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Objective:  This study aimed to describe patient characteristics, satisfaction, and outcome measures for patients undergoing outpatient cervical ripening., Study Design:  A retrospective cohort study using electronic health record data from March 2020 to March 2022 from a large health system. The sample included patients with a low-risk singleton pregnancy undergoing outpatient cervical ripening with either an osmotic dilator or Foley balloon catheter. A subset of patients completed satisfaction surveys. Frequencies and means were used to describe the population and conduct comparisons by device type. Inverse probability of treatment weighted estimates were generated to address baseline differences between patients in the two device groups., Results:  Outpatient cervical ripening was completed by 120 patients (80 osmotic dilators and 40 Foley balloon catheters). The mean time from insertion to inpatient admission was 16.2 ± 4.8 hours. The mean change in simplified Bishop score (SBS) was 1.8 ± 1.4 and the mean change in dilation was 1.8 ± 1.1 cm. There were no differences in the amount of cervical change by device type. Patients returned earlier than planned 16.7% of the time, primarily for contractions or rupture of membranes. Following outpatient cervical ripening, the time from admission to delivery was 19.9 ± 10.3 hours, with no difference by device type. Vaginal delivery occurred for 74.8% of patients. Patients reported overall satisfaction with the outpatient cervical ripening experience, with the highest satisfaction among those with osmotic dilators. Patients with both device types stated they would recommend outpatient cervical ripening to others, and experienced low levels of stress and discomfort at home prior to hospital admission., Conclusion:  Patients participating in outpatient cervical ripening with osmotic dilators or Foley balloon catheters experienced clinically meaningful changes in dilation and SBSs while at home and reported general satisfaction with the outpatient program experience., Key Points: · Outpatient use of osmotic dilators or Foley balloon catheters improved Bishop scores.. · Patient and device complications were comparable to other research findings.. · Patients reported overall satisfaction with outpatient cervical ripening.., Competing Interests: None declared., (Thieme. All rights reserved.)

While metabolic acidosis is one of the most common complications in patients with chronic kidney disease (CKD), there are several uncommon etiologies that are challenging to diagnose. Here, we describe a patient on peritoneal dialysis who developed high anion gap metabolic acidosis secondary to acquired 5-oxoprolinemia from acetaminophen use. While CKD is a known risk factor for developing this potentially serious complication, this case further highlights how 5-oxoproline accumulation can occur, even with therapeutic dosing of acetaminophen., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Post-infectious glomerulonephritis (PIGN) is an immune complex mediated glomerular injury occurring because of an infection, most commonly with group A beta-hemolytic streptococcus in children. C3 glomerulopathy (C3G) is a distinct clinicopathological entity occurring secondary to dysregulation of alternate complement pathway encompassing both C3 glomerulonephritis (C3GN) and dense deposit disease (DDD). While most patients with PIGN attain complete remission with normalized complement levels by 6-8 weeks after presentation, patients with C3G continue to have hypocomplementemia with high rates of progressive kidney disease. Here, we report a patient diagnosed with dense deposit disease after his initial presentation with PIGN three years prior. While current literature continues to explore the overlapping and distinguishing features of PIGN and C3G, including how underlying defects in the alternate complement pathway may commonly contribute to both diseases, this case further exemplifies the importance of recognizing the clinico-pathogenic features of PIGN and C3G in pediatric patients with glomerulonephritis., (© 2023. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Background: Infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can lead to post-acute sequelae of SARS-CoV-2 (PASC) that can persist for weeks to years following initial viral infection. Clinical manifestations of PASC are heterogeneous and often involve multiple organs. While many hypotheses have been made on the mechanisms of PASC and its associated symptoms, the acute biological drivers of PASC are still unknown., Methods: We enrolled 494 patients with COVID-19 at their initial presentation to a hospital or clinic and followed them longitudinally to determine their development of PASC. From 341 patients, we conducted multi-omic profiling on peripheral blood samples collected shortly after study enrollment to investigate early immune signatures associated with the development of PASC., Results: During the first week of COVID-19, we observed a large number of differences in the immune profile of individuals who were hospitalized for COVID-19 compared to those individuals with COVID-19 who were not hospitalized. Differences between individuals who did or did not later develop PASC were, in comparison, more limited, but included significant differences in autoantibodies and in epigenetic and transcriptional signatures in double-negative 1 B cells, in particular., Conclusions: We found that early immune indicators of incident PASC were nuanced, with significant molecular signals manifesting predominantly in double-negative B cells, compared with the robust differences associated with hospitalization during acute COVID-19. The emerging acute differences in B cell phenotypes, especially in double-negative 1 B cells, in PASC patients highlight a potentially important role of these cells in the development of PASC., Competing Interests: JL, MW, PK, CC, KD, GT, and CK maintain equity ownership and employment at Verily Life Sciences. NH, JA, CW, CP-K, and IM were employed at Oncimmune Limited. SP reports personal fees from Jazz Pharmaceuticals, Inc., and UpToDate, Inc., and grants from Philips, Inc., Sommetrics, Inc., and Regeneron. CD serves on advisory boards for Abbott Diagnostics, Ortho/Quidel Diagnostics, and Roche Diagnostics. JK receives research funding from Regeneron. JK has also provided consulting for GlaxoSmithKline, AstraZeneca, CereVu Medical, Propeller/ResMed, and BData, Inc. The remaining 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 © 2024 Leung, Wu, Kheradpour, Chen, Drake, Tong, Ridaura, Zisser, Conrad, Hudson, Allen, Welberry, Parsy-Kowalska, Macdonald, Tapson, Moy, deFilippi, Rosas, Basit, Krishnan, Parthasarathy, Prabhakar, Salvatore and Kim.)

