bromodomain fusions, with proof of concept of clinical benefit in a subset of patients treated with BET inhibitors. Development and regulatory pathway in this indication should include children and adolescents as well as adults. Beyond NUT carcinoma, it was proposed that further clinical development of other pan-BET inhibitors in children should await the results of the first paediatric clinical trial of BMS-986158, unless there is compelling rationale based on the specific agent of interest. BDII-selective inhibitors, central nervous system-penetrant BET inhibitors (e.g. CC-90010), and those dual-targeting BET/p300 bromodomain are of particular interest and warrant further pre-clinical investigation. This meeting emphasised the value of a coordinated and integrated strategy to drug development in paediatric oncology. A multi-stakeholder approach with multiple companies developing a consensus with academic investigators early in the development of a class of compounds, and then engaging regulatory agencies would improve efficiency, productivity, conserve resources and maximise potential benefit for children with cancer., Competing Interests: Conflict of interest statement KS has consulted for Kronos Bio and Auron Therapeutics, receives grant funding from Novartis for an unrelated project, holds stock options with Auron Therapeutics, and has given a sponsored presentation for Bristol Meyers Squibb. MK is an employee of Bristol Myers Squibb. KB is an employee of AbbVie. EG is an employee of Boehringer Ingelheim Pharma GmbH & Co KG. FG has consulted for Epigene Therapeutics. MH is an employee of Astra-Zeneca. KL is an employee of Constellation Pharmaceuticals. ZN is an employee of Celgene/Bristol Myers Squibb. AT is an employee of Plexxikon. FZ is an employee of Incyte. ADJP has participated in advisory boards for Novartis, Takeda, Merck, Lilly and Celgene. SGD has received fees for consulting and advisory board roles from Bayer and Loxo Oncology and has received travel expenses from Loxo Oncology, Roche/Genentech, and Salarius Pharmaceuticals. All remaining authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Acute central retinal artery occlusion (CRAO) is an ophthalmologic emergency that often results in permanent vision loss. Over 25% are associated with acute cerebral ischemia. In the absence of existing Level I treatment options, this study aims to examine institutional practice patterns and review the literature to develop a formalized approach to the treatment of CRAO in the era of ischemic stroke protocols., Materials and Methods: This is a retrospective review of institutional practices in the workup and treatment of patients diagnosed with acute non-arteritic (NA) CRAO at a single center from January 2017 to August 2020., Results: Of 91 patients managed for acute NA-CRAO, 62.6% were male and average age was 66.4 years. Only 20.9% of patients presented within 4 h of symptom onset. 12.1% of patients had evidence of acute stroke on MRI, and 27.5% had ipsilateral internal carotid artery stenosis >50%. Half (52.7%) did not receive any acute treatment for CRAO, excluding antiplatelet/anticoagulation. 48.5% of patients undergoing acute medical treatment had improved visual acuity compared to 29.4% without treatment (p=0.14)., Conclusions: There is a lack of clear protocol for the management of NA-CRAO. While not reaching statistical significance, our experience mirrors the literature with patients undergoing medical treatment demonstrating improved visual acuity over those without treatment. Given the presence of acute ischemic stroke, carotid disease, and/or stroke risk factors in over 25% of patients with CRAO, multidisciplinary involvement and modern stroke algorithms should be considered for this disease., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The title compound, catena -poly[[tetra-kis-(1-methyl-pyrrolidin-2-one-κ O )calcium(II)]-μ-( E )-1,1'-dimethyl-2,2'-dioxo-1,1',2,2'-tetra-hydro-[3,3'-bipyrrolyl-idene]-5,5'-bis-(thiol-ato)-κ 2 O : O '], [Ca(C 10 H 8 N 2 O 2 S 2 )(C 5 H 9 NO) 4 ] n , 1 , crystallizes in the triclinic space group P . The crystal studied was twinned by non-merohedry via two different twofold operations, about the normals to (001) and (10), giving four twin domains with refined occupancies of 0.412 (4), 0.366 (4), 0.055 (1), 0.167 (4). The Ca atoms are located on centers of inversion. Each Ca is surrounded by four 1-methyl-pyrrolidin-2-one (NMP) ligands and coordinated through one of the two O atoms to two ( E )-1,1'-dimethyl-2,2'-dioxo-1,1',2,2'-tetra-hydro-[3,3'-bipyrrolyl-idene]-5,5'-bis-(thiol-ate), [C 10 H 8 N 2 O 2 S 2 ] 2- , dianions (abbreviation: DMTBT). This dianion thus facilitates the formation of a 1-D polymer, which propagates in the [011] direction. These ribbons are linked by inter-molecular C-H⋯S inter-actions. Each Ca atom is in an octa-hedral CaO 6 six-coordinate environment with Ca-O bond lengths ranging from 2.308 (6) to 2.341 (6) Å, cis bond angles ranging from 88.2 (2) to 91.8 (2)° and the trans angles all 180° due to the Ca atoms being located on centers of inversion. Theoretical calculations were carried out using density functional theory (DFT) and the results showed that although the central DMTBT dianion is planar there is likely some resonance across the central bond between both aza-pentyl rings, but this is not sufficient to establish a ring current. The calculated UV-vis spectrum shows a peak at 625 nm, which accounts for the deep blue-purple color of solutions of the complex., (© Butcher et al. 2021.)

