Causal inference approaches reveal both positive and negative unintended effects of agricultural and urban management practices on instream biological condition.

Agricultural and urban management practices (MPs) are primarily designed and implemented to reduce nutrient and sediment concentrations in streams. However, there is growing interest in determining if MPs produce any unintended positive effects, or co-benefits, to instream biological and habitat conditions. Identifying co-benefits is challenging though because of confounding variables (i.e., those that affect both where MPs are applied and stream biota), which can be accounted for in novel causal inference approaches. Here, we used two causal inference approaches, propensity score matching (PSM) and Bayesian network learning (BNL), to identify potential MP co-benefits in the Chesapeake Bay watershed portion of Maryland, USA. Specifically, we examined how MPs may modify instream conditions that impact fish and macroinvertebrate indices of biotic integrity (IBI) and functional and taxonomic endpoints. We found evidence of positive unintended effects of MPs for both benthic macroinvertebrates and fish indicated by higher IBI scores and specific endpoints like the number of scraper macroinvertebrate taxa and lithophilic spawning fish taxa in a subset of regions. However, our results also suggest MPs have negative unintended effects, especially on sensitive benthic macroinvertebrate taxa and key instream habitat and water quality metrics like specific conductivity. Overall, our results suggest MPs offer co-benefits in some regions and catchments with largely degraded conditions but can have negative unintended effects in some regions, especially in catchments with good biological conditions. We suggest the number and types of MPs drove these mixed results and highlight carefully designed MP implementation that incorporates instream biological data at the catchment scale could facilitate co-benefits to instream biological conditions. Our study underscores the need for more research on identifying effects of individual MP types on instream biological and habitat conditions.

Observed and projected functional reorganization of riverine fish assemblages from global change.

Climate and land-use/land-cover change ("global change") are restructuring biodiversity, globally. Broadly, environmental conditions are expected to become warmer, potentially drier (particularly in arid regions), and more anthropogenically developed in the future, with spatiotemporally complex effects on ecological communities. We used functional traits to inform Chesapeake Bay Watershed fish responses to future climate and land-use scenarios (2030, 2060, and 2090). We modeled the future habitat suitability of focal species representative of key trait axes (substrate, flow, temperature, reproduction, and trophic) and used functional and phylogenetic metrics to assess variable assemblage responses across physiographic regions and habitat sizes (headwaters through large rivers). Our focal species analysis projected future habitat suitability gains for carnivorous species with preferences for warm water, pool habitats, and fine or vegetated substrates. At the assemblage level, models projected decreasing habitat suitability for cold-water, rheophilic, and lithophilic individuals but increasing suitability for carnivores in the future across all regions. Projected responses of functional and phylogenetic diversity and redundancy differed among regions. Lowland regions were projected to become less functionally and phylogenetically diverse and more redundant while upland regions (and smaller habitat sizes) were projected to become more diverse and less redundant. Next, we assessed how these model-projected assemblage changes 2005-2030 related to observed time-series trends (1999-2016). Halfway through the initial projecting period (2005-2030), we found observed trends broadly followed modeled patterns of increasing proportions of carnivorous and lithophilic individuals in lowland regions but showed opposing patterns for functional and phylogenetic metrics. Leveraging observed and predicted analyses simultaneously helps elucidate the instances and causes of discrepancies between model predictions and ongoing observed changes. Collectively, results highlight the complexity of global change impacts across broad landscapes that likely relate to differences in assemblages' intrinsic sensitivities and external exposure to stressors.

Hyperglycemia and Other Glycemic Measures Throughout Therapy for Pediatric Acute Lymphoblastic Leukemia and Lymphoma.

