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Selection pressure due to exposure to infectious pathogens endemic to Africa may explain distinct genetic variations in immune response genes. However, the impact of those genetic variations on human immunity remains understudied, especially within the context of modern lifestyles and living environments, which are drastically different from early humans in sub Saharan Africa. There are few data on population differences in constitutional immune environment, where genetic ancestry and environment are likely two primary sources of variation. In a study integrating genetic, molecular and epidemiologic data, we examined population differences in plasma levels of 14 cytokines involved in innate and adaptive immunity, including those implicated in chronic inflammation, and possible contributing factors to such differences, in 914 AA and 855 EA women. We observed significant differences in 7 cytokines, including higher plasma levels of CCL2, CCL11, IL4 and IL10 in EAs and higher levels of IL1RA and IFNα2 in AAs. Analyses of a wide range of demographic and lifestyle factors showed significant impact, with age, education level, obesity, smoking, and alcohol intake, accounting for some, but not all, observed population differences for the cytokines examined. Levels of two pro-inflammatory chemokines, CCL2 and CCL11, were strongly associated with percent of African ancestry among AAs. Through admixture mapping, the signal was pinpointed to local ancestry at 1q23, with fine-mapping analysis refined to the Duffy-null allele of rs2814778. In AA women, this variant was a major determinant of systemic levels of CCL2 (p = 1.1e-58) and CCL11 (p = 2.2e-110), accounting for 19% and 40% of the phenotypic variance, respectively. Our data reveal strong ancestral footprints in inflammatory chemokine regulation. The Duffy-null allele may indicate a loss of the buffering function for chemokine levels. The substantial immune differences by ancestry may have broad implications to health disparities between AA and EA populations.

Discovery and validation of genetic variants that influence disease severity in children with sickle cell anemia (SCA) could lead to early identification of high-risk patients, better screening strategies, and intervention with targeted and preventive therapy. We hypothesized that newly identified genetic risk factors for the general African American population could also impact laboratory biomarkers known to contribute to the clinical disease expression of SCA, including variants influencing the white blood cell count and the development of albuminuria and abnormal glomerular filtration rate. We first investigated candidate genetic polymorphisms in well-characterized SCA pediatric cohorts from three prospective NHLBI-supported clinical trials: HUSTLE, SWiTCH, and TWiTCH. We also performed whole exome sequencing to identify novel genetic variants, using both a discovery and a validation cohort. Among candidate genes, DARC rs2814778 polymorphism regulating Duffy antigen expression had a clear influence with significantly increased WBC and neutrophil counts, but did not affect the maximum tolerated dose of hydroxyurea therapy. The APOL1 G1 polymorphism, an identified risk factor for non-diabetic renal disease, was associated with albuminuria. Whole exome sequencing discovered several novel variants that maintained significance in the validation cohorts, including ZFHX4 polymorphisms affecting both the leukocyte and neutrophil counts, as well as AGGF1, CYP4B1, CUBN, TOR2A, PKD1L2, and CD163 variants affecting the glomerular filtration rate. The identification of robust, reliable, and reproducible genetic markers for disease severity in SCA remains elusive, but new genetic variants provide avenues for further validation and investigation.

Accurately simulating gross primary productivity (GPP) in terrestrial ecosystem models is critical because errors in simulated GPP propagate through the model to introduce additional errors in simulated biomass and other fluxes. We evaluated simulated, daily average GPP from 26 models against estimated GPP at 39 eddy covariance flux tower sites across the United States and Canada. None of the models in this study match estimated GPP within observed uncertainty. On average, models overestimate GPP in winter, spring, and fall, and underestimate GPP in summer. Models overpredicted GPP under dry conditions and for temperatures below 0°C. Improvements in simulated soil moisture and ecosystem response to drought or humidity stress will improve simulated GPP under dry conditions. Adding a low‐temperature response to shut down GPP for temperatures below 0°C will reduce the positive bias in winter, spring, and fall and improve simulated phenology. The negative bias in summer and poor overall performance resulted from mismatches between simulated and observed light use efficiency (LUE). Improving simulated GPP requires better leaf‐to‐canopy scaling and better values of model parameters that control the maximum potential GPP, such asεmax (LUE), Vcmax (unstressed Rubisco catalytic capacity) or Jmax (the maximum electron transport rate). Key Points Gross primary productivity (GPP) from 26 models tested at 39 flux tower sites Simulated light use efficiency controls model performance Models overpredict GPP under dry conditions