We sought to better understand the immune response during the immediate post-diagnosis phase of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by identifying molecular associations with longitudinal disease outcomes. Multi-omic analyses identified differences in immune cell composition, cytokine levels, and cell subset-specific transcriptomic and epigenomic signatures between individuals on a more serious disease trajectory (Progressors) as compared to those on a milder course (Non-progressors). Higher levels of multiple cytokines were observed in Progressors, with IL-6 showing the largest difference. Blood monocyte cell subsets were also skewed, showing a comparative decrease in non-classical CD14 - CD16 + and intermediate CD14 + CD16 + monocytes. In lymphocytes, the CD8 + T effector memory cells displayed a gene expression signature consistent with stronger T cell activation in Progressors. These early stage observations could serve as the basis for the development of prognostic biomarkers of disease risk and interventional strategies to improve the management of severe COVID-19. BACKGROUND: Much of the literature on immune response post-SARS-CoV-2 infection has been in the acute and post-acute phases of infection. TRANSLATIONAL SIGNIFICANCE: We found differences at early time points of infection in approximately 160 participants. We compared multi-omic signatures in immune cells between individuals progressing to needing more significant medical intervention and non-progressors. We observed widespread evidence of a state of increased inflammation associated with progression, supported by a range of epigenomic, transcriptomic, and proteomic signatures. The signatures we identified support other findings at later time points and serve as the basis for prognostic biomarker development or to inform interventional strategies., (Copyright © 2023 Verily Life Sciences LLC. Published by Elsevier Inc. All rights reserved.)

Background: The understanding of Post-acute sequelae of SARS-CoV-2 infection (PASC) can be improved by longitudinal assessment of symptoms encompassing the acute illness period. To gain insight into the various disease trajectories of PASC, we assessed symptom evolution and clinical factors associated with the development of PASC over 3 months, starting with the acute illness period., Methods: We conducted a prospective cohort study to identify parameters associated with PASC. We performed cluster and case control analyses of clinical data, including symptomatology collected over 3 months following infection., Results: We identified three phenotypic clusters associated with PASC that could be characterized as remittent, persistent, or incident based on the 3-month change in symptom number compared to study entry: remittent (median; min, max: -4; -17, 3), persistent (-2; -14, 7), or incident (4.5; -5, 17) ( p = 0.041 remittent vs. persistent, p < 0.001 remittent vs. incident, p < 0.001 persistent vs. incident). Despite younger age and lower hospitalization rates, the incident phenotype had a greater number of symptoms (15; 8, 24) and a higher proportion of participants with PASC (63.2%) than the persistent (6; 2, 9 and 52.2%) or remittent clusters (1; 0, 6 and 18.7%). Systemic corticosteroid administration during acute infection was also associated with PASC at 3 months [OR (95% CI): 2.23 (1.14, 4.36)]., Conclusion: An incident disease phenotype characterized by symptoms that were absent during acute illness and the observed association with high dose steroids during acute illness have potential critical implications for preventing PASC., Competing Interests: CC, JL, MW, KD, and CK maintain equity ownership and employment at Verily Life Sciences. SP reports personal fees from Jazz Pharmaceuticals, Inc., and UpToDate, Inc., and grants from Philips, Inc., Sommetrics, Inc., and Regeneron. CRd serves on advisory boards for Abbott Diagnostics, Ortho/Quidel Diagnostics, and Roche Diagnostics. JK receives research funding from Regeneron. JK has also provided consulting for GlaxoSmithKline, AstraZeneca, CereVu Medical, Propeller/ResMed, and BData, Inc. The remaining 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. The reviewer RP declared a past co-authorship with the author SP to the handling editor., (Copyright © 2023 Chen, Parthasarathy, Leung, Wu, Drake, Ridaura, Zisser, Conrad, Tapson, Moy, deFilippi, Rosas, Prabhakar, Basit, Salvatore, Krishnan and Kim.)

Identification of genes that reliably mark distinct cell types is key to leveraging single-cell RNA sequencing to better understand organismal biology. Such genes are usually chosen by measurement of differential expression between groups of cells and selecting those with the greatest magnitude or most statistically significant change. Many methods have been developed for performing such analyses, but no single, best method has emerged. Validating the results of these analyses is costly in terms of time, effort and resources. We demonstrate that applying an ensemble of such methods robustly identifies genes that mark cells that cluster together and that show restricted expression assessed by antisense mRNA in situ and immunofluorescence. This technique is easily extensible to any number of differential expression methods and the inclusion of additional methods is expected to result in further improvement in performance., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: The embryonic renal stroma consists of multiple molecularly distinct cell subpopulations, the functional significance of which is largely unknown. Previous work has demonstrated that the transcription factors YAP and TAZ play roles in the development and morphogenesis of the nephrons, collecting ducts, and nephron progenitor cells., Methods: In embryonic mouse kidneys, we identified a subpopulation of stromal cells with enriched activity in YAP and TAZ. To evaluate the function of these cell types, we genetically ablated both Yap and Taz from the stromal progenitor population and examined how gene activity and development of YAP/TAZ mutant kidneys are affected over a developmental time course., Results: We found that YAP and TAZ are active in a subset of renal interstitium and that stromal-specific coablation of YAP/TAZ disrupts cortical fibroblast, pericyte, and myofibroblast development, with secondary effects on peritubular capillary differentiation. We also demonstrated that the transcription factor SRF cooperates with YAP/TAZ to drive expression of at least a subset of renal myofibroblast target genes and to specify myofibroblasts but not cortical fibroblasts or pericytes., Conclusions: These findings reveal a critical role for YAP/TAZ in specific embryonic stromal cells and suggest that interaction with cofactors, such as SRF, influence the expression of cell type-specific target genes, thus driving stromal heterogeneity. Further, this work reveals functional roles for renal stroma heterogeneity in creating unique microenvironments that influence the differentiation and maintenance of the renal parenchyma., (Copyright © 2022 by the American Society of Nephrology.)