Transient hyperglycemia during induction chemotherapy is associated with increased morbidity and mortality in patients with acute lymphoblastic leukemia (ALL). Treatment with glucocorticoids, asparaginase, and stress are the proposed causal factors. Although these risks are not exclusive to induction, glycemic control throughout the remainder of ALL/lymphoma (ALL/ALLy) therapy has not been described. Furthermore, prior research has been limited to transient hyperglycemia. This study aimed to characterize glycemic control throughout ALL/ALLy and to evaluate risk factors and outcomes associated with increased mean glucose and glucose coefficient of variation (glucose CV) during induction chemotherapy. The records for 220 pediatric/young adult patients, age 1 to 26 years, who underwent treatment for ALL/ALLy from 2010 to 2014 at Children's Hospital Colorado were retrospectively reviewed. Measures of glycemic control were calculated for each cycle. For the cycle with the highest mean glucose, induction (n=208), multivariable models were performed to identify potential risk factors and consequences of increased glucose. Highest mean glucose by cycle were induction 116 mg/dL, pretreatment 108 mg/dL, delayed intensification 96 mg/dL, and maintenance 93 mg/dL; these cycles also had the most glycemic variability. During induction, patients with Down syndrome, or who were ≥12 years and overweight/obese, had higher mean glucoses; age and overweight/obese status were each associated with increased glucose CV. In multivariable analysis, neither induction mean glucose nor glucose CV were associated with increased hazard of infection, relapse, or death.

Shale gas development has limited effects on stream biology and geochemistry in a gradient-based, multiparameter study in Pennsylvania.

The number of horizontally drilled shale oil and gas wells in the United States has increased from nearly 28,000 in 2007 to nearly 127,000 in 2017, and research has suggested the potential for the development of shale resources to affect nearby stream ecosystems. However, the ability to generalize current studies is limited by the small geographic scope as well as limited breadth and integration of measured chemical and biological indicators parameters. This study tested the hypothesis that a quantifiable, significant relationship exists between the density of oil and gas (OG) development, increasing stream water concentrations of known geochemical tracers of OG extraction, and the composition of benthic macroinvertebrate and microbial communities. Twenty-five headwater streams that drain lands across a gradient of shale gas development intensity were sampled. Our strategy included comprehensive measurements across multiple seasons of sampling to account for temporal variability of geochemical parameters, including known shale OG geochemical tracers, and microbial and benthic macroinvertebrate communities. No significant relationships were found between the intensity of OG development, shale OG geochemical tracers, or benthic macroinvertebrate or microbial community composition, whereas significant seasonal differences in stream chemistry were observed. These results highlight the importance of considering spatial and temporal variability in stream chemistry and biota and not only the presence of anthropogenic activities in a watershed. This comprehensive, integrated study of geochemical and biological variability of headwater streams in watersheds undergoing OG development provides a robust framework for examining the effects of energy development at a regional scale.

Sex-based disparities in outcome in pediatric acute lymphoblastic leukemia: a Children's Oncology Group report.

BACKGROUND: Boys with acute lymphoblastic leukemia (ALL) have historically experienced inferior survival compared to girls. This study determined whether sex-based disparities persist with contemporary therapy and whether patterns of treatment failure vary by sex. METHODS: Patients 1 to 30.99 years old were enrolled on frontline Children's Oncology Group trials between 2004 and 2014. Boys received an additional year of maintenance therapy. Sex-based differences in the distribution of various prognosticators, event-free survival (EFS) and overall survival (OS), and subcategories of relapse by site were explored. RESULTS: A total of 8202 (54.4% male) B-cell ALL (B-ALL) and 1562 (74.3% male) T-cell ALL (T-ALL) patients were included. There was no sex-based difference in central nervous system (CNS) status. Boys experienced inferior 5-year EFS and OS (EFS, 84.6% ± 0.5% vs 86.0% ± 0.6%, P = .009; OS, 91.3% ± 0.4% vs 92.5% ± 0.4%, P = .02). This was attributable to boys with B-ALL, who experienced inferior EFS (hazard ratio [HR], 1.2; 95% confidence interval [95% CI], 1.1-1.3; P = .004) and OS (HR, 1.2; 95% CI, 1.0-1.4; P = .046) after adjustment for prognosticators. Inferior B-ALL outcomes in boys were attributable to more relapses (5-year cumulative incidence 11.2% ± 0.5% vs 9.6% ± 0.5%; P = .001), particularly involving the CNS (4.2% ± 0.3% vs 2.5% ± 0.3%; P < .0001). There was no difference in isolated bone marrow relapses (5.4% ± 0.4% vs 6.2% ± 0.4%; P = .49). There were no sex-based differences in EFS or OS in T-ALL. CONCLUSIONS: Sex-based disparities in ALL persist, attributable to increased CNS relapses in boys with B-ALL. Studies of potential mechanisms are warranted. Improved strategies to identify and modify treatment for patients at highest risk of CNS relapse may have particular benefit for boys.

