Precision treatment of Singleton Merten syndrome with ruxolitinib: a case report.

BACKGROUND Singleton-Merten syndrome 1 (SGMRT1) is a rare type I interferonopathy caused by heterozygous mutations in the IFIH1 gene. IFIH1 encodes the pattern recognition receptor MDA5 which senses viral dsRNA and activates antiviral type I interferon (IFN) signaling. In SGMRT1, IFIH1 mutations confer a gain-of-function which causes overactivation of type I interferon (IFN) signaling leading to autoinflammation. CASE PRESENTATION We report the case of a nine year old child who initially presented with a slowly progressive decline of gross motor skill development and muscular weakness. At the age of five years, he developed osteoporosis, acro-osteolysis, alveolar bone loss and severe psoriasis. Whole exome sequencing revealed a pathogenic de novo IFIH1 mutation, confirming the diagnosis of SGMRT1. Consistent with constitutive type I interferon activation, patient blood cells exhibited a strong IFN signature as shown by marked up-regulation of IFN-stimulated genes. The patient was started on the Janus kinase (JAK) inhibitor, ruxolitinib, which inhibits signaling at the IFN-α/β receptor. Within days of treatment, psoriatic skin lesions resolved completely and the IFN signature normalized. Therapeutic efficacy was sustained and over the course muscular weakness, osteopenia and growth also improved. CONCLUSIONS JAK inhibition represents a valuable therapeutic option for patients with SGMRT1. Our findings also highlight the potential of a patient-tailored therapeutic approach based on pathogenetic insight

Collective effects at frictional interfaces

We discuss the role of the long-range elastic interaction between the contacts inside an inhomogeneous frictional interface. The interaction produces a characteristic elastic correlation length $\lambda_c = a^2 E / k_c$ (where $a$ is the distance between the contacts, $k_c$ is the elastic constant of a contact, and $E$ is the Young modulus of the sliding body), below which the slider may be considered as a rigid body. The strong inter-contact interaction leads to a narrowing of the effective threshold distribution for contact breaking and enhances the chances for an elastic instability to appear. Above the correlation length, $r > \lambda_c$, the interaction leads to screening of local perturbations in the interface, or to appearance of collective modes --- frictional cracks propagating as solitary waves

Flavor in Minimal Conformal Technicolor

We construct a complete, realistic, and natural UV completion of minimal conformal technicolor that explains the origin of quark and lepton masses and mixing angles. As in "bosonic technicolor", we embed conformal technicolor in a supersymmetric theory, with supersymmetry broken at a high scale. The exchange of heavy scalar doublets generates higher-dimension interactions between technifermions and quarks and leptons that give rise to quark and lepton masses at the TeV scale. Obtaining a sufficiently large top quark mass requires strong dynamics at the supersymmetry breaking scale in both the top and technicolor sectors. This is natural if the theory above the supersymmetry breaking also has strong conformal dynamics. We present two models in which the strong top dynamics is realized in different ways. In both models, constraints from flavor-changing effects can be easily satisfied. The effective theory below the supersymmetry breaking scale is minimal conformal technicolor with an additional light technicolor gaugino. We argue that this light gaugino is a general consequence of conformal technicolor embedded into a supersymmetric theory. If the gaugino has mass below the TeV scale it will give rise to an additional pseudo Nambu-Goldstone boson that is observable at the LHC.Comment: 37 pages; references adde

Foot health education for people with rheumatoid arthritis : the practitioner's perspective

Background: Patient education is considered to be a key role for podiatrists in the management of patients with rheumatoid arthritis (RA). Patient education has undoubtedly led to improved clinical outcomes, however no attempts have been made to optimise its content or delivery to maximise benefits within the context of the foot affected by rheumatoid arthritis. The aim of this study was to identify the nature and content of podiatrists' foot health education for people with RA. Any potential barriers to its provision were also explored. Methods: A focus group was conducted. The audio dialogue was recorded digitally, transcribed verbatim and analysed using a structured, thematic approach. The full transcription was verified by the focus group as an accurate account of what was said. The thematic analysis framework was verified by members of the research team to ensure validity of the data. Results: Twelve members (all female) of the north west Podiatry Clinical Effectiveness Group for Rheumatology participated. Six overarching themes emerged: (i) the essence of patient education; (ii) the content; (iii) patient-centred approach to content and timing; (iv) barriers to provision; (v) the therapeutic relationship; and (vi) tools of the trade. Conclusion: The study identified aspects of patient education that this group of podiatrists consider most important in relation to its: content, timing, delivery and barriers to its provision. General disease and foot health information in relation to RA together with a potential prognosis for foot health, the role of the podiatrist in management of foot health, and appropriate self-management strategies were considered to be key aspects of content, delivered according to the needs of the individual. Barriers to foot health education provision, including financial constraints and difficulties in establishing effective therapeutic relationships, were viewed as factors that strongly influenced foot health education provision. These data will contribute to the development of a patient-centred, negotiated approach to the provision of foot health education for people with RA

B-L Cosmic Strings in Heterotic Standard Models

E_{8} X E_{8} heterotic string and M-theory, when compactified on smooth Calabi-Yau manifolds with SU(4) vector bundles, can give rise to softly broken N=1 supersymmetric theories with the exact matter spectrum of the MSSM, including three right-handed neutrinos and one Higgs-Higgs conjugate pair of supermultiplets. These vacua have the SU(3)_{C} X SU(2)_{L} X U(1)_{Y} gauge group of the standard model augmented by an additional gauged U(1)_{B-L}. Their minimal content requires that the B-L symmetry be spontaneously broken by a vacuum expectation value of at least one right-handed sneutrino. The soft supersymmetry breaking operators can induce radiative breaking of the B-L gauge symmetry with an acceptable B-L/electroweak hierarchy. In this paper, it is shown that U(1)_{B-L} cosmic strings occur in this context, potentially with both bosonic and fermionic superconductivity. We present a numerical analysis that demonstrates that boson condensates can, in principle, form for theories of this type. However, the weak Yukawa and gauge couplings of the right-handed sneutrino suggests that bosonic superconductivity will not occur in the simplest vacua in this context. The electroweak phase transition also disallows fermion superconductivity, although substantial bound state fermion currents can exist.Comment: 41 pages, 5 figure