Background: Current management of AKI, a potentially fatal disorder that can also initiate or exacerbate CKD, is merely supportive. Therefore, deeper understanding of the molecular pathways perturbed in AKI is needed to identify targets with potential to lead to improved treatment., Methods: We performed single-cell RNA sequencing (scRNA-seq) with the clinically relevant unilateral ischemia-reperfusion murine model of AKI at days 1, 2, 4, 7, 11, and 14 after AKI onset. Using real-time quantitative PCR, immunofluorescence, Western blotting, and both chromogenic and single-molecule in situ hybridizations, we validated AKI signatures in multiple experiments., Results: Our findings show the time course of changing gene expression patterns for multiple AKI stages and all renal cell types. We observed elevated expression of crucial injury response factors-including kidney injury molecule-1 (Kim1), lipocalin 2 (Lcn2), and keratin 8 (Krt8)-and of several novel genes ( Ahnak , Sh3bgrl3 , and Col18a1 ) not previously examined in kidney pathologies. AKI induced proximal tubule dedifferentiation, with a pronounced nephrogenic signature represented by Sox4 and Cd24a . Moreover, AKI caused the formation of "mixed-identity cells" (expressing markers of different renal cell types) that are normally seen only during early kidney development. The injured tubules acquired a proinflammatory and profibrotic phenotype; moreover, AKI dramatically modified ligand-receptor crosstalk, with potential pathologic epithelial-to-stromal interactions. Advancing age in AKI onset was associated with maladaptive response and kidney fibrosis., Conclusions: The scRNA-seq, comprehensive, cell-specific profiles provide a valuable resource for examining molecular pathways that are perturbed in AKI. The results fully define AKI-associated dedifferentiation programs, potential pathologic ligand-receptor crosstalk, novel genes, and the improved injury response in younger mice, and highlight potential targets of kidney injury., (Copyright © 2020 by the American Society of Nephrology.)

Kidney formation requires the coordinated growth of multiple cell types including the collecting ducts, nephrons, vasculature and interstitium. There is a long-held belief that interactions between progenitors of the collecting ducts and nephrons are primarily responsible for kidney development. However, over the last several years, it has become increasingly clear that multiple aspects of kidney development require signaling from the interstitium. How the interstitium orchestrates these various roles is poorly understood. Here, we show that during development the interstitium is a highly heterogeneous patterned population of cells that occupies distinct positions correlated to the adjacent parenchyma. Our analysis indicates that the heterogeneity is not a mere reflection of different stages in a linear developmental trajectory but instead represents several novel differentiated cell states. Further, we find that β-catenin has a cell autonomous role in the development of a medullary subset of the interstitium and that this non-autonomously affects the development of the adjacent epithelia. These findings suggest the intriguing possibility that the different interstitial subtypes may create microenvironments that play unique roles in development of the adjacent epithelia and endothelia., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2020. Published by The Company of Biologists Ltd.)

Wilms' tumor (WT) morphologically resembles the embryonic kidney, consisting of blastema, epithelial and stromal components, suggesting tumors arise from the dysregulation of normal development. β-Catenin activation is observed in a significant proportion of WTs; however, much remains to be understood about how it contributes to tumorigenesis. Although activating β-catenin mutations are observed in both blastema and stromal components of WT, current models assume that activation in the blastemal lineage is causal. Paradoxically, studies performed in mice suggest that activation of β-catenin in the nephrogenic lineage results in loss of nephron progenitor cell (NPC) renewal, a phenotype opposite to WT. Here, we show that activation of β-catenin in the stromal lineage non-autonomously prevents the differentiation of NPCs. Comparisons of the transcriptomes of kidneys expressing an activated allele of β-catenin in the stromal or nephron progenitor cells reveals that human WT more closely resembles the stromal-lineage mutants. These findings suggest that stromal β-catenin activation results in histological and molecular features of human WT, providing insights into how alterations in the stromal microenvironment may play an active role in tumorigenesis., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2020. Published by The Company of Biologists Ltd.)

Background: C3 glomerulopathy (C3G) is defined by dominant glomerular deposition of C3 and minimal or no immunoglobulin, with two subtypes-dense deposit disease (DDD) and C3 glomerulonephritis (C3GN)-distinguished by features on electron microscopy (EM). Given that this rare disease has generally unfavorable yet highly variable outcomes, we sought out to review the histopathology, complement/genetic studies, and renal outcomes of pediatric patients with C3G at our institution., Methods: All native kidney biopsies performed in a single pediatric hospital over a 10-year period were reviewed for features of C3G. Of 589 biopsy reports, we identified 9 patients fulfilling the diagnostic criteria for C3G and retrospectively reviewed their clinical chart and renal biopsy findings., Results: We identified 4 patients with DDD, 4 with C3GN, and 1 indeterminate case, with features of both C3GN and DDD. Five patients were positive for one or more nephritic factors (C3NeF, C4NeF, C5NeF) with 1 patient additionally positive for complement factor H (CFH) autoantibody. Genetic testing done in 5 of the 9 patients failed to identify any causative mutations. Three patients showed progressive renal dysfunction over a mean follow-up period of 33 months., Conclusions: Complement and genetic studies are now routinely recommended for patients with a histopathological diagnosis of C3G. Careful interpretation of these studies and their prognostic and therapeutic implications in conjunction with biopsy findings is needed to further understand the pathophysiology of this rare disease in children.