Although B-cell acute lymphoblastic leukemia (B-ALL) is the most common malignancy in children and while highly curable, it remains a leading cause of cancer-related mortality. The outgrowth of tumor subclones carrying mutations in genes responsible for resistance to therapy has led to a Darwinian model of clonal selection. Previous work has indicated that alterations in the epigenome might contribute to clonal selection, yet the extent to which the chromatin state is altered under the selective pressures of therapy is unknown. To address this, we performed chromatin immunoprecipitation, gene expression analysis, and enhanced reduced representation bisulfite sequencing on a cohort of paired diagnosis and relapse samples from individual patients who all but one relapsed within 36 months of initial diagnosis. The chromatin state at diagnosis varied widely among patients, while the majority of peaks remained stable between diagnosis and relapse. Yet a significant fraction was either lost or newly gained, with some patients showing few differences and others showing massive changes of the epigenetic state. Evolution of the epigenome was associated with pathways previously linked to therapy resistance as well as novel candidate pathways through alterations in pyrimidine biosynthesis and downregulation of polycomb repressive complex 2 targets. Three novel, relapse-specific superenhancers were shared by a majority of patients including one associated with S100A8, the top upregulated gene seen at relapse in childhood B-ALL. Overall, our results support a role of the epigenome in clonal evolution and uncover new candidate pathways associated with relapse. SIGNIFICANCE: This study suggests a major role for epigenetic mechanisms in driving clonal evolution in B-ALL and identifies novel pathways associated with drug resistance., (©2020 American Association for Cancer Research.)

Purpose of Review: Strategies to mitigate muscle cramps are a top research priority for patients receiving hemodialysis. As hypomagnesemia is a possible risk factor for cramping, we reviewed the literature to better understand the physiology of cramping as well as the epidemiology of hypomagnesemia and muscle cramps. We also sought to review the evidence from interventional studies on the effect of oral and dialysate magnesium-based therapies on muscle cramps., Sources of Information: Peer-reviewed articles., Methods: We searched for relevant articles in major bibliographic databases including MEDLINE and EMBASE. The methodological quality of interventional studies was assessed using a modified version of the Downs and Blacks criteria checklist., Key Findings: The etiology of muscle cramps in patients receiving hemodialysis is poorly understood and there are no clear evidence-based prevention or treatment strategies. Several factors may play a role including a low concentration of serum magnesium. The prevalence of hypomagnesemia (concentration of <0.7 mmol/L) in patients receiving hemodialysis ranges from 10% to 20%. Causes of hypomagnesemia include a low dietary intake of magnesium, use of medications that inhibit magnesium absorption (eg, proton pump inhibitors), increased magnesium excretion (eg, high-dose loop diuretics), and a low concentration of dialysate magnesium. Dialysate magnesium concentrations of ≤0.5 mmol/L may be associated with a decrease in serum magnesium concentration over time. Preliminary evidence from observational and interventional studies suggests a higher dialysate magnesium concentration will raise serum magnesium concentrations and may reduce the frequency and severity of muscle cramps. However, the quality of evidence supporting this benefit is limited, and larger, multicenter clinical trials are needed to further determine if magnesium-based therapy can reduce muscle cramps in patients receiving hemodialysis. In studies conducted to date, increasing the concentration of dialysate magnesium appears to be well-tolerated and is associated with a low risk of symptomatic hypermagnesemia., Limitations: Few interventional studies have examined the effect of magnesium-based therapy on muscle cramps in patients receiving hemodialysis and most were nonrandomized, pre-post study designs., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)

Background and Objectives: The kidney failure risk equation is a clinical tool commonly used for prediction of progression from CKD to kidney failure. The kidney failure risk equation's accuracy in advanced CKD and whether this varies by CKD etiology remains unknown. This study examined the kidney failure risk equation's discrimination and calibration at 2 and 5 years among a large tertiary care population with advanced CKD from heterogeneous etiologies., Design, Setting, Participants, & Measurements: This retrospective cohort study included 1293 patients with advanced CKD (median eGFR 15 ml/min per 1.73 m 2 ) referred to the Ottawa Hospital Multi-Care Kidney Clinic between 2010 and 2016, with follow-up clinical data available through 2018. Four-variable kidney failure risk equation scores for 2- and 5-year risks of progression to kidney failure (defined as dialysis or kidney transplantation) were calculated upon initial referral and correlated with the subsequent observed kidney failure incidence within these time frames. Receiver operating characteristic curves and calibration plots were used to measure the discrimination and calibration of the kidney failure risk equation both in the overall advanced CKD population and by CKD etiology: diabetic kidney disease, hypertensive nephrosclerosis, GN, polycystic kidney disease, and other. Pairwise comparisons of the receiver operating characteristic curves by CKD etiology were performed to compare kidney failure risk equation discrimination., Results: The kidney failure risk equation provided adequate to excellent discrimination in identifying patients with CKD likely to progress to kidney failure at the 2- and 5-year time points both overall (2-year area under the curve, 0.83; 95% confidence interval, 0.81 to 0.85; 5-year area under the curve, 0.81; 95% confidence interval, 0.77 to 0.84) and across CKD etiologies. The kidney failure risk equation displayed adequate calibration at the 2- and 5-year time points both overall and across CKD etiologies (Hosmer-Lemeshow P≥ 0.05); however, the predicted risks of kidney failure were higher than the observed risks across CKD etiologies with the exception of polycystic kidney disease., Conclusions: The kidney failure risk equation provides adequate discrimination and calibration in advanced CKD and across CKD etiologies., (Copyright © 2020 by the American Society of Nephrology.)

