Natural History of Very Early Onset Inflammatory Bowel Disease in North America: A Retrospective Cohort Study

Background: The incidence of very early onset inflammatory bowel disease (VEOIBD) is increasing, yet the phenotype and natural history of VEOIBD are not well described. Methods: We performed a retrospective cohort study of patients diagnosed with VEOIBD (6 years of age and younger) between 2008 and 2013 at 25 North American centers. Eligible patients at each center were randomly selected for chart review. We abstracted data at diagnosis and at 1, 3, and 5 years after diagnosis. We compared the clinical features and outcomes with VEOIBD diagnosed younger than 3 years of age with children diagnosed with VEOIBD at age 3 to 6 years. Results: The study population included 269 children (105 [39%] Crohn\u27s disease, 106 [39%] ulcerative colitis, and 58 [22%] IBD unclassified). The median age of diagnosis was 4.2 years (interquartile range 2.9-5.2). Most (94%) Crohn\u27s disease patients had inflammatory disease behavior (B1). Isolated colitis (L2) was the most common disease location (70% of children diagnosed younger than 3 years vs 43% of children diagnosed 3 years and older; P = 0.10). By the end of follow-up, stricturing/penetrating occurred in 7 (6.6%) children. The risk of any bowel surgery in Crohn\u27s disease was 3% by 1 year, 12% by 3 years, and 15% by 5 years and did not differ by age at diagnosis. Most ulcerative colitis patients had pancolitis (57% of children diagnosed younger than 3 years vs 45% of children diagnosed 3 years and older; P = 0.18). The risk of colectomy in ulcerative colitis/IBD unclassified was 0% by 1 year, 3% by 3 years, and 14% by 5 years and did not differ by age of diagnosis. Conclusions: Very early onset inflammatory bowel disease has a distinct phenotype with predominantly colonic involvement and infrequent stricturing/penetrating disease. The cumulative risk of bowel surgery in children with VEOIBD was approximately 14%-15% by 5 years. These data can be used to provide anticipatory guidance in this emerging patient population

Plant roots use a patterning mechanism to position lateral root branches toward available water

[EN] The architecture of the branched root system of plants is a major determinant of vigor. Water availability is known to impact root physiology and growth; however, the spatial scale at which this stimulus influences root architecture is poorly understood. Here we reveal that differences in the availability of water across the circumferential axis of the root create spatial cues that determine the position of lateral root branches. We show that roots of several plant species can distinguish between a wet surface and air environments and that this also impacts the patterning of root hairs, anthocyanins, and aerenchyma in a phenomenon we describe as hydropatterning. This environmental response is distinct from a touch response and requires available water to induce lateral roots along a contacted surface. X-ray microscale computed tomography and 3D reconstruction of soil-grown root systems demonstrate that such responses also occur under physiologically relevant conditions. Using early-stage lateral root markers, we show that hydropatterning acts before the initiation stage and likely determines the circumferential position at which lateral root founder cells are specified. Hydro-patterning is independent of endogenous abscisic acid signaling, distinguishing it from a classic water-stress response. Higher water availability induces the biosynthesis and transport of the lateral root-inductive signal auxin through local regulation of TRYPTOPHAN AMINOTRANSFERASE OF ARABIDOPSIS 1 and PIN-FORMED 3, both of which are necessary for normal hydropatterning. Our work suggests that water availability is sensed and interpreted at the suborgan level and locally patterns a wide variety of developmental processes in the root.We thank Jose Alonso, Fred Berger, Eva Benkova, Matt Evans, Annemarie Meijer, Ben Scheres, and Jian Xu for providing materials, and the J.R.D. laboratory for comments on the manuscript. Funding was provided by a Carnegie Institution for Science endowment, the National Research Foundation of Singapore, a National Science Foundation Graduate Research Fellowship under Grant DGE-1147470 (to N.E.R.), European Research Council FUTUREROOTS (C.J.S., M.C.T., S.J.M., and M.J.B.), and Biotechnology and Biological Sciences Research Council (C.J.S., S.J.M., and M.J.B.).Bao, Y.; Aggarwal, P.; Robbins, NEI.; Sturrock, CJ.; Thompson, MC.; Tan, HQ.; Tham, C.... (2014). Plant roots use a patterning mechanism to position lateral root branches toward available water. Proceedings of the National Academy of Sciences. 111(25):9319-9324. https://doi.org/10.1073/pnas.1400966111S931993241112

CBT for Anxiety and Associated Somatic Complaints in Pediatric Medical Settings: An Open Pilot Study

