The power of 1:Interventions and outcome measures for rare genetic neurodevelopmental disorders

The aim of this thesis is to enable evidence-based and personalized medicine for individuals with rare genetic neurodevelopmental disorders (RGNDs) and intellectual disability (ID). Treatment targets are increasingly identified. However, evidence for efficacy remains limited due to methodological challenges in these populations, such as rarity and heterogeneity, resulting in affected individuals missing out on possibly effective interventions. This thesis comprises a number of studies aiming to improve interventional research for RGNDs and ID. The thesis discusses the use of the N-of-1 design, a powerful alternative to conventional randomized controlled trials as these are often not feasible in small and heterogeneous populations. It enables investigation of treatment effectiveness at both an individual and group level, and addresses inter-individual variability in treatment response. A methodological framework and recommendations for conducting N-of-1 trials are provided, along with protocols exemplifying their application. As it is of great importance to measure what really matters in clinical trials, the use of outcome measures for RGNDs and ID is explored, recommendations are provided, and a disorder-specific outcome measure has been developed and validated. Considering that a genetic diagnosis provides opportunities for disorder-specific care, reporting of genetic diagnoses in multidisciplinary ID care is explored. To provide evidence-based treatment decisions and to prevent polypharmacy, this thesis emphasizes the significance of reporting genetic diagnosis in individuals with ID, personalized treatment approaches, use of the N-of-1 design, and the thorough selection of appropriate and relevant outcome measures, providing a much-needed bridge between practice and science

The power of 1:Interventions and outcome measures for rare genetic neurodevelopmental disorders

The aim of this thesis is to enable evidence-based and personalized medicine for individuals with rare genetic neurodevelopmental disorders (RGNDs) and intellectual disability (ID). Treatment targets are increasingly identified. However, evidence for efficacy remains limited due to methodological challenges in these populations, such as rarity and heterogeneity, resulting in affected individuals missing out on possibly effective interventions. This thesis comprises a number of studies aiming to improve interventional research for RGNDs and ID. The thesis discusses the use of the N-of-1 design, a powerful alternative to conventional randomized controlled trials as these are often not feasible in small and heterogeneous populations. It enables investigation of treatment effectiveness at both an individual and group level, and addresses inter-individual variability in treatment response. A methodological framework and recommendations for conducting N-of-1 trials are provided, along with protocols exemplifying their application. As it is of great importance to measure what really matters in clinical trials, the use of outcome measures for RGNDs and ID is explored, recommendations are provided, and a disorder-specific outcome measure has been developed and validated. Considering that a genetic diagnosis provides opportunities for disorder-specific care, reporting of genetic diagnoses in multidisciplinary ID care is explored. To provide evidence-based treatment decisions and to prevent polypharmacy, this thesis emphasizes the significance of reporting genetic diagnosis in individuals with ID, personalized treatment approaches, use of the N-of-1 design, and the thorough selection of appropriate and relevant outcome measures, providing a much-needed bridge between practice and science

Financial rogue waves

The financial rogue waves are reported analytically in the nonlinear option pricing model due to Ivancevic, which is nonlinear wave alternative of the Black-Scholes model. These solutions may be used to describe the possible physical mechanisms for rogue wave phenomenon in financial markets and related fields.Comment: 4 papges, 2 figures, Final version accepted in Commun. Theor. Phys., 201

New Results for the Correlation Functions of the Ising Model and the Transverse Ising Chain

In this paper we show how an infinite system of coupled Toda-type nonlinear differential equations derived by one of us can be used efficiently to calculate the time-dependent pair-correlations in the Ising chain in a transverse field. The results are seen to match extremely well long large-time asymptotic expansions newly derived here. For our initial conditions we use new long asymptotic expansions for the equal-time pair correlation functions of the transverse Ising chain, extending an old result of T.T. Wu for the 2d Ising model. Using this one can also study the equal-time wavevector-dependent correlation function of the quantum chain, a.k.a. the q-dependent diagonal susceptibility in the 2d Ising model, in great detail with very little computational effort.Comment: LaTeX 2e, 31 pages, 8 figures (16 eps files). vs2: Two references added and minor changes of style. vs3: Corrections made and reference adde

GTI-space : the space of generalized topological indices

A new extension of the generalized topological indices (GTI) approach is carried out torepresent 'simple' and 'composite' topological indices (TIs) in an unified way. Thisapproach defines a GTI-space from which both simple and composite TIs represent particular subspaces. Accordingly, simple TIs such as Wiener, Balaban, Zagreb, Harary and Randićconnectivity indices are expressed by means of the same GTI representation introduced for composite TIs such as hyper-Wiener, molecular topological index (MTI), Gutman index andreverse MTI. Using GTI-space approach we easily identify mathematical relations between some composite and simple indices, such as the relationship between hyper-Wiener and Wiener index and the relation between MTI and first Zagreb index. The relation of the GTI space with the sub-structural cluster expansion of property/activity is also analysed and some routes for the applications of this approach to QSPR/QSAR are also given

How does the electromagnetic field couple to gravity, in particular to metric, nonmetricity, torsion, and curvature?