The NSD2 p.E1099K (EK) mutation is observed in 10% of acute lymphoblastic leukemia (ALL) samples with enrichment at relapse indicating a role in clonal evolution and drug resistance. To discover mechanisms that mediate clonal expansion, we engineered B-precursor ALL (B-ALL) cell lines (Reh, 697) to overexpress wildtype (WT) and EK NSD2, but observed no differences in proliferation, clonal growth, or chemosensitivity. To address whether NSD2 EK acts collaboratively with other pathways, we used short hairpin RNAs to knockdown expression of NSD2 in B-ALL cell lines heterozygous for NSD2 EK (RS4;11, RCH-ACV, SEM). Knockdown resulted in decreased proliferation in all lines, decreased clonal growth in RCH-ACV, and increased sensitivity to cytotoxic chemotherapeutic agents, although the pattern of drug sensitivity varied among cell lines implying that the oncogenic properties of NSD2 mutations are likely cell context specific and rely on cooperative pathways. Knockdown of both Type II and REIIBP EK isoforms had a greater impact than knockdown of Type II alone, suggesting that both SET containing EK isoforms contribute to phenotypic changes driving relapse. Furthermore, in vivo models using both cell lines and patient samples revealed dramatically enhanced proliferation of NSD2 EK compared with WT and reduced sensitivity to 6-mercaptopurine in the relapse sample relative to diagnosis. Finally, EK-mediated changes in chromatin state and transcriptional output differed dramatically among cell lines further supporting a cell context-specific role of NSD2 EK. These results demonstrate a unique role of NSD2 EK in mediating clonal fitness through pleiotropic mechanisms dependent on the genetic and epigenetic landscape. IMPLICATIONS: NSD2 EK mutation leads to drug resistance and a clonal advantage in childhood B-ALL., (©2020 American Association for Cancer Research.)

Objectives. To evaluate the impact of duration and service category on HIV health outcomes among low-income adults living with HIV and enrolled in a housing program in 2014 to 2017. Methods. We estimated relative risk of engagement in care, viral suppression, and CD4 improvement for 561 consumers at first and second year after enrollment to matched controls through the New York City HIV surveillance registry, by enrollment length (enrolled for more than 1 year or not) and service category (housing placement assistance [HPA], supportive permanent housing [SPH], and rental assistance [REN]). Results. The SPH and REN consumers were enrolled longer and received more services, compared with HPA consumers. Long-term SPH and REN consumers had better engagement in care, viral suppression, and CD4 count than controls at both first and second year after enrollment, but the effect did not grow bigger from year 1 to 2. HPA consumers did not have better outcomes than controls regardless of enrollment length. Conclusions. Longer enrollment with timely housing placement and a higher number and more types of services are associated with better HIV health outcomes for low-income persons living with HIV with unmet housing needs.

Background The oblique lumbar interbody fusion or anterior-to-psoas (OLIF/ATP) technique relies on a corridor anterior to the psoas and posterior to the vasculature for lumbar interbody fusion. This is evaluated preoperatively with CT and/or MRI. To date, there have been no studies examining how intraoperative, lateral decubitus positioning may change the dimensions of this corridor when compared to preoperative imaging. Objective Our objective was to evaluate changes in the intraoperative corridor in the supine and lateral positions utilizing preoperative and intraoperative imaging. Methods We performed a retrospective analysis among patients who have undergone an OLIF/ATP approach at two tertiary care centers from 2016 to 2018 by measuring the distance between the left lateral border of the aorta or iliac vessels and anteromedial border of the psoas muscle from L1-L2 through L4-5 disc spaces. We compared this corridor between supine, preoperative MRI axial and intraoperative CT acquired in the right lateral decubitus position. Results Thirty-three patients, 15 of whom were female, were included in our study. The average age of the patients was 65.4 years and the average BMI was 31 kg/m 2 . The results revealed a statistically significant increase (p<.05) in the intraoperative corridor from supine to lateral decubitus positioning at all levels. However, age, BMI, and gender had no statistically significant impact on the preoperative versus intraoperative corridor. Conclusion This is the first study to provide objective evidence that lateral decubitus positioning increases the intraoperative corridor for OLIF/ATP. Our study demonstrates that lateral decubitus positioning provides a more favorable corridor for the OLIF/ATP technique from L1-L5 disc levels., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Zehri et al.)