Molecular and phenotypic diversity of CBL-mutated juvenile myelomonocytic leukemia.

Mutations in the gene CBL were first identified in adults with various myeloid malignancies. Some patients with juvenile myelomonocytic leukemia (JMML) were also noted to harbor mutations in CBL, but were found to have generally less aggressive disease courses compared to other forms of Ras pathway-mutant JMML. Importantly, and in contrast to most reports in adults, the majority of CBL mutations in JMML patients are germline with acquired uniparental disomy occurring in affected marrow cells. Here, we systematically studied a large cohort of 33 JMML patients with CBL mutations and found this disease to be highly diverse in presentation and overall outcome. Moreover, we discovered somatically-acquired CBL mutations in 15% of pediatric patients who presented with more aggressive disease. Neither clinical features nor methylation profiling were able to distinguish somatic CBL patients from germline CBL patients, highlighting the need for germline testing. Overall, we demonstrate that disease courses are quite heterogeneous even among germline CBL patients. Prospective clinical trials are warranted to find ideal treatment strategies for this diverse cohort of patients.

Pediatric Aggressive Mature B-Cell Lymphomas, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology.

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Pediatric Aggressive Mature B-Cell Lymphomas include recommendations for the diagnosis and management of pediatric patients with primary mediastinal large B-cell lymphoma (PMBL) and sporadic variants of Burkitt lymphoma and diffuse large B-cell lymphoma. PMBL is now considered as a distinct entity arising from mature thymic B-cells accounting for 2% of mature B-cell lymphomas in children and adolescents. This discussion section includes the recommendations outlined in the NCCN Guidelines for the diagnosis and management of pediatric patients with PMBL.

Explainable machine learning improves interpretability in the predictive modeling of biological stream conditions in the Chesapeake Bay Watershed, USA.

Anthropogenic alterations have resulted in widespread degradation of stream conditions. To aid in stream restoration and management, baseline estimates of conditions and improved explanation of factors driving their degradation are needed. We used random forests to model biological conditions using a benthic macroinvertebrate index of biotic integrity for small, non-tidal streams (upstream area ≤200 km2) in the Chesapeake Bay watershed (CBW) of the mid-Atlantic coast of North America. We utilized several global and local model interpretation tools to improve average and site-specific model inferences, respectively. The model was used to predict condition for 95,867 individual catchments for eight periods (2001, 2004, 2006, 2008, 2011, 2013, 2016, 2019). Predicted conditions were classified as Poor, FairGood, or Uncertain to align with management needs and individual reach lengths and catchment areas were summed by condition class for the CBW for each period. Global permutation and local Shapley importance values indicated percent of forest, development, and agriculture in upstream catchments had strong impacts on predictions. Development and agriculture negatively influenced stream condition for model average (partial dependence [PD] and accumulated local effect [ALE] plots) and local (individual condition expectation and Shapley value plots) levels. Friedman's H-statistic indicated large overall interactions for these three land covers, and bivariate global plots (PD and ALE) supported interactions among agriculture and development. Total stream length and catchment area predicted in FairGood conditions decreased then increased over the 19-years (length/area: 66.6/65.4% in 2001, 66.3/65.2% in 2011, and 66.6/65.4% in 2019). Examination of individual catchment predictions between 2001 and 2019 showed those predicted to have the largest decreases in condition had large increases in development; whereas catchments predicted to exhibit the largest increases in condition showed moderate increases in forest cover. Use of global and local interpretative methods together with watershed-wide and individual catchment predictions support conservation practitioners that need to identify widespread and localized patterns, especially acknowledging that management actions typically take place at individual-reach scales.

SARS-CoV-2 persistence in immunocompromised children.

