15 research outputs found

    Collective physician perspectives on non-oral medication approaches for the management of clinically relevant unresolved issues in Parkinson's disease: Consensus from an international survey and discussion program

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    Navigate PD was an educational program established to supplement existing guidelines and provide recommendations on the management of Parkinson's disease (PD) refractory to oral/transdermal therapies. It involved 103 experts from 13 countries overseen by an International Steering Committee (ISC) of 13 movement disorder specialists. The ISC identified 71 clinical questions important for device-aided management of PD. Fifty-six experts responded to a web-based survey, rating 15 questions as ‘critically important;’ these were refined to 10 questions by the ISC to be addressed through available evidence and expert opinion. Draft guidance was presented at international/national meetings and revised based on feedback. Key take-home points are: • Patients requiring levodopa >5 times daily who have severe, troublesome ‘off’ periods (>1–2 h/day) despite optimal oral/transdermal levodopa or non-levodopa-based therapies should be referred for specialist assessment even if disease duration is <4 years. • Cognitive decline related to non-motor fluctuations is an indication for device-aided therapies. If cognitive impairment is mild, use deep brain stimulation (DBS) with caution. For patients who have cognitive impairment or dementia, intrajejunal levodopa infusion is considered as both therapeutic and palliative in some countries. Falls are linked to cognitive decline and are likely to become more frequent with device-aided therapies. • Insufficient control of motor complications (or drug-resistant tremor in the case of DBS) are indications for device-aided therapies. Levodopa-carbidopa intestinal gel infusions or subcutaneous apomorphine pump may be considered for patients aged >70 years who have mild or moderate cognitive impairment, severe depression or other contraindications to DBS

    Metal-insulator transition in two-dimensional disordered systems with power-law transfer terms

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    We investigate a disordered two-dimensional lattice model for noninteracting electrons with long-range power-law transfer terms and apply the method of level statistics for the calculation of the critical properties. The eigenvalues used are obtained numerically by direct diagonalization. We find a metal-insulator transition for a system with orthogonal symmetry. The exponent governing the divergence of the correlation length at the transition is extracted from a finite size scaling analysis and found to be ν=2.6±0.15\nu=2.6\pm 0.15. The critical eigenstates are also analyzed and the distribution of the generalized multifractal dimensions is extrapolated.Comment: 4 pages with 4 figures, printed version: PRB, Rapid Communication

    Bosonic Excitations in Random Media

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    We consider classical normal modes and non-interacting bosonic excitations in disordered systems. We emphasise generic aspects of such problems and parallels with disordered, non-interacting systems of fermions, and discuss in particular the relevance for bosonic excitations of symmetry classes known in the fermionic context. We also stress important differences between bosonic and fermionic problems. One of these follows from the fact that ground state stability of a system requires all bosonic excitation energy levels to be positive, while stability in systems of non-interacting fermions is ensured by the exclusion principle, whatever the single-particle energies. As a consequence, simple models of uncorrelated disorder are less useful for bosonic systems than for fermionic ones, and it is generally important to study the excitation spectrum in conjunction with the problem of constructing a disorder-dependent ground state: we show how a mapping to an operator with chiral symmetry provides a useful tool for doing this. A second difference involves the distinction for bosonic systems between excitations which are Goldstone modes and those which are not. In the case of Goldstone modes we review established results illustrating the fact that disorder decouples from excitations in the low frequency limit, above a critical dimension dcd_c, which in different circumstances takes the values dc=2d_c=2 and dc=0d_c=0. For bosonic excitations which are not Goldstone modes, we argue that an excitation density varying with frequency as ρ(ω)ω4\rho(\omega) \propto \omega^4 is a universal feature in systems with ground states that depend on the disorder realisation. We illustrate our conclusions with extensive analytical and some numerical calculations for a variety of models in one dimension

    Whole-genome sequencing reveals host factors underlying critical COVID-19

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    Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

    Clinically Relevant Effects of Convection-Enhanced Delivery of AAV2-GDNF on the Dopaminergic Nigrostriatal Pathway in Aged Rhesus Monkeys

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    Growth factor therapy for Parkinson's disease offers the prospect of restoration of dopaminergic innervation and/or prevention of neurodegeneration. Safety and efficacy of an adeno-associated virus (AAV2) encoding human glial cell-derived neurotrophic factor (GDNF) was investigated in aged nonhuman primates. Positron emission tomography with 6-[18F]-fluoro-l-m-tyrosine (FMT-PET) in putamen was assessed 3 months before and after AAV2 infusion. In the right putamen, monkeys received either phosphate-buffered saline or low-dose (LD) or high-dose (HD) AAV2-GDNF. Monkeys that had received putaminal phosphate-buffered saline (PBS) infusions additionally received either PBS or HD AAV2-GDNF in the right substantia nigra (SN). The convection-enhanced delivery method used for infusion of AAV2-GDNF vector resulted in robust volume of GDNF distribution within the putamen. AAV2-GDNF increased FMT-PET uptake in the ipsilateral putamen as well as enhancing locomotor activity. Within the putamen and caudate, the HD gene transfer mediated intense GDNF fiber and extracellular immunoreactivity (IR). Retrograde and anterograde transport of GDNF to other brain regions was observed. AAV2-GDNF did not significantly affect dopamine in the ipsilateral putamen or caudate, but increased dopamine turnover in HD groups. HD putamen treatment increased the density of dopaminergic terminals in these regions. HD treatments, irrespective of the site of infusion, increased the number of nonpigmented TH-IR neurons in the SN. AAV2-GDNF gene transfer does not appear to elicit adverse effects, delivers therapeutic levels of GDNF within target brain areas, and enhances utilization of striatal dopamine and dopaminergic nigrostriatal innervation
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