Background/aim: Few studies have evaluated the role of miRNAs in pediatric acute lymphoblastic leukemia (ALL) relapse and a consensus of a clinically significant miRNA signature is yet to be identified. In this study, we evaluated miRNAs associated with pediatric B-ALL early relapse in two independent sample sets., Materials and Methods: We performed global miRNA profiling on diagnostic bone marrow specimens from six early relapse (≤3 years after diagnosis) and six age- and cytogenetics-matched prolonged remission (≥4 years) patients (first set) and an independent set of 14 early relapse and 14 matched prolonged remission specimens (second set)., Results: Twelve and 39 top differentially expressed miRNAs were observed in the first and second sets, respectively; however, there was no overlap between the top candidates. In post-hoc analyses six miRNAs (miR-101-3p, miR-4774-5p, miR-1324, miR-631, miR-4699-5p and miR-922) among the top candidates in the second, but not the first set, were consistently upregulated in early relapse compared to remission specimens in both first (fold change=1.13-2.19, q<0.38) and second (fold change=1.48-4.78, all q<0.05) sets. Four (miR-631, mir-101-3p, miR-922 and miR-1324) of these miRNAs have been previously implicated in key functional oncogenic pathways in adult cancers., Conclusion: This study suggests that six candidate miRNAs, not previously implicated in pediatric ALL, are associated with early relapse in pediatric B-ALL. Validation and investigation of mechanistic roles of these miRNAs in a larger cohort are warranted, so that they may be used as prognostic markers for early relapse of pediatric B-ALL., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: Treatment failure from drug resistance is the primary reason for relapse in acute lymphoblastic leukemia (ALL). Improving outcomes by targeting mechanisms of drug resistance is a potential solution., Patients and Methods: We report results investigating the epigenetic modulators decitabine and vorinostat with vincristine, dexamethasone, mitoxantrone, and PEG-asparaginase for pediatric patients with relapsed or refractory B-cell ALL (B-ALL). Twenty-three patients, median age 12 years (range, 1-21) were treated in this trial., Results: The most common grade 3-4 toxicities included hypokalemia (65%), anemia (78%), febrile neutropenia (57%), hypophosphatemia (43%), leukopenia (61%), hyperbilirubinemia (39%), thrombocytopenia (87%), neutropenia (91%), and hypocalcemia (39%). Three subjects experienced dose-limiting toxicities, which included cholestasis, steatosis, and hyperbilirubinemia ( n = 1); seizure, somnolence, and delirium ( n = 1); and pneumonitis, hypoxia, and hyperbilirubinemia ( n = 1). Infectious complications were common with 17 of 23 (74%) subjects experiencing grade ≥3 infections including invasive fungal infections in 35% (8/23). Nine subjects (39%) achieved a complete response (CR + CR without platelet recovery + CR without neutrophil recovery) and five had stable disease (22%). Nine (39%) subjects were not evaluable for response, primarily due to treatment-related toxicities. Correlative pharmacodynamics demonstrated potent in vivo modulation of epigenetic marks, and modulation of biologic pathways associated with functional antileukemic effects., Conclusions: Despite encouraging response rates and pharmacodynamics, the combination of decitabine and vorinostat on this intensive chemotherapy backbone was determined not feasible in B-ALL due to the high incidence of significant infectious toxicities. This study is registered at http://www.clinicaltrials.gov as NCT01483690., (©2020 American Association for Cancer Research.)

Background: The kidney failure risk equation (KFRE) is a validated risk algorithm for predicting the risk of kidney failure in chronic kidney disease (CKD) patients regardless of etiology. Patients with autosomal dominant polycystic kidney disease (AD-PCKD) experience long disease trajectories and as such identifying individuals at risk of kidney failure would aid in intervention., Objective: To examine the utility of the KFRE in predicting adverse kidney outcomes compared with existing risk factors in a cohort of patients with AD-PCKD., Methods: Retrospective cohort study of AD-PCKD patients referred to a tertiary care center with a baseline kidney ultrasound and a KFRE calculation. Cox proportional hazards were used to examine the association of the KFRE and composite of an eGFR decline of >30% or the need for dialysis/transplantation. Discrimination and calibration of a parsimonious fully adjusted model and a model containing only total kidney volume (TKV) with and without the addition of the KFRE was determined., Results: Of 340 patients with AD-PCKD eligible, 221 (65%) met inclusion criteria. Older age, cardiac disease, cancer, higher systolic blood pressure, albuminuria, lower eGFR and a higher initial TKV were more common in patients with a higher KFRE. A total of 120 events occurred over a median patient follow-up time of 3.2 years. KFRE was independently associated with the composite kidney outcome. Addition of the KFRE significantly improved discrimination and calibration in a TKV only model and a fully adjusted model., Conclusions: In a diverse, referral population with AD-PCKD, the KFRE was associated with adverse kidney outcomes and improved risk prediction., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)

Hybrid dialysis involves combining peritoneal and hemodialysis (HD) in patients with end-stage renal disease. Its reported use is quite limited outside of Japan. We present a retrospective review of 18 patients at our center that received this therapy and describe their ultimate disposition. We observed that 39% of the population on hybrid dialysis ultimately transitioned to full in center HD, 28% continue until death, and 33% either transition to home HD or received a transplant. In our center, hybrid dialysis was successful as a bridging therapy or in balancing continuation of dialysis with quality of life among those with a limited prognosis.

Tuberocephalus tsengi (Tao, 1963) STAT. REV., an aphid species described from China, is reported feeding on Artemisia vulgaris in southern England. This species is here redescribed and distinguished from T. sasakii (Matsumura, 1917), with which it has previously been synonymised.

We present ground-state electronic properties of the liquid crystal 4-cyano-4^{'}-pentylbiphenyl (5CB) on the two-dimensional materials monolayer graphene, hexagonal boron nitride, and phosphorene. Our density functional theory results show that the physisorption is robust on all surfaces with the strongest binding of 5CB on phosphorene. All surfaces exhibit flexural distortion, especially monolayer graphene and hexagonal boron nitride. While we find type-I alignment for all three substrates, meaning the Fermi level of the system is in the HOMO-LUMO gap of 5CB, the band structures are qualitatively different. Unlike for graphene and phosphorene, the HOMO-LUMO of 5CB appear as localized states within the band gap of boron nitride. In addition, we find that the valence band for boron nitride is sensitive to the orientation of 5CB relative to the surface. The qualitatively different band structures demonstrate the importance of substrate selection for tailoring the electronic and optoelectronic properties of nematic liquid crystals on two-dimensional materials.