OBJECTIVES: We evaluated the length of time immunocompromised children (ICC) remain positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), identified factors associated with viral persistence, and determined cycle threshold (CT ) values of children with viral persistence as a surrogate of viral load. METHODS: We conducted a retrospective cohort study of ICC at a pediatric hospital from March 2020 to March 2021. Immunocompromised status was defined as primary, secondary, or acquired due to medical comorbidities/immunosuppressive treatment. The primary outcome was time to first of two consecutive negative SARS-CoV-2 polymerase chain reaction (PCR) tests at least 24 hours apart. Testing of sequential clinical specimens from the same subject was conducted using the Centers for Disease Control (CDC) 2019-nCoV real-time reverse transcriptase (RT)-PCR Diagnostic Panel assay. Descriptive statistics, Kaplan-Meier curve median event times and log-rank tests were used to compare outcomes between groups. RESULTS: Ninety-one children met inclusion criteria. Median age was 15.5 years (interquartile range [IQR] 8-18), 64% were male, 58% were White, and 43% were Hispanic/Latinx. Most (67%) were tested in outpatient settings and 58% were asymptomatic. The median time to two negative tests was 42 days (IQR 25.0-55.0), with no differences in median time by illness presentation or level of immunosuppression. Seven children had more than one sample available for repeat testing, and five of seven (71%) children had initial CT values of <30 (moderate to high viral load); four children had CT values of <30, 3-4 weeks later, suggesting persistent moderate to high viral loads. CONCLUSIONS: Most ICC with SARS-CoV-2 infection had mild disease, with prolonged viral persistence >6 weeks and moderate to high viral load.

Using expert knowledge to support Endangered Species Act decision-making for data-deficient species.

Many questions relevant to conservation decision-making are characterized by extreme uncertainty due to lack of empirical data and complexity of the underlying ecologic processes, leading to a rapid increase in the use of structured protocols to elicit expert knowledge. Published ecologic applications often employ a modified Delphi method, where experts provide judgments anonymously and mathematical aggregation techniques are used to combine judgments. The Sheffield elicitation framework (SHELF) differs in its behavioral approach to synthesizing individual judgments into a fully specified probability distribution for an unknown quantity. We used the SHELF protocol remotely to assess extinction risk of three subterranean aquatic species that are being considered for listing under the U.S. Endangered Species Act. We provided experts an empirical threat assessment for each known locality over a video conference and recorded judgments on the probability of population persistence over four generations with online submission forms and R-shiny apps available through the SHELF package. Despite large uncertainty for all populations, there were key differences between species' risk of extirpation based on spatial variation in dominant threats, local land use and management practices, and species' microhabitat. The resulting probability distributions provided decision makers with a full picture of uncertainty that was consistent with the probabilistic nature of risk assessments. Discussion among experts during SHELF's behavioral aggregation stage clearly documented dominant threats (e.g., development, timber harvest, animal agriculture, and cave visitation) and their interactions with local cave geology and species' habitat. Our virtual implementation of the SHELF protocol demonstrated the flexibility of the approach for conservation applications operating on budgets and time lines that can limit in-person meetings of geographically dispersed experts.

Uso del Conocimiento Experto para Respaldar la Toma de Decisiones del Acta de Especies en Peligro para Especies con Información Deficiente Resumen Muchas preguntas relevantes para la toma de decisiones de conservación se caracterizan por una incertidumbre extrema causada por la falta de información empírica y por la complejidad de los procesos ecológicos subyacentes. Esto lleva a un rápido incremento en el uso de protocolos estructurados para obtener conocimiento de los expertos en el tema. Las aplicaciones ecológicas publicadas con frecuencia emplean un método Delphi modificado, en el cual los expertos proporcionan dictámenes anónimamente y luego se usan técnicas de agregación matemática para combinar estos dictámenes. El marco de trabajo de obtención Sheffield (SHELF) difiere en su enfoque conductual para sintetizar los dictámenes individuales en una distribución de probabilidad completamente especificada para una cantidad desconocida. Usamos el protocolo SHELF remotamente para evaluar el riesgo de extinción de tres especies acuáticas subterráneas que están siendo consideradas para ser incluidas en el Acta de Especies en Peligro de los E.U.A. Les proporcionamos a los expertos una evaluación empírica de la amenaza para cada localidad conocida durante una videoconferencia y registramos los dictámenes sobre la probabilidad de la persistencia poblacional durante cuatro generaciones por medio de formularios enviados en línea y las apps R-shiny disponibles a través del paquete SHELF. A pesar de la gran incertidumbre para todas las poblaciones, hubo diferencias importantes entre el riesgo de extirpación de las especies con base en la variación espacial en las amenazas dominantes, el uso del suelo local y las prácticas de manejo, y el microhábitat de las especies. Las distribuciones resultantes de la probabilidad proporcionaron al órgano decisorio un cuadro completo de la incertidumbre que fue consistente con la naturaleza probabilística de las evaluaciones de riesgo. Las discusiones entre los expertos durante la fase de agregación conductual de SHELF documentaron claramente las amenazas dominantes (p. ej.: desarrollo, extracción de madera, agricultura animal y visitas a las cuevas) y sus interacciones con la geología de las cuevas locales y el hábitat de la especie. Nuestra implementación virtual del protocolo SHELF demostró la flexibilidad del enfoque para las aplicaciones de la conservación que operan con presupuestos y líneas de tiempo que pueden limitar las reuniones en persona de expertos dispersados geográficamente.

