Definable group extensions in semi-bounded o-minimal structures

In this note we show: Let ℛ = 〈 R, <, +, 0,...〉 be a semi-bounded (respectively, linear) o-minimal expansion of an ordered group, and G a group definable in R of linear dimension m ([2]). Then G is a definable extension of a bounded (respectively, definably compact) definable group B by 〈 Rm, +〉.FCT Financiamento Base 2008 - USFL/1/209; FCT grant SFRH/BPD/35000/200

Moyamoya-like cerebrovascular disease in a child with a novel mutation in myosin heavy chain 11

Heterozygous mutations in the MYH11 gene affecting the C-terminal coiled-coil region of the smooth muscle myosin heavy chain, a contractile protein of smooth muscle cells (SMC), have been described to cause thoracic aortic aneurysm or aortic dissection (TAAD) and patent ductus arteriosus (PDA).1 Herein we expand the phenotype associated with MYH11 mutations to include moyamoya-like cerebrovascular disease

Nonlinear magnetoinductive transmission lines

Power transmission in one-dimensional nonlinear magnetic metamaterials driven at one end is investigated numerically and analytically in a wide frequency range. The nonlinear magnetic metamaterials are composed of varactor-loaded split-ring resonators which are coupled magnetically through their mutual inductances, forming thus a magnetoiductive transmission line. In the linear limit, significant power transmission along the array only appears for frequencies inside the linear magnetoinductive wave band. We present analytical, closed form solutions for the magnetoinductive waves transmitting the power in this regime, and their discrete frequency dispersion. When nonlinearity is important, more frequency bands with significant power transmission along the array may appear. In the equivalent circuit picture, the nonlinear magnetoiductive transmission line driven at one end by a relatively weak electromotive force, can be modeled by coupled resistive-inductive-capacitive (RLC) circuits with voltage-dependent capacitance. Extended numerical simulations reveal that power transmission along the array is also possible in other than the linear frequency bands, which are located close to the nonlinear resonances of a single nonlinear RLC circuit. Moreover, the effectiveness of power transmission for driving frequencies in the nonlinear bands is comparable to that in the linear band. Power transmission in the nonlinear bands occurs through the linear modes of the system, and it is closely related to the instability of a mode that is localized at the driven site.Comment: 11 pages, 11 figures, submitted to International Journal of Bifurcation and Chao

Microparticle-mediated VZV propagation and endothelial activation: Mechanism of VZV vasculopathy

OBJECTIVE: Varicella zoster virus (VZV) can spread anterogradely and infect cerebral arteries causing VZV vasculopathy and arterial ischemic stroke. In this study, we tested the hypothesis that virus-infected cerebrovascular fibroblasts undergo phenotypic changes that promote vascular remodeling and facilitate virus transmission in an in vitro model of VZV vasculopathy. The aims of this project were therefore to examine the changes that virus-infected human brain adventitial vascular fibroblasts (HBVAFs) undergo in an in vitro model of VZV vasculopathy and to identify disease biomarkers relating to VZV-related vasculopathy. METHODS: HBVAFs were infected with VZV, and their ability to migrate, proliferate, transdifferentiate, and interact with endothelial cells was studied with flow cytometry. Microparticles (MPs) released from these cells were isolated and imaged with transmission electron microscopy, and their protein content was analyzed with mass spectrometry. Circulating MP profiles were also studied in children with VZV and non-VZV vasculopathy and compared with controls. RESULTS: VZV-infected HBVAFs transdifferentiated into myofibroblasts with enhanced proliferative and migratory capacity. Interaction of VZV-infected HBVAFs with endothelial cells resulted in endothelial dysfunction. These effects were, in part, mediated by the release of MPs from VZV-infected HBVAFs. These MPs contained VZV virions that could transmit VZV to neighboring cells, highlighting a novel model of VZV cell-to-cell viral dissemination. MPs positive for VZV were significantly higher in children with VZV-related vasculopathy compared to children with non-VZV vasculopathy (p = 0.01) and controls (p = 0.007). CONCLUSIONS: VZV-infected HBVAFs promote vascular remodeling and facilitate virus transmission. These effects were mediated by the release of apoptotic MPs that could transmit VZV infection to neighboring cells through a Trojan horse means of productive viral infection. VZV+ MPs may represent a disease biomarker worthy of further study