Lineage tracing has resulted in fundamental discoveries in kidney development and disease and remains a powerful technique to study mechanisms of organogenesis, homeostasis, and repair/regeneration. Following decades of research on the cellular and molecular regulation of renal organogenesis, the kidney has become one of the most well-characterized organs, resulting in exciting advancements in pluripotent stem cell differentiation, tissue bioengineering, and the potential for developing novel regenerative therapies for kidney disease. Lineage tracing, or the labeling of progeny cells arising from a single cell or group of cells, allows for spatial and temporal analyses of dynamic in vivo and in vitro processes. As lineage tracing techniques expand across disciplines of developmental biology, stem cell biology, and regenerative medicine, careful experimental design and interpretation, along with an understanding of the basic principles and technical limitations, are essential for utilizing genetically complex lineage tracing models to further understand kidney development and disease., (© 2019 Elsevier Inc. All rights reserved.)

CITRUS is a supervised machine learning algorithm designed to analyze single cell data, identify cell populations, and identify changes in the frequencies or functional marker expression patterns of those populations that are significantly associated with an outcome. The algorithm is a black box that includes steps to cluster cell populations, characterize these populations, and identify the significant characteristics. This chapter describes how to optimize the use of CITRUS by combining it with upstream and downstream data analysis and visualization tools.

Background: Although a preponderance of pre-clinical data demonstrates the immunosuppressive potential of mesenchymal stromal cells (MSCs), significant heterogeneity and lack of critical quality attributes (CQAs) based on immunosuppressive capacity likely have contributed to inconsistent clinical outcomes. This heterogeneity exists not only between MSC lots derived from different donors, tissues and manufacturing conditions, but also within a given MSC lot in the form of functional subpopulations. We therefore explored the potential of functionally relevant morphological profiling (FRMP) to identify morphological subpopulations predictive of the immunosuppressive capacity of MSCs derived from multiple donors, manufacturers and passages., Methods: We profiled the single-cell morphological response of MSCs from different donors and passages to the functionally relevant inflammatory cytokine interferon (IFN)-γ. We used the machine learning approach visual stochastic neighbor embedding (viSNE) to identify distinct morphological subpopulations that could predict suppression of activated CD4 + and CD8 + T cells in a multiplexed quantitative assay., Results: Multiple IFN-γ-stimulated subpopulations significantly correlated with the ability of MSCs to inhibit CD4 + and CD8 + T-cell activation and served as effective CQAs to predict the immunosuppressive capacity of additional manufactured MSC lots. We further characterized the emergence of morphological heterogeneity following IFN-γ stimulation, which provides a strategy for identifying functional subpopulations for future single-cell characterization and enrichment techniques., Discussion: This work provides a generalizable analytical platform for assessing functional heterogeneity based on single-cell morphological responses that could be used to identify novel CQAs and inform cell manufacturing decisions., (Published by Elsevier Inc.)

Even with effective viral control, HIV-infected individuals are at a higher risk for morbidities associated with older age than the general population, and these serious non-AIDS events (SNAEs) track with plasma inflammatory and coagulation markers. The cell subsets driving inflammation in aviremic HIV infection are not yet elucidated. Also, whether ART-suppressed HIV infection causes premature induction of the inflammatory events found in uninfected elderly or if a novel inflammatory network ensues when HIV and older age co-exist is unclear. In this study we measured combinational expression of five inhibitory receptors (IRs) on seven immune cell subsets and 16 plasma markers from peripheral blood mononuclear cells (PBMC) and plasma samples, respectively, from a HIV and Aging cohort comprised of ART-suppressed HIV-infected and uninfected controls stratified by age (≤35 or ≥50 years old). For data analysis, multiple multivariate computational algorithms [cluster identification, characterization, and regression (CITRUS), partial least squares regression (PLSR), and partial least squares-discriminant analysis (PLS-DA)] were used to determine if immune parameter disparities can distinguish the subject groups and to investigate if there is a cross-impact of aviremic HIV and age on immune signatures. IR expression on gamma delta (γδ) T cells exclusively separated HIV+ subjects from controls in CITRUS analyses and secretion of inflammatory cytokines and cytotoxic mediators from γδ T cells tracked with TIGIT expression among HIV+ subjects. Also, plasma markers predicted the percentages of TIGIT+ γδ T cells in subjects with and without HIV in PSLR models, and a PLS-DA model of γδ T cell IR signatures and plasma markers significantly stratified all four of the subject groups (uninfected younger, uninfected older, HIV+ younger, and HIV+ older). These data implicate γδ T cells as an inflammatory driver in ART-suppressed HIV infection and provide evidence of distinct "inflamm-aging" processes with and without ART-suppressed HIV infection.