Pediatric mediastinal mass algorithm: A quality improvement initiative to reduce time from presentation to biopsy.

BACKGROUND: Mediastinal masses in children may present with compression of the great vessels and airway. An interdisciplinary plan for rapid diagnosis, acute management, and treatment prevents devastating outcomes and optimizes care. Emergency pretreatment with steroids or radiation is more likely to be administered when care is variable, which may delay and complicate diagnosis and treatment. Strategies to standardize care and expedite diagnosis may improve acute patient safety and long-term outcomes. AIMS: The aim of this quality improvement project was to decrease time from presentation to diagnostic biopsy for children with an anterior mediastinal mass by 50% over 3 years within a tertiary healthcare system. METHODS: This quality improvement project involved a single center with data collected and analyzed retrospectively and prospectively for 71 patients presenting with anterior mediastinal mass between February 2008 and January 2018. The Model for Improvement was utilized for project design and development of a driver diagram and smart aim. An algorithm was implemented to facilitate communication between teams and standardize initial care of patients with mediastinal masses. The algorithm underwent multiple Plan-Do-Study-Act (PDSA) cycles. Data were collected before and after algorithm implementation and between each PDSA cycle. The primary outcome measure included time from presentation to biopsy, which was monitored with a statistical process control chart. Several process measures were evaluated with Student's t-tests including administration of emergency pretreatment. RESULTS: Nineteen patients preintervention and 52 patients postintervention were included in the analysis. Time from presentation to biopsy significantly decreased from 48 h at baseline to 24 h postimplementation. Although not statistically significant, emergency pretreatment decreased from a baseline of 26.3% to 6.7% postimplementation. CONCLUSION: Implementation of a diagnostic and management algorithm coordinating care among multidisciplinary teams significantly reduced time to biopsy for children presenting with mediastinal mass and may result in decreased use of emergent pretreatment.

Linking Altered Flow Regimes to Biological Condition: an Example Using Benthic Macroinvertebrates in Small Streams of the Chesapeake Bay Watershed.

Regionally scaled assessments of hydrologic alteration for small streams and its effects on freshwater taxa are often inhibited by a low number of stream gages. To overcome this limitation, we paired modeled estimates of hydrologic alteration to a benthic macroinvertebrate index of biotic integrity data for 4522 stream reaches across the Chesapeake Bay watershed. Using separate random-forest models, we predicted flow status (inflated, diminished, or indeterminant) for 12 published hydrologic metrics (HMs) that characterize the main components of flow regimes. We used these models to predict each HM status for each stream reach in the watershed, and linked predictions to macroinvertebrate condition samples collected from streams with drainage areas less than 200 km2. Flow alteration was calculated as the number of HMs with inflated or diminished status and ranged from 0 (no HM inflated or diminished) to 12 (all 12 HMs inflated or diminished). When focused solely on the stream condition and flow-alteration relationship, degraded macroinvertebrate condition was, depending on the number of HMs used, 3.8-4.7 times more likely in a flow-altered site; this likelihood was over twofold higher in the urban-focused dataset (8.7-10.8), and was never significant in the agriculture-focused dataset. Logistic regression analysis using the entire dataset showed for every unit increase in flow-alteration intensity, the odds of a degraded condition increased 3.7%. Our results provide an indication of whether altered streamflow is a possible driver of degraded biological conditions, information that could help managers prioritize management actions and lead to more effective restoration efforts.