Efficacy and safety of anakinra for undifferentiated autoinflammatory diseases in children: a retrospective case review

Objective: The aim was to carry out a retrospective review of the efficacy and safety of anakinra in paediatric patients with undifferentiated autoinflammatory disease (uAID). Methods: We carried out a retrospective study of children with uAID at a single quaternary centre. The clinical efficacy of anakinra was evaluated using physician global assessment (PGA) and serological response assessed by levels of serum amyloid A and CRP. Safety was assessed by exploring adverse events, including infection and drug reactions. Results: This study included 22 patients, 64% females and 36% males of median age 7.1 years (range 0.13-14.11 years), with uAID. The median starting dose of anakinra was 2 mg/kg (range 2-6 mg/kg) and the median duration of treatment 19.6 months (range 0.8-100 months). Before anakinra treatment, the median PGA, on a three-point Likert scale, was 2 (range 1-2), which fell to 1 (range 0-2) within 3 months of treatment. Eight of 22 (36%) patients achieved complete clinical and serological remission; 8/22 (36%) achieved a partial response; and 6/22 (28%) had no response to anakinra. Adverse events included death (3/22, 14%) and allogeneic haematopoietic stem cell transplantation (1/22, 5%). There were no new safety signals, and anakinra was well tolerated overall. Conclusion: Retrospectively, 72% of children with uAID responded well to anakinra, with 36% achieving full clinical and serological remission within 3 months. This suggests that empirical trials of IL-1 blockade might be warranted in children with uAID. Clear stopping criteria based on predefined parameters should be considered, because non-responders required alternative therapies, facilitated by a definitive molecular diagnosis where possible

Memristive Effects in Oxygenated Amorphous Carbon Nanodevices

This is the author accepted manuscript. The final version is available from IOP Publishing via the DOI in this record.Computing with resistive-switching (memristive) memory devices has shown much recent progress and offers an attractive route to circumvent the von-Neumann bottleneck, i.e. the separation of processing and memory, which limits the performance of conventional computer architectures. Due to their good scalability and nanosecond switching speeds, carbon-based resistive-switching memory devices could play an important role in this respect. However, devices based on elemental carbon, such as tetrahedral amorphous carbon or t-aC, typically suffer from a low cycling endurance. A material that has proven to be capable of combining the advantages of elemental carbon-based memories with simple fabrication methods and good endurance performance for binary memory applications is oxygenated amorphous carbon, or a-COx. Here, we examine the memristive capabilities of nanoscale a-COx devices, in particular their ability to provide the multilevel and accumulation properties that underpin computing type applications. We show the successful operation of nanoscale a-COx memory cells for both the storage of multilevel states (here 3-level) and for the provision of an arithmetic accumulator. We implement a base-16, or hexadecimal, accumulator and show how such a device can carry out hexadecimal arithmetic and simultaneously store the computed result in the self-same a-COx cell, all using fast (sub-10 ns) and low-energy (sub-pJ) input pulses.This work was funded by the EU Research & Innovation project CareRAMM, grant no. 30998

A rapid turnaround gene panel for severe autoinflammation: Genetic results within 48 hours

There is an important unmet clinical need for fast turnaround next generation sequencing (NGS) to aid genetic diagnosis of patients with acute and sometimes catastrophic inflammatory presentations. This is imperative for patients who require precise and targeted treatment to prevent irreparable organ damage or even death. Acute and severe hyper- inflammation may be caused by primary immunodeficiency (PID) with immune dysregulation, or more typical autoinflammatory diseases in the absence of obvious immunodeficiency. Infectious triggers may be present in either immunodeficiency or autoinflammation. We compiled a list of 25 genes causing monogenetic immunological diseases that are notorious for their acute first presentation with fulminant inflammation and which may be amenable to specific treatment, including hemophagocytic lymphohistiocytosis (HLH); and autoinflammatory diseases that can present with early-onset stroke or other irreversible neurological inflammatory complications. We designed and validated a pipeline that enabled return of clinically actionable results in hours rather than weeks: the Rapid Autoinflammation Panel (RAP). We demonstrated accuracy of this new pipeline, with 100% sensitivity and 100% specificity. Return of results to clinicians was achieved within 48-hours from receiving the patient's blood or saliva sample. This approach demonstrates the potential significant diagnostic impact of NGS in acute medicine to facilitate precision medicine and save "life or limb" in these critical situations