Background: Neuropsychiatric conditions such as depression, delirium and cognitive impairment are common in patients with end-stage kidney disease (ESKD) and individuals suffering from ESKD are more likely to commit suicide than members of the general population. Self-harm gestures are not infrequent for ESKD patients suffering from depression, but not well described in other conditions., Case Presentation: We present a case of self-harm in a patient with ESKD suffering from acute delirium. A man in his mid-seventies was admitted with fungal peritoneal dialysis (PD) associated peritonitis. On the first day post operatively, he was found with absent vital signs due to exsanguination from newly inserted central catheter which he which had self-severed. He died a few days later as a result of the self-harm gesture., Conclusion: This case highlights that delirium may lead to self-harm events in ESKD and identifies a few strategies to help reduce the risk of self-harm events.

Background: Controversy exists as to whether the insertion of temporary hemodialysis catheters (THDCs) should remain a mandatory requirement of nephrology fellowship training in Canada. A survey conducted by our group in 2012 showed that many nephrology trainees reported inadequate training to achieve procedural competence., Objective: To determine the current practices and training of the insertion of THDCs in nephrology fellowship programs in Canada and how this has evolved since 2012., Design: A survey study was designed comprising the following sections: demographics, details regarding the number and types of THDCs inserted within the past 6 months of fellowship training, adherence to sterile techniques, the use of ultrasound guidance during THDC insertion, training for THDC insertion received before and during nephrology fellowship, and self-perceived adequacy of training and competence in THDC insertion., Setting: The survey was distributed by e-mail in May 2018 either directly or through Canadian nephrology training programs., Participants: Current trainees of Canadian adult nephrology training programs., Measurements: Descriptive statistics were used to analyze the summarized data. The means and interquartile ranges (IQRs) were used to summarize the number of THDC insertions performed, and the categorical data, including data on training and self-perceived competency, were reported using frequencies and percentages. A chi-squared test was used to evaluate the relationship between those who received simulation-based training and self-perceived confidence in either internal jugular or femoral catheter insertion., Methods: An online survey, available in both English and French, was distributed to all adult nephrology trainees in Canada in May 2018 either directly or through their respective programs., Results: Completed surveys were received from 46 of 136 nephrology trainees across Canada (34%). Of those who responded, the median (IQR) number of combined femoral and/or internal jugular THDCs inserted in the past 6 months of fellowship training was 3 (1-6). Eight respondents (17%) indicated that they had not inserted a THDC in the past 6 months. However, only 7 of 42 respondents (17%) indicated that they did not feel competent or adequately trained to perform either femoral or internal jugular THDC insertion., Limitations: Limitations of the study include participation of trainees at different stages of their training. Many trainees indicated that it was not a requirement to keep a formal log of their procedures performed and likely had recall bias when reporting their procedure details., Conclusions: Nephrology fellows in Canada are performing fewer THDC insertions compared to 2012 but report higher levels of self-perceived competence and better training. This may be as a result of significantly more simulation-based training. Our data suggest that training to procedural mastery using simulation-based techniques may be a path to ensuring adequate training for THDC insertion despite fewer procedures being performed during training., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2019.)

A compendium of pnictogen and chalcogen substituted boron heterocycles were assessed for their aromatic character by first principles density functional theory. Group-15 and Group-16 elements were placed at the ortho-, meta-, and para-positions of six-membered rings relative to boron to assess their impact on the aromaticity of the unsaturated heterocycles. Aromaticity was analyzed by a multidimensional approach using nuclear independent chemical shifts, gauge-including magnetically induced current, as well as natural bond orbital and natural resonance theory analyses. Based on these methods, we observe a general decline of aromaticity in heavier pnictaborines while the chalcogen analogues maintain relatively strong aromatic character. These general trends result from complementary π-π* natural bond order interactions that sustain resonance within the ring of each heterocycle establishing a pattern of cyclic delocalization. Consequently, natural resonance theory displays strong resonance, which is corroborated with the signed modulus of ring current, toroidal vortices of current maps, and elevated average induced current throughout the ring. The 1,3-configurations for pnictaborines and chalcogenaborines are generally more aromatic compared to the 1,2- and 1,4-isomers, which contain π-holes that limit diatropism within the heterocycles. However, an energetic trend favors the 1,2-heterocycles in both groups, with a few exceptions driven in large-part by π-donation of the lone pair on the heteroatom to the pz orbital on the adjacent boron resulting in stabilization. The importance of planarity for high aromaticity is demonstrated, especially in the pnictaborine isomers where pyramidalization at the pnictogen is favored, while bond regularity seems a less important criterion.

Aphid specimens belonging to the genus Aphis (Hemiptera, Aphididae, Aphidinae) collected on species of Baccharis (Asteraceae) in localities of Argentina and Chile, preserved in the Natural History Museum in London and in the Universidad de León collections, have been studied. They belong to six species: Aphis craccivora, Aphis gossypii and Aphis spiraecola, which are widely-distributed and polyphagous, and the new species: Aphis ingeborgae Nieto Nafría and Brown sp. n., Aphis conspicua Nieto Nafría and Mier Durante sp. n. and Aphis fuentesi Nieto Nafría and Ortego sp. n. which are here described from apterous and alate viviparous females, and also from oviparous females and males in the case of Aphis fuentesi. These six species plus the native and monophagous A. coridifoliae are those known in southern South America living on plants of Baccharis. Diagnostic features of new species and an identification key for apterous viviparous females of these seven species are presented.

