Rapid Recurrence of Eosinophilic Esophagitis Activity After Successful Treatment in the Observation Phase of a Randomized, Double-Blind, Double-Dummy Trial

Background & Aims: Eosinophilic esophagitis (EoE) is chronic and recurs if treatment is discontinued. We aimed to determine rates of recurrence, and whether initial treatment with oral viscous budesonide (OVB) resulted in less recurrence than fluticasone from a multidose inhaler (MDI). Methods: This was the observation phase of a randomized, double-blind, double-dummy trial comparing OVB with MDI for initial EoE treatment. Subjects with a histologic response (<15 eosinophils/high-power field) in the trial entered an observation phase in which treatment was discontinued and symptoms were monitored. Patients underwent an endoscopy or a biopsy when symptoms recurred or at 1 year. We analyzed time to symptom recurrence and assessed endoscopic severity and histologic relapse (≥15 eosinophils/high-power field) at follow-up endoscopy. Results: Thirty-three of the 58 subjects (57%) had symptom recurrence before 1 year. The overall median time to symptom recurrence was 244 days. There was no difference in the rate of symptom recurrence for subjects treated with OVB vs MDI (hazard ratio, 1.04; 95% CI, 0.52–2.08). At symptom recurrence, 78% of patients had histologic relapse. The patients had significant increases in mean Dysphagia Symptom Questionnaire score (3.8 vs 8.7; P < .001), and the EoE Endoscopic Reference Score (1.3 vs 4.6; P < .001) compared with end of treatment. Conclusions: EoE disease activity recurred rapidly after initial histologic response to topical steroids (either OVB or MDI). Because most subjects had recurrent endoscopic and histologic signs not reliably detected by symptoms, maintenance therapy should be recommended in EoE patients achieving histologic response to topical steroids. Clinicaltrials.gov no: NCT02019758

A terminal assessment of stages theory : introducing a dynamic states approach to entrepreneurship

Stages of Growth models were the most frequent theoretical approach to understanding entrepreneurial business growth from 1962 to 2006; they built on the growth imperative and developmental models of that time. An analysis of the universe of such models (N=104) published in the management literature shows no consensus on basic constructs of the approach, nor is there any empirical confirmations of stages theory. However, by changing two propositions of the stages models, a new dynamic states approach is derived. The dynamic states approach has far greater explanatory power than its precursor, and is compatible with leading edge research in entrepreneurship

Observing the First Stars and Black Holes

The high sensitivity of JWST will open a new window on the end of the cosmological dark ages. Small stellar clusters, with a stellar mass of several 10^6 M_sun, and low-mass black holes (BHs), with a mass of several 10^5 M_sun should be directly detectable out to redshift z=10, and individual supernovae (SNe) and gamma ray burst (GRB) afterglows are bright enough to be visible beyond this redshift. Dense primordial gas, in the process of collapsing from large scales to form protogalaxies, may also be possible to image through diffuse recombination line emission, possibly even before stars or BHs are formed. In this article, I discuss the key physical processes that are expected to have determined the sizes of the first star-clusters and black holes, and the prospect of studying these objects by direct detections with JWST and with other instruments. The direct light emitted by the very first stellar clusters and intermediate-mass black holes at z>10 will likely fall below JWST's detection threshold. However, JWST could reveal a decline at the faint-end of the high-redshift luminosity function, and thereby shed light on radiative and other feedback effects that operate at these early epochs. JWST will also have the sensitivity to detect individual SNe from beyond z=10. In a dedicated survey lasting for several weeks, thousands of SNe could be detected at z>6, with a redshift distribution extending to the formation of the very first stars at z>15. Using these SNe as tracers may be the only method to map out the earliest stages of the cosmic star-formation history. Finally, we point out that studying the earliest objects at high redshift will also offer a new window on the primordial power spectrum, on 100 times smaller scales than probed by current large-scale structure data.Comment: Invited contribution to "Astrophysics in the Next Decade: JWST and Concurrent Facilities", Astrophysics & Space Science Library, Eds. H. Thronson, A. Tielens, M. Stiavelli, Springer: Dordrecht (2008

Efficacy of Budesonide vs Fluticasone for Initial Treatment of Eosinophilic Esophagitis in a Randomized Controlled Trial