Hox genes are important regulators of development. The 39 mammalian Hox genes have considerable functional overlap, greatly confounding their study. In this report, we generated mice with multiple combinations of paralogous and flanking Abd-B Hox gene mutations to investigate functional redundancies in kidney development. The resulting mice developed a number of kidney abnormalities, including hypoplasia, agenesis, and severe cysts, with distinct Hox functions observed in early metanephric kidney formation and nephron progenitor maintenance. Most surprising, however, was that extensive removal of Hox shared function in these kidneys resulted in cellular level lineage infidelity. Strikingly, mutant nephron tubules consisted of intermixed cells with proximal tubule, loop of Henle, and collecting duct identities, with some single cells expressing markers associated with more than one nephron segment. These results indicate that Hox genes are required for proper lineage selection/maintenance and full repression of genes involved in cell fate restriction in the developing kidney.

Microplasma is generated in an ultra-high-pure H 2 and N 2 gas mixture with a Nd:YAG laser device that is operated at the fundamental wavelength of 1064 nm. The gas mixture ratio of H 2 and N 2 is 9 to 1 at a pressure of 1.21 ± 0.03 10 5 Pa inside a chamber. A Czerny-Turner-type spectrometer and an intensified charge-coupled device are utilized for the recording of plasma emission spectra. The line-of-sight measurements are Abel inverted to determine the radial distributions of electron number density and temperature. Recently derived empirical formulas are utilized for the extraction of values for electron density. The Boltzmann plot and line-to-continuum methods are implemented for the diagnostic of electron excitation temperature. The expansion speed of the plasma kernel maximum electron temperature amounts to 1  km/s at a time delay of 300 ns. The microplasma, initiated by focusing 14 ns, 140 mJ pulses, can be described by an isentropic expansion model.

Background & Aims: In patients with inflammatory bowel diseases, the combination of infliximab and thiopurines (such as 6-thioguanine) is more effective treatment than monotherapy. We assessed the correlation between serum levels of 6-thioguanine (6-TGN) and infliximab levels or antibodies to infliximab (ATI)., Methods: We performed a cross-sectional study of 72 patients receiving maintenance therapy with infliximab and a thiopurine for inflammatory bowel disease at the Crohn's and Colitis Center of the University of Miami, FL. We collected clinical, endoscopic, and biochemical data, and levels of thiopurine metabolites. The primary outcomes were trough level of infliximab and the presence of ATI., Results: Levels of 6-TGN correlated with those of infliximab (ρ, 0.53; P < .0001). The cut-off point of 6-TGN that best predicted a higher level of infliximab was 125 pmol/8 × 10(8) red blood cells (RBCs) (area under receiver operating characteristic, 0.86; P < .001). Patients in the lowest quartile of 6-TGN had infliximab levels that were similar to patients on no thiopurines (4.3 vs. 4.8 mcg/mL, respectively; P = .8). An infliximab level of 8.3 mcg/mL or greater was associated with mucosal healing. Only 8 patients (11%) had detectable ATI. Patients with 6-TGN levels less than 125 pmol/8 × 10(8) RBCs were significantly more likely to have ATI (odds ratio, 1.3; 95% confidence interval, 2.3-72.5; P < .01)., Conclusions: Although 6-TGN levels of greater than 230 pmol/8 × 10(8) RBCs have been associated with improved outcomes in patients on monotherapy, a level of 6-thioguanine of 125 pmol/8 × 10(8) RBCs or greater may be adequate to achieve therapeutic levels of infliximab. In the long term, this may minimize the toxicity for patients on combination therapy., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Childhood asthma prevalence and morbidity varies among Latinos in the United States, with Puerto Ricans having the highest and Mexicans the lowest., Objective: To determine whether genetic ancestry is associated with the odds of asthma among Latinos, and secondarily whether genetic ancestry is associated with lung function among Latino children., Methods: We analyzed 5493 Latinos with and without asthma from 3 independent studies. For each participant, we estimated the proportion of African, European, and Native American ancestry using genome-wide data. We tested whether genetic ancestry was associated with the presence of asthma and lung function among subjects with and without asthma. Odds ratios (OR) and effect sizes were assessed for every 20% increase in each ancestry., Results: Native American ancestry was associated with lower odds of asthma (OR = 0.72, 95% CI: 0.66-0.78, P = 8.0 × 10(-15)), while African ancestry was associated with higher odds of asthma (OR = 1.40, 95% CI: 1.14-1.72, P = .001). These associations were robust to adjustment for covariates related to early life exposures, air pollution, and socioeconomic status. Among children with asthma, African ancestry was associated with lower lung function, including both pre- and post-bronchodilator measures of FEV1 (-77 ± 19 mL; P = 5.8 × 10(-5) and -83 ± 19 mL; P = 1.1 x 10(-5), respectively) and forced vital capacity (-100 ± 21 mL; P = 2.7 × 10(-6) and -107 ± 22 mL; P = 1.0 x 10(-6), respectively)., Conclusion: Differences in the proportions of genetic ancestry can partially explain disparities in asthma susceptibility and lung function among Latinos., (Copyright © 2014 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Background: Asthma is a complex disease with both genetic and environmental causes. Genome-wide association studies of asthma have mostly involved European populations, and replication of positive associations has been inconsistent., Objective: We sought to identify asthma-associated genes in a large Latino population with genome-wide association analysis and admixture mapping., Methods: Latino children with asthma (n = 1893) and healthy control subjects (n = 1881) were recruited from 5 sites in the United States: Puerto Rico, New York, Chicago, Houston, and the San Francisco Bay Area. Subjects were genotyped on an Affymetrix World Array IV chip. We performed genome-wide association and admixture mapping to identify asthma-associated loci., Results: We identified a significant association between ancestry and asthma at 6p21 (lowest P value: rs2523924, P < 5 × 10(-6)). This association replicates in a meta-analysis of the EVE Asthma Consortium (P = .01). Fine mapping of the region in this study and the EVE Asthma Consortium suggests an association between PSORS1C1 and asthma. We confirmed the strong allelic association between SNPs in the 17q21 region and asthma in Latinos (IKZF3, lowest P value: rs90792, odds ratio, 0.67; 95% CI, 0.61-0.75; P = 6 × 10(-13)) and replicated associations in several genes that had previously been associated with asthma in genome-wide association studies., Conclusions: Admixture mapping and genome-wide association are complementary techniques that provide evidence for multiple asthma-associated loci in Latinos. Admixture mapping identifies a novel locus on 6p21 that replicates in a meta-analysis of several Latino populations, whereas genome-wide association confirms the previously identified locus on 17q21., (Published by Mosby, Inc.)