Measurable residual disease detection by high-throughput sequencing improves risk stratification for pediatric B-ALL.

Early response to induction chemotherapy is an important prognostic factor in B-lymphoblastic leukemia (B-ALL). Here, we compare high-throughput sequencing (HTS) of IGH and TRG genes vs flow cytometry (FC) for measurable residual disease (MRD) detection at the end of induction chemotherapy in pediatric patients with newly diagnosed B-ALL. Six hundred nineteen paired pretreatment and end-of-induction bone marrow samples from Children's Oncology Group studies AALL0331 (clinicaltrials.gov #NCT00103285) (standard risk [SR]; with MRD by FC at any level) and AALL0232 (clinicaltrials.gov #NCT00075725) (high risk; with day 29 MRD <0.1% by FC) were evaluated by HTS and FC for event-free (EFS) and overall survival (OS). HTS and FC showed similar 5-year EFS and OS for MRD-positive and -negative patients using an MRD threshold of 0.01%. However, there was a high discordant rate with HTS identifying 55 (38.7%) more patients MRD positive at this threshold. These discrepant patients have worse outcomes than FC MRD-negative patients. In addition, the increased analytic sensitivity of HTS permitted identification of 19.9% of SR patients without MRD at any detectable level who had excellent 5-year EFS (98.1%) and OS (100%). The higher analytic sensitivity and lower false-negative rate of HTS improves upon FC for MRD detection in pediatric B-ALL by identifying a novel subset of patients at end of induction who are essentially cured using current chemotherapy and identifying MRD at 0.01% in up to one-third of patients who are missed at the same threshold by FC.

Genomic and outcome analyses of Ph-like ALL in NCI standard-risk patients: a report from the Children's Oncology Group.

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL; BCR-ABL1-like ALL) in children with National Cancer Institute (NCI) intermediate- or high-risk (HR) ALL is associated with poor outcome. Ph-like ALL is characterized by genetic alterations that activate cytokine receptor and kinase signaling and may be amenable to treatment with tyrosine kinase inhibitors. The prevalence, outcome, and potential for targeted therapy of Ph-like ALL in standard-risk (SR) ALL is less clear. We retrospectively analyzed a cohort of 1023 SR childhood B-ALL consecutively enrolled in the Children's Oncology Group AALL0331 clinical trial. The Ph-like ALL gene expression profile was identified in 206 patients, and 67 patients with either BCR-ABL1 (n = 6) or ETV6-RUNX1 (n = 61) were excluded from downstream analysis, leaving 139 of 1023 (13.6%) as Ph-like. Targeted reverse transcription polymerase chain reaction assays and RNA-sequencing identified kinase-activating alterations in 38.8% of SR Ph-like cases, including CRLF2 rearrangements (29.5% of Ph-like), ABL-class fusions (1.4%), JAK2 fusions (1.4%), an NTRK3 fusion (0.7%), and other sequence mutations (IL7R, KRAS, NRAS; 5.6%). Patients with Ph-like ALL had inferior 7-year event-free survival compared with non-Ph-like ALL (82.4 ± 3.6% vs 90.7 ± 1.0%, P = .0022), with no difference in overall survival (93.2 ± 2.4% vs 95.8 ± 0.7%, P = .14). These findings illustrate the significant differences in the spectrum of kinase alterations and clinical outcome of Ph-like ALL based on presenting clinical features and establish that genomic alterations potentially targetable with approved kinase inhibitors are less frequent in SR than in HR ALL.

Disentangling the potential effects of land-use and climate change on stream conditions.