Background and Aims: Topical steroid treatments for eosinophilic esophagitis (EoE) include swallowed fluticasone from a multi-dose inhaler (MDI) or oral viscous budesonide (OVB) slurry, but the 2 have never been compared. We assessed whether OVB was more effective than MDI for initial treatment of patients with EoE. Methods: In a double-blind, double-dummy trial, patients with a new diagnosis of EoE were randomly assigned to groups given 8 weeks of either OVB (1 mg/4 mL) twice daily plus a placebo inhaler (n = 56) or fluticasone MDI (880 μg) twice daily plus a placebo slurry (n = 55). Primary outcomes were post-treatment maximum eosinophil counts per high-power field (eos/hpf) and a validated dysphagia score (dysphagia symptom questionnaire [DSQ]) at week 8. Secondary outcomes included endoscopic severity (validated EoE endoscopic reference score), histologic response (<15 eos/hpf), and safety. Results: In a modified intention-to-treat analysis, the subjects had baseline peak eosinophil counts of 73 and 77 eos/hpf in the OVB and MDI groups, respectively, and DSQ scores of 11 and 8. Post-treatment eosinophil counts were 15 and 21 in the OVB and MDI groups, respectively (P =.31), with 71% and 64% achieving histologic response (P =.38). DSQ scores were 5 and 4 in the OVB and MDI groups (P =.70). Similar trends were noted for post-treatment total EoE endoscopic reference scores (2 vs 3; P =.06). Esophageal candidiasis developed in 12% of patients receiving OVB and 16% receiving MDI; oral thrush was observed in 3% and 2%, respectively. Conclusions: In a randomized clinical trial, initial treatment of EoE with either OVB or fluticasone MDI produced a significant decrease in esophageal eosinophil counts and improved dysphagia and endoscopic features. However, OVB was not superior to MDI, so either is an acceptable treatment for EoE. ClinicalTrials.gov ID NCT02019758

Abel's Functional Equation and Eigenvalues of Composition Operators on Spaces of Real Analytic Functions

We obtain full description of eigenvalues and eigenvectors of composition operators Cϕ : A (R) → A (R) for a real analytic self map ϕ : R → R as well as an isomorphic description of corresponding eigenspaces. We completely characterize those ϕ for which Abel’s equation f ◦ ϕ = f + 1 has a real analytic solution on the real line. We find cases when the operator Cϕ has roots using a constructed embedding of ϕ into the so-called real analytic iteration semigroups.(1) The research of the authors was partially supported by MEC and FEDER Project MTM2010-15200 and MTM2013-43540-P and the work of Bonet also by GV Project Prometeo II/2013/013. The research of Domanski was supported by National Center of Science, Poland, Grant No. NN201 605340. (2) The authors are very indebted to K. Pawalowski (Poznan) for providing us with references [26,27,47] and also explaining some topological arguments of [10]. The authors are also thankful to M. Langenbruch (Oldenburg) for providing a copy of [29].Bonet Solves, JA.; Domanski, P. (2015). Abel's Functional Equation and Eigenvalues of Composition Operators on Spaces of Real Analytic Functions. Integral Equations and Operator Theory. 81(4):455-482. https://doi.org/10.1007/s00020-014-2175-4S455482814Abel, N.H.: Determination d’une function au moyen d’une equation qui ne contient qu’une seule variable. In: Oeuvres Complètes, vol. II, pp. 246-248. Christiania (1881)Baker I.N.: Zusammensetzung ganzer Funktionen. Math. Z. 69, 121–163 (1958)Baker I.N.: Permutable power series and regular iteration. J. Aust. Math. Soc. 2, 265–294 (1961)Baker I.N.: Permutable entire functions. Math. Z. 79, 243–249 (1962)Baker I.N.: Fractional iteration near a fixpoint of multiplier 1. J. Aust. Math. Soc. 4, 143–148 (1964)Baker I.N.: Non-embeddable functions with a fixpoint of multiplier 1. Math. Z. 99, 337–384 (1967)Baker I.N.: On a class of nonembeddable entire functions. J. Ramanujan Math. 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RNC Workshop Jyväskylä 2003, Rep. Univ. Jyväskylä Dept. Math. Stat., vol. 92, pp. 39–55 (2003)Contreras, M.D.: Iteración de funciones analíticas en el disco unidad. Universidad de Sevilla (2009). (Preprint)Contreras M.D., Díaz-Madrigal S., Pommerenke Ch.: Some remarks on the Abel equation in the unit disk. J. Lond. Math. Soc. 75(2), 623–634 (2007)Cowen C.: Iteration and the solution of functional equations for functions analytic in the unit disc. Trans. Am. Math. Soc. 265, 69–95 (1981)Cowen C.C., MacCluer B.D.: Composition operators on spaces of analytic functions. In: Studies in Advanced Mathematics. CRC Press, Boca Raton (1995)Domański, P.: Notes on real analytic functions and classical operators. In: Topics in Complex Analysis and Operator Theory (Winter School in Complex Analysis and Operator Theory, Valencia, February 2010). Contemporary Math., vol. 561, pp. 3–47. Am. Math. 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Adaptive Behaviour and Cognitive Skills: Stability and Change from 7 Months to 7 Years in Siblings at High Familial Risk of Autism Spectrum Disorder.