Background: The primary rescue medication to treat acute asthma exacerbation is the short-acting β₂-adrenergic receptor agonist; however, there is variation in how well a patient responds to treatment. Although these differences might be due to environmental factors, there is mounting evidence for a genetic contribution to variability in bronchodilator response (BDR)., Objective: To identify genetic variation associated with bronchodilator drug response in Latino children with asthma., Methods: We performed a genome-wide association study (GWAS) for BDR in 1782 Latino children with asthma using standard linear regression, adjusting for genetic ancestry and ethnicity, and performed replication studies in an additional 531 Latinos. We also performed admixture mapping across the genome by testing for an association between local European, African, and Native American ancestry and BDR, adjusting for genomic ancestry and ethnicity., Results: We identified 7 genetic variants associated with BDR at a genome-wide significant threshold (P < 5 × 10(-8)), all of which had frequencies of less than 5%. Furthermore, we observed an excess of small P values driven by rare variants (frequency, <5%) and by variants in the proximity of solute carrier (SLC) genes. Admixture mapping identified 5 significant peaks; fine mapping within these peaks identified 2 rare variants in SLC22A15 as being associated with increased BDR in Mexicans. Quantitative PCR and immunohistochemistry identified SLC22A15 as being expressed in the lung and bronchial epithelial cells., Conclusion: Our results suggest that rare variation contributes to individual differences in response to albuterol in Latinos, notably in SLC genes that include membrane transport proteins involved in the transport of endogenous metabolites and xenobiotics. Resequencing in larger, multiethnic population samples and additional functional studies are required to further understand the role of rare variation in BDR., (Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

BKV has emerged as a significant pathogen in the field of transplantation, predominantly causing BKV nephropathy in renal transplant recipients and hemorrhagic cystitis in HSCT recipients. However, case reports describe more diverse complications, and we too present three unusual cases of BKV infections in pediatric renal transplant recipients. First, we describe a case of biopsy-proven renal damage secondary to BKV prior to the onset of viremia, demonstrating that BKV nephropathy can occur without preceding viremia. We also present two renal transplant recipients with persistent BK viruria, one with BKV-associated hemorrhagic cystitis and the other with microscopic hematuria. Therefore, we conclude that BKV manifestations may be more diverse than previously thought and suggest clinical utility in urine BKV qPCR testing in specific transplant recipients., (© 2012 John Wiley & Sons A/S.)

Background: Polymorphisms in more than 100 genes have been associated with asthma susceptibility, yet much of the heritability remains to be explained. Asthma disproportionately affects different racial and ethnic groups in the United States, suggesting that admixture mapping is a useful strategy to identify novel asthma-associated loci., Objective: We sought to identify novel asthma-associated loci in Latino populations using case-control admixture mapping., Methods: We performed genome-wide admixture mapping by comparing levels of local Native American, European, and African ancestry between children with asthma and nonasthmatic control subjects in Puerto Rican and Mexican populations. Within candidate peaks, we performed allelic tests of association, controlling for differences in local ancestry., Results: Between the 2 populations, we identified a total of 62 admixture mapping peaks at a P value of less than 10(-3) that were significantly enriched for previously identified asthma-associated genes (P= .0051). One of the peaks was statistically significant based on 100 permutations in the Mexican sample (6q15); however, it was not significant in Puerto Rican subjects. Another peak was identified at nominal significance in both populations (8q12); however, the association was observed with different ancestries., Conclusion: Case-control admixture mapping is a promising strategy for identifying novel asthma-associated loci in Latino populations and implicates genetic variation at 6q15 and 8q12 regions with asthma susceptibility. This approach might be useful for identifying regions that contribute to both shared and population-specific differences in asthma susceptibility., (Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Feather pecking in laying hens is a major welfare and production problem for commercial egg producers, resulting in mortality, loss of production as well as welfare issues for the damaged birds. Damaging outbreaks of feather pecking are currently impossible to control, despite a number of proposed interventions. However, the ability to predict feather damage in advance would be a valuable research tool for identifying which management or environmental factors could be the most effective interventions at different ages. This paper proposes a framework for forecasting the damage caused by injurious pecking based on automated image processing and statistical analysis. By frame-by-frame analysis of video recordings of laying hen flocks, optical flow measures are calculated as indicators of the movement of the birds. From the optical flow datasets, measures of disturbance are extracted using hidden Markov models. Based on these disturbance measures and age-related variables, the levels of feather damage in flocks in future weeks is predicted. Applying the proposed method to real-world datasets, it is shown that the disturbance measures offer improved predictive values for feather damage thus enabling an identification of flocks with probable prevalence of damage and injury later in lay.