Land-use and climate change are significantly affecting stream ecosystems, yet understanding of their long-term impacts is hindered by the few studies that have simultaneously investigated their interaction and high variability among future projections. We modeled possible effects of a suite of 2030, 2060, and 2090 land-use and climate scenarios on the condition of 70,772 small streams in the Chesapeake Bay watershed, United States. The Chesapeake Basin-wide Index of Biotic Integrity, a benthic macroinvertebrate multimetric index, was used to represent stream condition. Land-use scenarios included four Special Report on Emissions Scenarios (A1B, A2, B1, and B2) representing a range of potential landscape futures. Future climate scenarios included quartiles of future climate changes from downscaled Coupled Model Intercomparison Project - Phase 5 (CMIP5) and a watershed-wide uniform scenario (Lynch2016). We employed random forests analysis to model individual and combined effects of land-use and climate change on stream conditions. Individual scenarios suggest that by 2090, watershed-wide conditions may exhibit anywhere from large degradations (e.g., scenarios A1B, A2, and the CMIP5 25th percentile) to small degradations (e.g., scenarios B1, B2, and Lynch2016). Combined land-use and climate change scenarios highlighted their interaction and predicted, by 2090, watershed-wide degradation in 16.2% (A2 CMIP5 25th percentile) to 1.0% (B2 Lynch2016) of stream kilometers. A goal for the Chesapeake Bay watershed is to restore 10% of stream kilometers over a 2008 baseline; our results suggest meeting and sustaining this goal until 2090 may require improvement in 11.0%-26.2% of stream kilometers, dependent on land-use and climate scenario. These results highlight inherent variability among scenarios and the resultant uncertainty of predicted conditions, which reinforces the need to incorporate multiple scenarios of both land-use (e.g., development, agriculture, etc.) and climate change in future studies to encapsulate the range of potential future conditions.

Pediatric Aggressive Mature B-Cell Lymphomas, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology.

Pediatric aggressive mature B-cell lymphomas are the most common types of non-Hodgkin lymphoma in children, and they include Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL). These diseases are highly aggressive but curable, the treatment is complex, and patients may have many complicated supportive care issues. The NCCN Guidelines for Pediatric Aggressive Mature B-Cell Lymphomas provide guidance regarding pathology and diagnosis, staging, initial treatment, disease reassessment, surveillance, therapy for relapsed/refractory disease, and supportive care for clinicians who treat sporadic pediatric BL and DLBCL.

Single-center pediatric experience with venetoclax and azacitidine as treatment for myelodysplastic syndrome and acute myeloid leukemia.

BACKGROUND: The BCL-2 inhibitor venetoclax (ven) has revolutionized the treatment of acute myeloid leukemia (AML) in elderly adults, leading to its recent FDA approval for this population in combination regimens. Although extensive data exist for adult myeloid malignancies, there are limited preclinical data on the efficacy and/or dosing of venetoclax for pediatric myelodysplastic syndrome (MDS) or AML and thus little information to guide use of this regimen in pediatric patients. Our objective was to describe our single-center experience with venetoclax in combination with the hypomethylating agent 5-azacitidine (aza) in pediatric patients with MDS or AML. PROCEDURE: We conducted a retrospective chart review of patients treated at Children's Hospital Colorado prior to March 2020 with at least one cycle of ven/aza. Patients were included if between the ages of 1 and 25 years with a diagnosis of high-grade MDS or AML. AML patients had relapsed or primary refractory disease or were deemed poor candidates for standard chemotherapy. RESULTS: Eight patients received ven/aza, two for high-grade MDS and six for AML. Ven/aza was well tolerated by all patients. The most common adverse events seen with this regimen were gastrointestinal and hematologic. Morphologic responses were seen in six patients including both patients with MDS. All four AML responders became minimal residual disease negative. Three responders have thus far proceeded to allogeneic hematopoietic stem cell transplant following ven/aza. CONCLUSIONS: Our clinical experience suggests that ven/aza is a safe and promising regimen that should be further explored with late-phase clinical trials.

Comparison of self-report and electronic monitoring of 6MP intake in childhood ALL: a Children's Oncology Group study.