The coupling of the electromagnetic field to gravity is an age-old problem. Presently, there is a resurgence of interest in it, mainly for two reasons: (i) Experimental investigations are under way with ever increasing precision, be it in the laboratory or by observing outer space. (ii) One desires to test out alternatives to Einstein's gravitational theory, in particular those of a gauge-theoretical nature, like Einstein-Cartan theory or metric-affine gravity. A clean discussion requires a reflection on the foundations of electrodynamics. If one bases electrodynamics on the conservation laws of electric charge and magnetic flux, one finds Maxwell's equations expressed in terms of the excitation H=(D,H) and the field strength F=(E,B) without any intervention of the metric or the linear connection of spacetime. In other words, there is still no coupling to gravity. Only the constitutive law H= functional(F) mediates such a coupling. We discuss the different ways of how metric, nonmetricity, torsion, and curvature can come into play here. Along the way, we touch on non-local laws (Mashhoon), non-linear ones (Born-Infeld, Heisenberg-Euler, Plebanski), linear ones, including the Abelian axion (Ni), and find a method for deriving the metric from linear electrodynamics (Toupin, Schoenberg). Finally, we discuss possible non-minimal coupling schemes.Comment: Latex2e, 26 pages. Contribution to "Testing Relativistic Gravity in Space: Gyroscopes, Clocks, Interferometers ...", Proceedings of the 220th Heraeus-Seminar, 22 - 27 August 1999 in Bad Honnef, C. Laemmerzahl et al. (eds.). Springer, Berlin (2000) to be published (Revised version uses Springer Latex macros; Sec. 6 substantially rewritten; appendices removed; the list of references updated

Spectral Properties of Quasiparticle Excitations Induced by Magnetic Moments in Superconductors

The consequences of localized, classical magnetic moments in superconductors are explored and their effect on the spectral properties of the intragap bound states is studied. Above a critical moment, a localized quasiparticle excitation in an s-wave superconductor is spontaneously created near a magnetic impurity, inducing a zero-temperature quantum transition. In this transition, the spin quantum number of the ground state changes from zero to 1/2, while the total charge remains the same. In contrast, the spin-unpolarized ground state of a d-wave superconductor is found to be stable for any value of the magnetic moment when the normal-state energy spectrum possesses particle-hole symmetry. The effect of impurity scattering on the quasiparticle states is interpreted in the spirit of relevant symmetries of the clean superconductor. The results obtained by the non-self-consistent (T matrix) and the self-consistent mean-field approximations are compared and qualitative agreement between the two schemes is found in the regime where the coherence length is longer than the Fermi length.Comment: to appear in Phys. Rev. B55, May 1st (1997

Onset of magnetism in B2 transition metals aluminides

Ab initio calculation results for the electronic structure of disordered bcc Fe(x)Al(1-x) (0.4<x<0.75), Co(x)Al(1-x) and Ni(x)Al(1-x) (x=0.4; 0.5; 0.6) alloys near the 1:1 stoichiometry, as well as of the ordered B2 (FeAl, CoAl, NiAl) phases with point defects are presented. The calculations were performed using the coherent potential approximation within the Korringa-Kohn-Rostoker method (KKR-CPA) for the disordered case and the tight-binding linear muffin-tin orbital (TB-LMTO) method for the intermetallic compounds. We studied in particular the onset of magnetism in Fe-Al and Co-Al systems as a function of the defect structure. We found the appearance of large local magnetic moments associated with the transition metal (TM) antisite defect in FeAl and CoAl compounds, in agreement with the experimental findings. Moreover, we found that any vacancies on both sublattices enhance the magnetic moments via reducing the charge transfer to a TM atom. Disordered Fe-Al alloys are ferromagnetically ordered for the whole range of composition studied, whereas Co-Al becomes magnetic only for Co concentration >0.5.Comment: 11 pages with 9 embedded postscript figures, to be published in Phys.Rev.

Nonlinear Realization of Chiral Symmetry on the Lattice

We formulate lattice theories in which chiral symmetry is realized nonlinearly on the fermion fields. In this framework the fermion mass term does not break chiral symmetry. This property allows us to use the Wilson term to remove the doubler fermions while maintaining exact chiral symmetry on the lattice. Our lattice formulation enables us to address non-perturbative questions in effective field theories of baryons interacting with pions and in models involving constituent quarks interacting with pions and gluons. We show that a system containing a non-zero density of static baryons interacting with pions can be studied on the lattice without encountering complex action problems. In our formulation one can also decide non-perturbatively if the chiral quark model of Georgi and Manohar provides an appropriate low-energy description of QCD. If so, one could understand why the non-relativistic quark model works.Comment: 34 pages, 2 figures, revised version to be published in J. High Energy Phys. (changes in the 1st paragraph, additional descriptions on the nature of the coordinate singularities in Sec.2, references added