1. Feather pecking is one of the major problems facing the egg industry in non-cage systems and is set to become even more of an issue with the European Union ban on the keeping of laying hens in barren battery cages which comes into force in 2012 and the prospect of a ban on beak-trimming. Reducing feather pecking without resorting to beak treatment is an important goal for the poultry industry. 2. We report here a longitudinal study that included over 335,500 birds from 22 free range and organic laying farms. Accelerated failure time models and proportional hazards models were used to examine the effects of a wide range of factors (management, environment and bird) on development of substantial feather damage in lay. Particular emphasis was placed on risk factors during rear and on practices that could feasibly be changed or implemented. 3. The age at which a flock exhibits substantial feather damage could be predicted both by factors in the environment and by early symptoms in the birds themselves. Factors that were associated with earlier onset of severe feather damage included the presence of chain feeders, raised levels of carbon dioxide and ammonia, higher sound and light levels, particularly in younger birds. Increased feather damage (even very slight) in birds at 17-20 weeks of age was also highly predictive of the time of onset of severe feather damage during lay. Increased feed intake also indicated that a flock was at risk of early severe feather damage. 4. Birds that stayed on the same farm for rearing and lay showed later onset of serious feather damage than those that experienced a change in farm from rearing to lay. However, an increased number of changes between rearing and lay (feeder type, drinker type, light intensity etc) was not associated with earlier onset of serious feather damage. Further research needs to be done on the role of the transition from rearing to lay as a risk factor for FP in lay.

Iron is essential for fetal organ development, but the effect of isolated iron deficiency on nephrogenesis is unknown. Human premature infants are at risk for disrupted nephrogenesis because glomerular development is incomplete until 36-wk gestation. We modeled the effects of iron on postnatal glomerulogenesis in four groups of immature rats from P4 to P12: dam fed controls (DF), dam fed with sham gastrostomy surgery (DF + SS), iron-deficiency anemia (IDA), fed iron-deficient formula through gastrostomy apart from the dam, and IDA plus simultaneous enteral iron rescue (IDA+Fe). Hematocrit, plasma ferritin, and body and kidney tissue iron contents were measured. Tissue was examined. Rats grew similarly, but IDA rats exhibited lower hematocrit, plasma ferritin, and body and kidney iron contents than DF, DF + SS, or IDA + Fe. IDA exhibited 1.7 fewer radial glomerular counts (RGCs), 26% reduced glomerular density, and 29% less planar glomerular surface area than DF, with partial improvement in IDA + Fe. Compared with DF or DF + SS, we observed elevated plasma CRP levels and tubulointerstitial fibrosis in the IDA and IDA + Fe groups. IDA reduced glomerular density, glomerular surface area, and promoted fibrosis. Iron substantially rescued renal growth and development, supporting the critical role of iron in late nephrogenesis.

Early blight of potato (Solanum tuberosum L.) caused by Alternaria solani Sorauer is a frequent concern for potato growers in Canada. Management of early blight has relied on foliar fungicides that often include quinone outside inhibitor (QoI) fungicides such as azoxystrobin. In recent years, isolates of A. solani with reduced sensitivity to QoI fungicides, conferred by the presence of the F129L mutation (in the cytochrome b gene causing amino acid substitution of phenylalanine with leucine at position 129), have become widespread in potato-production areas of the United States, leading to a reduced efficacy of these products (3). Observations of reduced fungicide efficacy, following application of QoI fungicides to commercial fields in Manitoba, Canada in 2007, prompted an examination of the fungicide sensitivity of isolates of A. solani collected from fields in this province. Nine isolates of A. solani were obtained from potato foliage with typical early blight symptoms from four fields in Manitoba using standard protocols (2). Isolates were maintained on clarified V8 agar (1) and identified to species level based on conidial morphology (4). The sensitivity of each isolate to azoxystrobin was determined by assessing conidial germination on water agar plates amended with 0, 0.001, 0.01, 0.1, 1.0, or 10.0 mg/liter of azoxystrobin with protocols described previously (1). Two reference isolates of A. solani from North Dakota with known sensitivities to azoxystrobin and one isolate from Prince Edward Island (PEI), Canada, (a province yielding only isolates sensitive to azoxystrobin in previous surveys; R. D. Peters, unpublished data) were included in the assays. Calculated effective concentration (EC 50 ) values (azoxystrobin concentration inhibiting conidial germination by 50%) were determined for each isolate response from two replications of the assays. The reference isolates of A. solani from North Dakota were sensitive or had reduced sensitivity to azoxystrobin with mean EC 50 values of 0.02 and 0.2 mg/liter, respectively. The isolate from PEI was sensitive to azoxystrobin with a mean EC 50 value of 0.04 mg/liter. By contrast, isolates of A. solani from Manitoba had reduced sensitivity to azoxystrobin with mean EC 50 values from 0.2 to 0.8 mg/liter. Real-time PCR analysis of each isolate was performed (2) and confirmed the presence of the F129L mutation in the Manitoba isolates and the isolate with reduced sensitivity to azoxystrobin from North Dakota. The F129L mutation was absent in the azoxystrobin-sensitive wild-type isolates from PEI and North Dakota. To our knowledge, this is the first report of isolates of A. solani with reduced sensitivity to azoxystrobin in Canada. Since cross resistance among QoI fungicides has been demonstrated in A. solani isolates with the F129L mutation (3), adoption of resistance management strategies, including alternating QoI fungicides with fungicides having different modes of action and further monitoring pathogen populations for QoI sensitivity in Canadian production areas, is recommended. References: (1) J. S. Pasche et al. Plant Dis. 88:181, 2004. (2) J. S. Pasche et al. Plant Dis. 89:269, 2005. (3) J. S. Pasche and N. C. Gudmestad. Crop Prot. 27:427, 2008. (4) J. Rotem. The Genus Alternaria: Biology, Epidemiology, and Pathogenicity. The American Phytopathological Society, St. Paul, MN, 1994.