Neuropsychological and neuroimaging characteristics of classical superficial siderosis

OBJECTIVE: To define the neuropsychological and neuroimaging characteristics of classical infratentorial superficial siderosis (iSS), a rare but disabling disorder defined by hemosiderin deposition affecting the superficial layers of the cerebellum, brainstem and spinal cord, usually associated with a slowly progressive neurological syndrome of deafness, ataxia and myelopathy. METHODS: We present the detailed neuropsychological and neuroimaging findings in 16 patients with iSS (mean age 57 years; 6 female). RESULTS: Cognitive impairment was present in 8/16 (50%) of patients: executive dysfunction was the most prevalent (44%), followed by impairment of visual recognition memory (27%); other cognitive domains were largely spared. Disease symptom duration was significantly correlated with the number of cognitive domains impaired (r = 0.59, p = 0.011). Mood disorders were also common (anxiety 62%, depression 38%, both 69%) but not associated with disease symptom duration. MRI findings revealed siderosis was not only in infratentorial brain regions, but also in characteristic widespread symmetrical supratentorial brain regions, independent of disease duration and degree of cognitive impairment. The presence of small vessel disease markers was very low and did not account for the cognitive impairment observed. CONCLUSION: Neuropsychological disturbances are common in iSS and need to be routinely investigated. The lack of association between the anatomical extent of hemosiderin and cognitive impairment or disease duration suggests that hemosiderin itself is not directly neurotoxic. Additional biomarkers of iSS disease severity and progression are needed for future research and clinical trials

Intermittent implosion and pattern formation of trapped Bose-Einstein condensates with attractive interaction

The collapsing dynamics of a trapped Bose-Einstein condensate (BEC) with attractive interaction are revealed to exhibit two previously unknown phenomena. During the collapse, BEC undergoes a series of rapid implosions that occur {\it intermittently} within a very small region. When the sign of the interaction is suddenly switched from repulsive to attractive, e.g., by the Feshbach resonance, density fluctuations grow to form various patterns such as a shell structure.Comment: 5 pages, 2 figures, RevTeX, epsf.sty, corrected loss rate

Systemic juvenile idiopathic arthritis: The Great Ormond Street Hospital experience (2005–2021)

Systemic juvenile idiopathic arthritis (sJIA) is a complex, systemic inflammatory disorder driven by both innate and adaptive immunity. Improved understanding of sJIA pathophysiology has led to recent therapeutic advances including a growing evidence base for the earlier use of IL-1 or IL-6 blockade as first-line treatment. We conducted a retrospective case notes review of patients diagnosed with sJIA over a 16-year period (October 2005-October 2021) at Great Ormond Street Hospital for Children. We describe the clinical presentation, therapeutic interventions, complications, and remission rates at different timepoints over the disease course. We examined our data, which spanned a period of changing therapeutic landscape, to try and identify potential therapeutic signals in patients who received biologic treatment early in the disease course compared to those who did not. A total of 76-children (female n = 40, 53%) were diagnosed with sJIA, median age 4.5 years (range 0.6-14.1); 36% (27/76) presented with suspected or confirmed macrophage activation syndrome. A biologic disease-modifying anti-rheumatic drug (bDMARD) alone was commenced as first-line treatment in 28% (n = 21/76) of the cohort; however, at last review, 84% (n = 64/76) had received treatment with a bDMARD. Clinically inactive disease (CID) was achieved by 88% (n = 67/76) of the cohort at last review; however, only 32% (24/76) achieved treatment-free CID. At 1-year follow-up, CID was achieved in a significantly greater proportion of children who received treatment with a bDMARD within 3 months of diagnosis compared to those who did not (90% vs. 53%, p = 0.002). Based on an ever-increasing evidence base for the earlier use of bDMARD in sJIA and our experience of the largest UK single-centre case series described to date, we now propose a new therapeutic pathway for children diagnosed with sJIA in the UK based on early use of bDMARDs. Reappraisal of the current National Health Service commissioning pathway for sJIA is now urgently required