Cognitive and adaptive behaviour abilities early in life provide important clinical prognostic information. We examined stability of such skills in children at high familial risk for ASD who either met diagnostic criteria for ASD at age 7 years (HR-ASD, n = 15) or did not (HR-non-ASD, n = 24) and low-risk control children (LR, n = 37), prospectively studied from infancy. For both HR groups, cognitive skills were consistently lower across time than those of LR children. HR-ASD children showed increasing difficulties in adaptive behaviour over time compared to LR children, while the HR-non-ASD children showed no such difficulties. This pattern of change may inform our understanding of developmental profiles of HR siblings beyond core ASD symptoms

Mapping the link between socio-economic factors, autistic traits and mental health across different settings

Autistic individuals experience higher rates of externalising and internalising symptoms that may vary with environmental factors. However, there is limited research on variation across settings that may highlight common factors with globally generalisable effects. Data were taken from two cohorts: a multinational European sample (n = 764; 453 autistic; 311 non-autistic; 6–30 years), and a South African sample (n = 100 non-autistic; 3–11 years). An exploratory factor analysis aggregated clinical (Verbal Comprehension and Perceptual Index), adaptive traits (Vineland Adaptive Behaviour Scale) and socio-economic variables (parental employment and education, home and family characteristics) in each cohort separately. With regression, we investigated the effect of these factors and autistic traits on internalising and externalising scores (measured with the Strengths and Difficulties Questionnaire). Cohorts showed similar four-factor structures (Person Characteristics, Family System, Parental and Material Resources). The ‘Family System’ factor captured family size and maternal factors and was associated with lower internalising and externalising symptoms in both cohorts. In the European cohort, high autistic traits reduced this effect; the opposite was found in the South Africa cohort. Our exploratory findings from two separate analyses represent consistent evidence that Family System is associated with internalising and externalising symptoms, with a context-specific impact in persons with high autism traits

Latent trajectories of adaptive behaviour in infants at high and low familial risk for autism spectrum disorder

Background: Autism Spectrum Disorder (ASD) is characterized by persisting difficulties in everyday functioning. Adaptive behaviour is heterogeneous across individuals with ASD, and it is not clear to what extent early development of adaptive behaviour relates to ASD outcome in toddlerhood. This study aims to identify subgroups of infants based on early development of adaptive skills and investigate their association with later ASD outcome. Methods: Adaptive behaviour was assessed on infants at high (n=166) and low (n=74) familial risk for ASD between 8 and 36 months using the Vineland Adaptive Behavior Scales (VABS-II). The four domains of VABS-II were modelled in parallel using growth mixture modelling to identify distinct classes of infants based on adaptive behaviour. Then, we associated class membership with clinical outcome and ASD symptoms at 36 months, and longitudinal measures of cognitive development. Results: We observed three classes characterised by: decreasing trajectories below age-appropriate norms (8.3%); stable trajectories around age-appropriate norms (73.8%); increasing trajectories reaching average scores by age 2 (17.9%). Infants with declining adaptive behaviour had a higher risk [odd ratio, OR=4.40 (confidence interval, CI: 1.90; 12.98)] for ASD and higher parent-reported symptoms in the social, communication and repetitive behaviour domains at 36 months. Furthermore, there was a discrepancy between adaptive and cognitive functioning as the class with improving adaptive skills showed stable cognitive development around average scores. Conclusions: Findings confirm the heterogeneity of trajectories of adaptive functioning in infancy, with a higher risk for ASD in toddlerhood linked to a plateau in the development of adaptive functioning after the first year of life