Asthma is a common but complex respiratory disease caused by the interaction of genetic and environmental factors. Significant racial and ethnic disparities in prevalence, mortality and drug response have been described. These disparities may be explained by racial and ethnic-specific variation in genetic, environmental, social and psychological risk factors. In addition, race, ethnicity and social class are important proxies for unmeasured factors that influence health outcomes. Herein, we review salient differences in the etiologies of asthma by race, ethnicity and social class, and argue for their continued use as variables in asthma research.

Potato (Solanum tuberosum L.) diseases incited by Fusarium spp. include postharvest dry rot and seed-piece decay. Fusarium seed-piece decay is commonly controlled by preplant applications of chemical seed treatments. However, isolates of Fusarium spp. resistant to benzimidazole fungicides have been reported (2,4). In the spring of 2007, samples of cut seed tubers (cvs. Shepody and Russet Burbank) showing extensive symptoms of decay were received from three seedlots in Prince Edward Island (PE) and one seedlot in Saskatchewan (SK), Canada. All seed tubers had been treated with fludioxonil (Maxim Potato Seed Protectant [PSP], 0.5% fludioxonil) following cutting and then stored for 10 to 14 days prior to planting. Using standard isolation protocols (4), the 19 potato tuber pieces examined from PE and 2 from SK yielded 21 Fusarium isolates for further study. Five isolates (including both isolates from SK) were identified as Fusarium sambucinum Fuckel and the remaining 16 isolates were identified as F. coeruleum (Libert) Sacc. (3). To confirm identifications, isolates were compared with two known standards of each of F. sambucinum and F. coeruleum identified by K. Seifert (Agriculture and Agri-Food Canada, Ottawa, ON) by DNA sequencing of the partial β-tubulin gene or the translation elongation factor 1-α ( http://fusarium.cbio.psu.edu ; [1]). These standard isolates were also used as fludioxonil-sensitive controls in amended agar assays for chemical sensitivity. Agar plugs (5 mm in diameter) taken from the margins of 7-day-old cultures of the Fusarium isolates were transferred to petri dishes containing ½-strength potato dextrose agar amended with 0, 0.1, 1.0, 10.0, or 100.0 mg/liter of fludioxonil. Fludioxonil (Maxim PSP, 0.5% a.i.) was prepared as a stock solution in sterile distilled water and added to the molten agar after autoclaving. Culture incubation and mycelial growth measurements were performed as described previously (4). Measurements from four replicate petri dishes per concentration of fludioxonil were taken. Calculated EC 50 values (fludioxonil concentration inhibiting pathogen growth by 50%) were obtained. The trial was repeated three times. The two standard isolates of F. sambucinum were sensitive to fludioxonil, with mean EC 50 values of 0.002 (±0.002 standard error [SE]) and 0.005 (±0.002 SE) mg/liter. The two standard isolates of F. coeruleum were also sensitive to fludioxonil, with mean EC 50 values of 0.17 (±0.005 SE) and 0.19 (± 0.005 SE) mg/liter. All other tested isolates of F. sambucinum and F. coeruleum were resistant to fludioxonil and showed no growth inhibition even at 100 mg of fludioxonil per liter. To our knowledge, this is the first report of resistance to fludioxonil in isolates of Fusarium spp. causing potato seed-piece decay. Since the isolates of F. sambucinum were also resistant to thiophanate-methyl and thiabendazole (data not shown), multiclass (benzimidazole and pyrrole) resistance was also documented. References: (1) D. M. Geiser et al. Eur. J. Plant Pathol. 110:473, 2004. (2) L. M. Kawchuk et al. Am. Potato J. 71:185, 1994. (3) P. E. Nelson et al. Fusarium Species: An Illustrated Manual for Identification. Pennsylvania State University Press, 1983. (4) R. D. Peters et al. Plant Dis. 85:1030, 2001.

The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors activated by fatty acids and their metabolites. The PPARdelta subtype is believed to be involved in lipoprotein regulation and may have a role in reverse cholesterol transport. While the range of biological roles of PPARdelta still remains unclear, it is of therapeutic interest in cardiovascular diseases. Here we report a homogeneous in vitro assay for studying ligand activation of PPARdelta. We surveyed a panel of peptides containing the LXXLL motifs derived from coactivator protein sequences. Peptides with the best response were used to develop a sensitive and homogeneous recruitment assay for PPARdelta. The optimized assay has a signal-to-background ratio of about 8:1 and an assay quality parameter Z'-factor value of 0.8. The assay signal generated is stable for hours to even overnight. This simple recruitment assay can provide agonist and/or antagonist information that cannot be assessed by receptor-binding assay, and can be used for characterization and screening of ligands that modulate the activation of PPARdelta., ((c)2002 Elsevier Science (USA).)