The severity and incidence of climatic extremes, including drought, have increased as a result of climate warming. Analyses of observational and reanalysis data suggest that the strength of the western North American carbon sink declined by 30–298 Tg carbon per year during the drought at the turn of the century. Fossil fuel emissions aside, temperate North America is a net sink of carbon dioxide at present 1 , 2 , 3 . Year-to-year variations in this carbon sink are linked to variations in hydroclimate that affect net ecosystem productivity 3 , 4 . The severity and incidence of climatic extremes, including drought, have increased as a result of climate warming 5 , 6 , 7 , 8 . Here, we examine the effect of the turn of the century drought in western North America on carbon uptake in the region, using reanalysis data, remote sensing observations and data from global monitoring networks. We show that the area-integrated strength of the western North American carbon sink declined by 30–298 Tg C yr −1 during the 2000–2004 drought. We further document a pronounced drying of the terrestrial biosphere during this period, together with a reduction in river discharge and a loss of cropland productivity. We compare our findings with previous palaeoclimate reconstructions 7 and show that the last drought of this magnitude occurred more than 800 years ago. Based on projected changes in precipitation and drought severity, we estimate that the present mid-latitude carbon sink of 177–623 Tg C yr −1 in western North America could disappear by the end of the century.

Spinocerebellar ataxia type 7 (SCA7) is a late-onset neurodegenerative disease characterized by ataxia and vision loss with no effective treatments in the clinic. The most striking feature is the degeneration of Purkinje neurons of the cerebellum caused by the presence of polyglutamine-expanded ataxin-7. Ataxin-7 is part of a transcriptional complex, and, in the setting of mutant ataxin-7, there is misregulation of target genes. Here, we designed RNAi sequences to reduce the expression of both wildtype and mutant ataxin-7 to test if reducing ataxin-7 in Purkinje cells is both tolerated and beneficial in an animal model of SCA7. We observed sustained reduction of both wildtype and mutant ataxin-7 as well as a significant improvement of ataxia phenotypes. Furthermore, we observed a reduction in cerebellar molecular layer thinning and nuclear inclusions, a hallmark of SCA7. In addition, we observed recovery of cerebellar transcripts whose expression is disrupted in the presence of mutant ataxin-7. These data demonstrate that reduction of both wildtype and mutant ataxin-7 by RNAi is well tolerated, and contrary to what may be expected from reducing a component of the Spt-Taf9-Gcn5 acetyltransferase complex, is efficacious in the SCA7 mouse.

With increasing early and upfront use of rituximab and caplacizumab in the modern management of immune-mediated thrombotic thrombocytopenic purpura (iTTP), the risk of refractory disease is expected to decline. However, despite the use of adequate initial therapy, a small subset of patients develop a refractory disease which is difficult to manage. Bortezomib has come to be known as a safe and effective treatment option for refractory iTTP, but its use in children is limited. Here, we describe the case of an adolescent patient with refractory iTTP who had a satisfactory and sustained response to the use of bortezomib.

Post-transplant erythrocytosis (PTE) is a well-documented complication in adult renal transplant recipients but is less commonly reported in pediatric cases. We present an eight-year-old female patient with end-stage renal disease (ESRD) secondary to immune complex-mediated glomerulonephritis, who developed erythrocytosis 10 months after a deceased donor kidney transplant. Despite normal erythropoietin levels and mild obstructive sleep apnea, her hemoglobin (17 g/dL) and hematocrit (52%) remained elevated. She was initially treated with enalapril (2.5 mg daily), leading to hemoglobin normalization, later switched to losartan (titrated to 50 mg daily) for hypertension and proteinuria. Over five years, her hemoglobin has remained within the target range (11.5-14.5 g/dL), with controlled blood pressure and proteinuria. This case highlights the successful long-term management of pediatric PTE with renin-angiotensin system blockade while preserving graft function.