To date, four subgroups of avian metapneumoviruses have been defined (AMPV-A, B, C and D) based on genetic and antigenic differences. The extent of infection in the three principal species (turkeys, chickens and ducks) by these subgroups is, however, not well defined. Here, a series of controlled and ethically approved experimental infections were performed in specific pathogen-free turkeys, chickens and ducks with each of the four AMPV subgroups. For subgroup C, one strain isolated from turkeys in the USA (turkey AMPV-C) and one isolated from ducks in France (duck AMPV-C) were compared. Globally, these extensive experimental trials demonstrated that AMPV-A, B, turkey C and D were well adapted to Galliformes, especially turkeys; however, chickens showed limited clinical signs and differences in seroconversion and transmission. Notably, chickens did not transmit AMPV-A to contacts and were shown for the first time to be susceptible to AMPV-D. The duck AMPV-C was well adapted to ducks; however, chickens and turkeys seroconverted and were positive by virus isolation. In addition, seroconversion of contact turkeys to duck AMPV-C demonstrated horizontal transmission of this virus in a non-palmiped species under our experimental conditions. Interestingly, in chickens and turkeys, duck AMPV-C isolation was possible despite a lack of detection of viral RNA. Likewise, the turkey AMPV-C virus was well adapted to turkeys yet was also isolated from chickens despite a lack of detection of viral RNA. These results would suggest a selection for viral genetic sequences that differ from the original strain upon adaptation to a 'non-conventional host'.

Background: Asparaginase is a critical component of lymphoblastic leukemia therapy, with intravenous pegaspargase (PEG) as the current standard product. Acute adverse events (aAEs) during PEG infusion are difficult to interpret, representing a mix of drug-inactivating hypersensitivity and noninactivating reactions. Asparaginase Erwinia chrysanthemi (ERW) is approved for PEG hypersensitivity, but is less convenient, more expensive, and yields lower serum asparaginase activity (SAA). We began a policy of universal premedication and SAA testing for PEG, hypothesizing this would reduce aAEs and unnecessary drug substitutions., Procedure: Retrospective chart review of patients receiving asparaginase before and after universal premedication before PEG was conducted, with SAA performed 1 week later. We excluded patients who had nonallergic asparaginase AEs. Primary end point was substitution to ERW. Secondary end points included aAEs, SAA testing, and cost., Results: We substituted to ERW in 21 of 122 (17.2%) patients pre-policy, and 5 of 68 (7.4%) post-policy (RR, 0.427; 95% CI, 0.27-0.69, P = 0.028). All completed doses of PEG yielded excellent SAA (mean, 0.90 units/mL), compared with ERW (mean, 0.15 units/mL). PEG inactivation post-policy was seen in 2 of 68 (2.9%), one silent and one with breakthrough aAE. The rate of aAEs pre/post-policy was 17.2% versus 5.9% (RR, 0.342; 95% CI, 0.20-0.58, P = 0.017). Grade 4 aAE rate pre/post-policy was 15% versus 0%. Cost analysis predicts $125 779 drug savings alone per substitution prevented ($12 402/premedicated patient)., Conclusions: Universal premedication reduced substitutions to ERW and aAE rate. SAA testing demonstrated low rates of silent inactivation, and higher SAA for PEG. A substantial savings was achieved. We propose universal premedication for PEG be standard of care., (© 2019 Wiley Periodicals, Inc.)

Purpose: To examine the relationship between lung radiation dose and survival outcomes in children undergoing total body irradiation (TBI)-based hematopoietic stem cell transplantation (HSCT) for acute lymphoblastic leukemia on the Children's Oncology Group trial., Methods and Materials: TBI (1200 or 1320 cGy given twice daily in 6 or 8 fractions) was used as part of 3 HSCT preparative regimens, allowing institutional flexibility regarding TBI techniques, including lung shielding. Lung doses as reported by each participating institution were calculated for different patient setups, with and without shielding, with a variety of dose calculation techniques. The association between lung dose and transplant-related mortality, relapse-free survival, and overall survival (OS) was examined using the Cox proportional hazards regression model controlling for the following variables: TBI dose rate, TBI fields, patient position during TBI, donor type, and pre-HSCT minimal residual disease level., Results: Of a total of 143 eligible patients, 127 had lung doses available for this analysis. The TBI techniques were heterogeneous. The mean lung dose was reported as 904.5 cGy (standard deviation, ±232.3). Patients treated with lateral fields were more likely to receive lung doses ≥800 cGy (P < .001). The influence of lung dose ≥800 cGy on transplant-related mortality was not significant (hazard ratio [HR], 1.78; P = .21). On univariate analysis, lung dose ≥800 cGy was associated with inferior relapse-free survival (HR, 1.76; P = .04) and OS (HR, 1.85; P = .03). In the multivariate analysis, OS maintained statistical significance (HR, 1.85; P = .04)., Conclusions: The variability in TBI techniques resulted in uncertainty with reported lung doses. Lateral fields were associated with higher lung dose, and thus they should be avoided. Patients treated with lung dose <800 cGy in this study had better outcomes. This approach is currently being investigated in the Children's Oncology Group AALL1331 study. Additionally, the Imaging and Radiation Oncology Core Group is evaluating effects of TBI techniques on lung doses using a phantom., (Copyright © 2019 Elsevier Inc. All rights reserved.)