Heterotic T-folds with a small number of neutral moduli

We discuss non-geometric supersymmetric heterotic string models in D=4, in the framework of the free fermionic construction. We perform a systematic scan of models with four a priori left-right asymmetric Z_2 projections and shifts. We analyze some 2^{20} models, identifying 18 inequivalent classes and addressing variants generated by discrete torsions. They do not contain geometrical or trivial neutral moduli, apart from the dilaton. However, we show the existence of flat directions in the form of exactly marginal deformations and identify patterns of symmetry breaking where product gauge groups, realized at level one, are broken to their diagonal at higher level. We also describe an "inverse Gepner map" from Heterotic to Type II models that could be used, in certain non geometric settings, to define "effective" topological invariants.Comment: 37 page

Use of technology in children's dietary assessment

Background: Information on dietary intake provides some of the most valuable insights for mounting intervention programmes for the prevention of chronic diseases. With the growing concern about adolescent overweight, the need to accurately measure diet becomes imperative. Assessment among adolescents is problematic as this group has irregular eating patterns and they have less enthusiasm for recording food intake. Subjects/Methods: We used qualitative and quantitative techniques among adolescents to assess their preferences for dietary assessment methods.Results: Dietary assessment methods using technology, for example, a personal digital assistant (PDA) or a disposable camera, were preferred over the pen and paper food record. Conclusions: There was a strong preference for using methods that incorporate technology such as capturing images of food. This suggests that for adolescents, dietary methods that incorporate technology may improve cooperation and accuracy. Current computing technology includes higher resolution images, improved memory capacity and faster processors that allow small mobile devices to process information not previously possible. Our goal is to develop, implement and evaluate a mobile device (for example, PDA, mobile phone) food record that will translate to an accurate account of daily food and nutrient intake among adolescents. This mobile computing device will include digital images, a nutrient database and image analysis for identification and quantification of food consumption. Mobile computing devices provide a unique vehicle for collecting dietary information that reduces the burden on record keepers. Images of food can be marked with a variety of input methods that link the item for image processing and analysis to estimate the amount of food. Images before and after the foods are eaten can estimate the amount of food consumed. The initial stages and potential of this project will be described

Strong negative feedback from Erk to Raf confers robustness to MAPK signalling

This study shows that MAPK signalling is robust against protein level changes due to a strong negative feedback from Erk to Raf. Surprisingly, robustness is provided through a fast post-translational mechanism although variation of Erk levels occurs on a timescale of days

Non-supersymmetric heterotic model building

We investigate orbifold and smooth Calabi-Yau compactifications of the non-supersymmetric heterotic SO(16)xSO(16) string. We focus on such Calabi-Yau backgrounds in order to recycle commonly employed techniques, like index theorems and cohomology theory, to determine both the fermionic and bosonic 4D spectra. We argue that the N=0 theory never leads to tachyons on smooth Calabi-Yaus in the large volume approximation. As twisted tachyons may arise on certain singular orbifolds, we conjecture that such tachyonic states are lifted in the full blow-up. We perform model searches on selected orbifold geometries. In particular, we construct an explicit example of a Standard Model-like theory with three generations and a single Higgs field.Comment: 1+30 pages latex, 11 tables; v2: references and minor revisions added, matches version published in JHE

Local reactions after the fourth-dose of acellular pertussis vaccine in South Australia

The document attached has been archived with permission from the editor of the Medical Journal of Australia. An external link to the publisher’s copy is included.ObjectiveTo assess the reported rate of local reactions after administration of acellular pertussis vaccine (DTPa) according to dose number and type of pertussis vaccine (whole-cell or acellular) used for the primary course, and to document the severity and outcome of fourth-dose local reactions.Design and settingRetrospective review. Reports of adverse events after vaccination in South Australia between 1 January 1997 and 31 December 2000 were reviewed, and a questionnaire administered to all parents who reported a local reaction after the fourth dose of DTPa.Main outcome measuresThe number, and rate per 100 000 administered doses, of local reactions following the primary and booster doses of DTPa, and of local reactions after the fourth-dose in cohorts of children whose primary vaccinations were with either DTPw or DTPa. Redness and/or swelling at the injection site as reported by parents.ResultsOf 581 reported adverse events after vaccination, 138 were local reactions after a pertussis-containing vaccine. Primary vaccinations with DTPa was a significant risk factor for a fourth-dose local reaction (relative risk, 6.7; 95% CI, 2.4-18.5). Parental questionnaires were completed for 45 of the 71 children (63%) with reported local reactions after the fourth dose of DTPa; extensive limb swelling was reported in 8 children (18%) and all except one child had recovered by the time of review.ConclusionsParents should be informed that children receiving booster doses of DTPa vaccine, after primary doses with DTPa, are at increased risk of local reactions (which tend to resolve spontaneously) but not of systemic effects. Studies should be initiated to investigate the pathogenesis and the risk of recurrence of local reactions to further improve vaccination schedules.Michael S Gold, Sara Noonan, Maggi Osbourn, Stella Precepa and Ann E Kemp