Terrestrial biosphere models can help identify physical processes that control carbon dynamics, including land-atmosphere CO2 fluxes, and have great potential to predict the terrestrial ecosystem response to changing climate. The skill of models that provide continental scale carbon flux estimates, however, remains largely untested. This paper evaluates the performance of continental-scale flux estimates from 17 models against observations from 36 North American flux towers. Fluxes extracted from regional model simulations are compared with co-located flux tower observations at monthly and annual time increments. Site-level model simulations are used to help interpret sources of the mismatch between the regional simulations and site-based observations. On average the regional model runs overestimate the annual gross primary productivity (5%) and total respiration (15%), and significantly underestimate the annual net carbon uptake (64%) during the time period 2000-2005. Comparison with site-level simulations implicate choices specific to regional model simulations as contributors to the gross flux biases, but not the net carbon uptake bias. The models perform the best at simulating carbon exchange at deciduous broadleaf sites; likely because a number of models use prescribed phenology to simulate seasonal fluxes. The models do not perform as well for crop, grass and evergreen sites. The regional models match the observations most closely in terms of seasonal correlation and seasonal magnitude of variation, but have very little skill at inter-annual correlation and minimal skill at inter-annual magnitude of variability. The comparison of site versus regional level model runs demonstrate that 1) the inter-annual correlation is higher for site-level model runs but the skill remains low, and 2) the underestimation of year-to-year variability for all fluxes is an inherent weakness of the models. The best performing regional models that do not use flux tower calibration are CLM-CN, CASA-GFEDv2 and SIB3. Two flux tower calibrated, empirical models, EC-MOD and MOD17+, perform as well as the best process-based models. This suggests that 1) empirical, calibrated models can perform as well as complex, process-based models, and 2) combining process-based model structure with relevant constraining data could significantly improve model performance.

Atypical hemolytic uremic syndrome (aHUS) is a rare disease in pediatrics with 6-10% of cases associated with complement factor H autoantibodies Ravulizumab is a new treatment option available for long-term management through blockage of the terminal complement cascade. We report a case of a previously healthy eight-year-old female who presented with hemolytic anemia, thrombocytopenia, and acute kidney injury. Low complement C3, normal ADAMTS13, and negative rheumatology and infectious disease panels suggested aHUS. A follow-up complement aHUS/TMA gene panel was negative for ADAMTS13, C3, CD46, CFB, CFD, CFH, CFHR1, CFHR3, CFHR5, CRI, DGKE, PLG, and THBD mutations and positive for MCP/CD46 haplotype and CFH-H3 haplotype. Further testing found decreased factor H (B1H) plasma level and increased factor H autoantibody, suggesting anti-factor H antibody-associated aHUS. She received hemodialysis (2 treatments) and eculizumab was initiated promptly. The patient had complete renal recovery after one month of therapy, and anemia, thrombocytopenia, and hemolysis resolved after two months of therapy. After five months of therapy, eculizumab was successfully switched to ravulizumab. After 12 months of initial diagnosis, complement C3 and factor H normalized, however, factor H autoantibody remained elevated. The case supports the notion that timely recognition of anti-FH-associated aHUS is important for disease management and that early specific therapy with immunosuppression results in favorable outcomes. It also illustrates that the blockade of the terminal complement cascade using eculizumab holds promise for pediatric cases. Finally, eculizumab can be safely switched to ravulizumab with an optimal longer duration between treatments in the context of aHUS.

A rise in hospital‐acquired venous thromboembolism (HA‐VTE) in children has led to increased awareness regarding VTE prophylaxis and risk assessment. Despite no consensus exists regarding these practices in pediatrics. To describe common practices in VTE prophylaxis, VTE risk assessment models, and anticoagulation dosing strategies in pediatric hospitals that are members of the Children's Hospital Acquired Thrombosis (CHAT) Consortium. An electronic survey of 44 questions evaluating practices surrounding pediatric HA‐VTE risk assessment and prevention was distributed between August 9, 2021, and August 30, 2021, to the primary investigators from the 32 institutions within the CHAT Consortium. The survey response rate was 100% (n = 32). In total, 85% (n = 27) of the institutions assess HA‐VTE, but only 63% (n = 20) have formal hospital guidelines. Within the institutions with formal guidelines, 100% (n = 20) include acute systemic inflammation or infection and presence of a central venous catheter (CVC) as risk factors for VTE. Pharmacologic prophylaxis is prescribed at 87% (28) of institutions, with enoxaparin being the most frequent (96%, n = 27). Variability in responses persisted regarding risk factors, risk assessment, thromboprophylaxis, dosing of prophylactic anticoagulation or anticoagulant drug monitoring. A majority of providers were comfortable providing thromboprophylaxis across all age groups. In addition, the global coronavirus disease 2019 increased the providers' use of prophylactic anticoagulation 78% (n = 25). Practices among institutions are variable in regard to use of HA‐VTE prophylaxis, risk assessment, or guideline implementation, highlighting the need for further research and a validated risk assessment model through groups like the CHAT Consortium.