While survival in paediatric acute lymphoblastic leukaemia (ALL) is excellent, survival following relapse is poor. Previous studies suggest proteasome inhibition with chemotherapy improves relapse ALL response rates. This phase 2 Children's Oncology Group study tested the hypothesis that adding the proteasome inhibitor bortezomib to chemotherapy increases complete response rates (CR2). Evaluable patients (n = 135, 103 B-ALL, 22 T-ALL, 10 T-lymphoblastic lymphoma) were treated with reinduction chemotherapy plus bortezomib. Overall CR2 rates were 68 ± 5% for precursor B-ALL patients (<21 years of age), 63 ± 7% for very early relapse (<18 months from diagnosis) and 72 ± 6% for early relapse (18-36 months from diagnosis). Relapsed T-ALL patients had an encouraging CR2 rate of 68 ± 10%. End of induction minimal residual disease (MRD) significantly predicted survival. MRD negative (MRDneg; MRD <0·01%) rates increased from 29% (post-cycle 1) to 64% following cycle 3. Very early relapse, end-of-induction MRDneg precursor B-ALL patients had 70 ± 14% 3-year event-free (EFS) and overall survival (OS) rates, vs. 3-year EFS/OS of 0-3% (P = 0·0001) for MRDpos (MRD ≥0·01) patients. Early relapse patients had similar outcomes (MRDneg 3-year EFS/OS 58-65% vs. MRDpos 10-19%, EFS P = 0·0014). These data suggest that adding bortezomib to chemotherapy in certain ALL subgroups, such as T-cell ALL, is worthy of further investigation. This study is registered at http://www.clinical.trials.gov as NCT00873093., (© 2019 British Society for Haematology and John Wiley & Sons Ltd.)

In February 2019, following the annual taxon ratification vote, the order Mononegavirales was amended by the addition of four new subfamilies and 12 new genera and the creation of 28 novel species. This article presents the updated taxonomy of the order Mononegavirales as now accepted by the International Committee on Taxonomy of Viruses (ICTV).

Background: Obesity is increasing globally. Chronic kidney disease (CKD) is strongly associated with obesity. Kidney function is commonly estimated with equations using creatinine (such as CKD-EPI equation) which is a product of muscle metabolism. Decisions about categorizing CKD, planning modality of renal replacement therapies, and adjusting dosages of medications excreted by the kidneys are done using these equations. However, it is not well appreciated that creatinine-based equations may not accurately estimate kidney function in obese individuals. We plan a systematic review of diagnostic studies which will compare estimating equations to actual measured kidney function., Methods: We will systematically search electronic bibliographic databases including MEDLINE, EMBASE, and the Cochrane Library with no restrictions on language or specific dates. The search terms will be adapted for the different databases using a combination of Medical Subject Heading and relevant keywords contained in titles and abstracts. Our preliminary search strategy using Cochrane, MEDLINE, and EMBASE databases have identified 190, 1246, and 1660 citations, respectively. For all studies selected, we will extract information on general study characteristics, study participant (age, sex, ethnicity, weight, height, BMI, BSA), type and protocol of reference standard utilized, the index test studied, the methodology of measurement of index test, categories of GFR, the proportion of eGFR within 10, 20, 30, 40, and 50% of measured GFR, and bias between eGFR and measured GFR. If the quality of methods and risk of bias are adequate, we will perform a meta-analysis. We will assess the heterogeneity using the χ 2 and the I 2 statistics to examine whether the estimates from studies included could be pooled. Sensitivity and multivariate meta-regression analyses will be performed to assess the effects of clinical factors and socio-demographic characteristics reported in included studies on the meta-analytic estimates. All analysis will be performed using the Comprehensive Meta-analysis software., Discussion: This systematic review might help to inform clinicians on the best equation to use in patients with obesity and CKD for staging of CKD and for medication dosing. If no equation is deemed suitable, this review will form a basis for future studies of GFR in obese individuals., Systematic Review Registration: PROSPERO CRD42018104345.

Background: Critically ill patients frequently develop acute kidney injury that necessitates renal replacement therapy (RRT). At some centers, critically ill patients who are hemodynamically unstable and require RRT are treated with slow low-efficiency dialysis (SLED). Unfortunately, hypotension is a frequent complication that occurs during SLED treatments and may limit the recovery of kidney function. Hypotension may also limit the amount of fluid that can be removed by ultrafiltration with SLED. Fluid overload can be exacerbated as a consequence, and fluid overload is associated with increased mortality.Occasionally, intravenous albumin fluid is given to prevent or treat low blood pressure during SLED. The intent of doing so is to increase the colloid oncotic pressure in the circulation to draw in extravascular fluid, increase the blood pressure, and enable more aggressive fluid removal with ultrafiltration. Nonetheless, there is little evidence to support this practice and theoretical reasons why it may not be especially effective at augmenting fluid removal in critically ill patients. At the same time, albumin fluid is expensive.As such, we present a protocol for a study to assess the feasibility of a randomized controlled trial evaluating the use of albumin fluid versus saline in critically ill patients receiving SLED., Methods: This study is a single-center, double-blind, and randomized controlled pilot trial with two parallel arms. It involves randomly assigning patients receiving SLED treatment in the ICU to receive either albumin (25%) boluses or normal saline fluid boluses (placebo) to prevent and treat low blood pressure., Discussion: The results of this pilot trial will help with planning a larger trial comparing the efficacy of the interventions in achieving fluid removal in critically ill patients with AKI on SLED. They will establish whether enough participants would participate in a larger study and accept the study procedures., Trial Registration: This trial is registered on ClinicalTrials.gov Identifier NCT03665311, registered on September 11, 2018., Competing Interests: Competing interestsThe authors declare that they have no competing interests.