Objective: To examine the initial feasibility and potential efficacy of a cognitive-behavioral intervention for youth with anxiety disorders and non-medical somatic symptoms. Background: Based on a strong relationship between somatic complaints and anxiety disorders, screening youngsters seeking medical care due to physical symptoms with no organic basis may enhance the recognition of anxiety disorders and facilitate access to appropriate services. Method: Seven boys and girls, ages 8 through 15, with medically unexplained gastrointestinal complaints and anxiety disorders received a 12-session cognitive-behavioral intervention targeting anxiety and physical symptoms. Assessments were conducted at baseline and following treatment. Results: All participants were classified as treatment responders. Three of the seven participants no longer met diagnostic criteria for their principal anxiety disorder. Children\u27s physical discomfort decreased from a moderate to minimal level based on self- and parent-reports. Conclusions: Our modified cognitive-behavioral approach has promise for reducing anxiety and somatic symptoms in children seeking medical care

Spatio-temporal sequence of cross-regulatory events in root meristem growth

A central question in developmental biology is how multicellular organisms coordinate cell division and differentiation to determine organ size. In Arabidopsis roots, this balance is controlled by cytokinin-induced expression of SHORT HYPOCOTYL 2 (SHY2) in the so-called transition zone of the meristem, where SHY2 negatively regulates auxin response factors (ARFs) by protein–protein interaction. The resulting down-regulation of PIN-FORMED (PIN) auxin efflux carriers is considered the key event in promoting differentiation of meristematic cells. Here we show that this regulation involves additional, intermediary factors and is spatio-temporally constrained. We found that the described cytokinin–auxin crosstalk antagonizes BREVIS RADIX (BRX) activity in the developing protophloem. BRX is an auxin-responsive target of the prototypical ARF MONOPTEROS (MP), a key promoter of vascular development, and transiently enhances PIN3 expression to promote meristem growth in young roots. At later stages, cytokinin induction of SHY2 in the vascular transition zone restricts BRX expression to down-regulate PIN3 and thus limit meristem growth. Interestingly, proper SHY2 expression requires BRX, which could reflect feedback on the auxin responsiveness of SHY2 because BRX protein can directly interact with MP, likely acting as a cofactor. Thus, cross-regulatory antagonism between BRX and SHY2 could determine ARF activity in the protophloem. Our data suggest a model in which the regulatory interactions favor BRX expression in the early proximal meristem and SHY2 prevails because of supplementary cytokinin induction in the later distal meristem. The complex equilibrium of this regulatory module might represent a universal switch in the transition toward differentiation in various developmental contexts

Phosphorylation and activation of PINOID by the phospholipid signaling kinase 3-phosphoinositide-dependent protein kinase 1 (PDK1) in Arabidopsis

Activity of the serine-threonine protein kinase PINOID (PID) has been implicated in the asymmetrical localization of the membrane-associated PINFORMED (PIN) family of auxin transport facilitators. However, the means by which PID regulates PIN protein distribution is unknown. We have used recombinant PID protein to dissect the regulation of PID activity in vitro. We demonstrate that intramolecular PID autophosphorylation is required for the ability of PID to phosphorylate an exogenous substrate. PID-like mammalian AGC kinases act in a phosphorylation cascade initiated by the phospholipid-associated kinase, 3-phosphoinositide-dependent protein kinase 1 (PDK1), which binds to the C-terminal hydrophobic PDK1-interacting fragment (PIF) domain found in PDK1 substrates. We find that Arabidopsis PDK1 interacts with PID, and that transphosphorylation by PDK1 increases PID autophosphorylation. We show that a PID activation loop serine is required for PDK1-dependent PID phosphorylation. This activation is rapid and requires the PIF domain. Cell extracts from flowers and seedling shoots dramatically increase PID phosphorylation in a tissue-specific manner. A PID protein variant in which the PIF domain was mutated failed to be activated by the seedling shoot extracts. PID immunoprecipitated from Arabidopsis cells in which PDK1 expression was inhibited by RNAi showed a dramatic reduction in transphosphorylation of myelin basic protein substrate. These results indicate that AtPDK1 is a potent enhancer of PID activity and provide evidence that phospholipid signaling may play a role in the signaling processes controlling polar auxin transport

Implementing a Novel Quality Improvement-Based Approach to Data Quality Monitoring and Enhancement in a Multipurpose Clinical Registry

Objective: To implement a quality improvement based system to measure and improve data quality in an observational clinical registry to support a Learning Healthcare System. Data Source: ImproveCareNow Network registry, which as of September 2019 contained data from 314,250 visits of 43,305 pediatric Inflammatory Bowel Disease (IBD) patients at 109 participating care centers. Study Design: The impact of data quality improvement support to care centers was evaluated using statistical process control methodology. Data quality measures were defined, performance feedback of those measures using statistical process control charts was implemented, and reports that identified data items not following data quality checks were developed to enable centers to monitor and improve the quality of their data. Principal Findings: There was a pattern of improvement across measures of data quality. The proportion of visits with complete critical data increased from 72 percent to 82 percent. The percent of registered patients improved from 59 percent to 83 percent. Of three additional measures of data consistency and timeliness, one improved performance from 42 percent to 63 percent. Performance declined on one measure due to changes in network documentation practices and maturation. There was variation among care centers in data quality. Conclusions: A quality improvement based approach to data quality monitoring and improvement is feasible and effective