Adequate exposure to oral 6-mercaptopurine (6MP) during maintenance therapy for childhood acute lymphoblastic leukemia (ALL) is critical for sustaining durable remissions; accuracy of self-reported 6MP intake is unknown. We aimed to directly compare self-report to electronic monitoring (Medication Event Monitoring System [MEMS]) and identify predictors of overreporting in a cohort of 416 children with ALL in first remission over 4 study months (1344 patient-months for the cohort) during maintenance therapy. Patients were classified as "perfect reporters" (self-report agreed with MEMS), "overreporters" (self-report was higher than MEMS by ≥5 days/month for ≥50% of study months), and "others" (not meeting criteria for perfect reporter or overreporter). Multivariable logistic regression examined sociodemographic and clinical characteristics, 6MP dose intensity, TPMT genotype, thioguanine nucleotide levels, and 6MP nonadherence (MEMS-based adherence <95%) associated with the overreporter phenotype; generalized estimating equations compared 6MP intake by self-report and MEMS. Self-reported 6MP intake exceeded MEMS at least some of the time in 84% of patients. Fifty patients (12%) were classified as perfect reporters, 98 (23.6%) as overreporters, 2 (0.5%) as underreporters, and 266 (63.9%) as others. In multivariable analysis, the following variables were associated with the overreporter phenotype: non-white race: Hispanic, odds ratio (OR), 2.4, P = .02; Asian, OR, 3.1, P = .02; African American, P < .001; paternal education less than college (OR, 1.4, P = .05); and 6MP nonadherence (OR, 9.4, P < .001). Self-report of 6MP intake in childhood ALL overestimates true intake, particularly in nonadherent patients, and should be used with caution.

Successful Use of EPOCH-R in 2 Young Adult Patients With Burkitt Lymphoma and Acute Kidney Injury: A Case Report.

Pediatric Burkitt lymphoma has historically been treated with intensive methotrexate-based chemotherapy, which improves patient survival while causing severe toxicities. Young patients typically have better outcomes with intensive therapies, while adults and immunocompromised patients have higher toxicities and worse outcomes. Newer treatment regimens, including etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab (EPOCH-R), show promise for these patients. However, few studies exist to demonstrate efficacy and improved toxicity profile with EPOCH-R. We present 2 cases: a 25-year-old male with Down syndrome and an 18-year-old male with Burkitt lymphoma and significant renal injury who were successfully treated with EPOCH-R with minimal toxicities.

Genetic risk factors for the development of osteonecrosis in children under age 10 treated for acute lymphoblastic leukemia.

Osteonecrosis is a dose-limiting toxicity in the treatment of pediatric acute lymphoblastic leukemia (ALL). Prior studies on the genetics of osteonecrosis have focused on patients ≥10 years of age, leaving the genetic risk factors for the larger group of children <10 years incompletely understood. Here, we perform the first evaluation of genetic risk factors for osteonecrosis in children <10 years. The discovery cohort comprised 82 cases of osteonecrosis and 287 controls treated on Children's Oncology Group (COG) standard-risk ALL protocol AALL0331 (NCT00103285, https://clinicaltrials.gov/ct2/show/NCT00103285), with results tested for replication in 817 children <10 years treated on COG protocol AALL0232 (NCT00075725, https://clinicaltrials.gov/ct2/show/NCT00075725). The top replicated single nucleotide polymorphisms (SNPs) were near bone morphogenic protein 7 [BMP7: rs75161997, P = 5.34 × 10(-8) (odds ratio [OR] 15.0) and P = .0498 (OR 8.44) in the discovery and replication cohorts, respectively] and PROX1-antisense RNA1 (PROX1-AS1: rs1891059, P = 2.28 × 10(-7) [OR 6.48] and P = .0077 [OR 3.78] for the discovery and replication cohorts, respectively). The top replicated nonsynonymous SNP, rs34144324, was in a glutamate receptor gene (GRID2, P = 8.65 × 10(-6) [OR 3.46] and P = .0136 [OR 10.8] in the discovery and replication cohorts, respectively). In a meta-analysis, the BMP7 and PROX1-AS1 variants (rs75161997 and rs1891059, respectively) met the significance threshold of <5 × 10(-8). Top replicated SNPs were enriched in enhancers active in mesenchymal stem cells, and analysis of annotated genes demonstrated enrichment in glutamate receptor and adipogenesis pathways. These data may provide new insights into the pathophysiology of osteonecrosis.