Three new species of Neuquenaphis Blanchard are described from aphids collected in southernmost South America on several species of Nothofagus, southern beeches: Neuquenaphis blackmani Nieto Nafría and Brown, sp. n. from apterous and alate viviparous females and alatoid nymphs collected on Nothofagus dombeyi in Los Lagos and Los Ríos regions (Chile) and on Nothofagus nitida in Los Ríos region, Neuquenaphis aurata Mier Durante and von Dohlen, sp. n. from apterous and alate viviparous females collected on Nothofagus betuloides in Magallanes region (Chile) and Tierra del Fuego province (Argentina), and Neuquenaphis ramireziNieto Nafría and Ortego, sp. n. from apterous viviparous females collected on Nothofagus pumilio and N. antarctica in Tierra del Fuego province (Argentina) and La Araucanía, Aysén and Magallanes regions (Chile). Sequences of the mitochondrial COI "barcode" region and the tRNAleu-COII locus support the distinction of these new species from described Neuquenaphis species. Morphological characteristics that differentiate the new species from already described species of the genus are discussed. Partial identification keys for known apterous and alate viviparous females of Neuquenaphis species are presented on the basis of those established by Quednau (2010).

Survival outcomes for older adults with acute lymphoblastic leukemia (ALL) are poor and optimal management is challenging due to higher-risk leukemia genetics, comorbidities, and lower tolerance to intensive therapy. A critical understanding of these factors guides the selection of frontline therapies and subsequent treatment strategies. In addition, there have been recent developments in minimal/measurable residual disease (MRD) testing and blinatumomab use in the context of MRD-positive disease after therapy. These NCCN Guidelines Insights discuss recent updates to the NCCN Guidelines for ALL regarding upfront therapy in older adults and MRD monitoring/testing in response to ALL treatment.

In October 2018, the order Mononegavirales was amended by the establishment of three new families and three new genera, abolishment of two genera, and creation of 28 novel species. This article presents the updated taxonomy of the order Mononegavirales as now accepted by the International Committee on Taxonomy of Viruses (ICTV).

Background: Unplanned dialysis initiation is common in patients with chronic kidney disease (CKD)., Objective: To determine common definitions and patient risk factors for unplanned dialysis., Design: Systematic review., Setting: MEDLINE, EMBASE, and the Cochrane Library were searched from inception to February 2018., Patients: Studies that included incident chronic dialysis patients or patients with CKD that cited a definition or examined risk factors for unplanned dialysis were included., Measurements: Definitions and criteria for unplanned dialysis reported across studies. Patient characteristics associated with unplanned dialysis., Methods: Two reviewers independently extracted data using a standardized data abstraction form and assessed study quality using a modified New Castle Ottawa Scale., Results: From 2797 citations, 48 met eligibility criteria. Reported definitions for unplanned dialysis were variable. Most publications cited dialysis initiation under emergency conditions and/or with a central venous catheter. The association of patient characteristics with unplanned dialysis was reported in 26 studies, 18 were retrospective and 21 included incident dialysis patients. The most common risk factors in univariate analyses were (number of studies) increased age (n = 7), cause of kidney disease (n = 6), presence of cardiovascular disease (n = 7), lower serum hemoglobin (n = 9), lower serum albumin (n = 10), higher serum phosphate (n = 6), higher serum creatinine or lower estimated glomerular filtration rate (eGFR) at dialysis initiation (n = 7), late referral (n = 5), lack of dialysis education (n = 6), and lack of follow-up in a predialysis clinic prior to dialysis initiation (n = 5). A minority of studies performed multivariable analyses (n = 10); the most common risk factors were increased age (n = 4), increased comorbidity score (n = 3), late referral (n = 5), and lower eGFR at dialysis initiation (n = 3)., Limitations: Comparison of results across studies was limited by inconsistent definitions for unplanned dialysis. High-quality data on patient risk factors for unplanned dialysis are lacking., Conclusions: Well-designed prospective studies to determine modifiable risk factors are needed. The lack of a consensus definition for unplanned dialysis makes research and quality improvement initiatives in this area more challenging., Competing Interests: Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: K.S.B. reports the receipt of personal fees from the Ontario Renal Network unrelated to this work.

Persons with HIV who are receiving housing services often have high rates of engagement in care, yet many are not virally suppressed. We linked data from the New York City Housing Opportunities for Persons with AIDS (HOPWA) program to electronically reported laboratory tests from the HIV surveillance registry to examine factors associated with a lack of viral suppression. Of 1491 HOPWA consumers, 523 (35.1%) were not durably suppressed, and 253 (17.0%) were unsuppressed at their last viral load test. Substance use, age < 27 years, and emergency housing all independently predicted lack of durable viral suppression and lack of viral suppression at last viral load test.

Subgroup C Avian Metapneumoviruses (AMPV-C) has two lineages, one mostly in turkeys and one mostly in ducks. To investigate the molecular basis of AMPV-C host tropism, a reverse genetics system for a duck AMPV-C virus was developed. A recombinant copy and a recombinant virus in which the SH protein had been exchanged for that of a turkey AMPV-C were rescued. No change in cytopathogenic effect or replication profile in vitro were observed for either virus compared to the wild type. In SPF Muscovy ducks the wild type and its recombinant copy were equally pathogenic. Exchanging the SH in the recombinant copy produced the same results. In SPF turkeys, neither recombinant virus was pathogenic, although both showed a low level of replication. Thus, from the current model, it appears that AMPV-C SH proteins derived from the different species are compatible and that turkey SH does not affect duck AMPV-C pathogenicity., (Copyright © 2018 Elsevier Inc. All rights reserved.)