Factores determinantes de cooperación en I+D: una perspectiva institucional

Existing literature on the determinants of research & development (R&D) cooperation discusses mainly the factors which are specific to organization. But the issues of institutional environment in which such interactions take place remain relatively less explored. This study identifies some particular institutions such as ‘Research and Technology Transfer’, and the ‘regulatory’ institutions which promote R&D cooperation in a country. The study is limited to some particular formal institutions which help improve R&D cooperation. The conclusions of the study have important policy implications for less developed countries so that they could improve the R&D resources of their organizations by attracting foreign organizations through the establishment of institutions necessary for R&D cooperation.La bibliografía sobre los factores que determinan la cooperación en investigación y desarrollo (I+D) estudia principalmente los factores que son específicos de la organización. Pero los aspectos relacionados con el entorno institucional, en el que tales interacciones tienen lugar, permanecen relativamente menos estudiados. Este trabajo identifica algunas instituciones específicas como “centros de investigación y de transferencia de tecnología” y las instituciones regulatorias que promocionan la cooperación en I+D en un país. El estudio está limitado a algunas instituciones específicas pero formales que ayudan a mejorar la cooperación en I+D. Las conclusiones del estudio pueden tener implicaciones políticas importantes para los países en vías de desarrollo que pueden mejorar los recursos de I+D de sus organizaciones atrayendo a las organizaciones externas por medio del establecimiento de las instituciones necesarias para la cooperación de I+D

Blocking two-component signalling enhances Candida albicans virulence and reveals adaptive mechanisms that counteract sustained SAPK activation

This work was funded by the UK Biotechnology and Biological Research Council [www.bbsrc.ac.uk] JQ (BB/K016393/1); AJPB (BB/K017365/1). The work was also supported by the Wellcome Trust [www.wellcome.ac.uk], JQ (086048, 097377); AJPB (097377)); LPE (097377). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Genetic influences on disease course and severity, 30 years after a clinically isolated syndrome

Genetics; Multiple sclerosis; PhenotypeGenética; Esclerosis múltiple; FenotipoGenètica; Esclerosi múltiple; FenotipMultiple sclerosis risk has a well-established polygenic component, yet the genetic contribution to disease course and severity remains unclear and difficult to examine. Accurately measuring disease progression requires long-term study of clinical and radiological outcomes with sufficient follow-up duration to confidently confirm disability accrual and multiple sclerosis phenotypes. In this retrospective study, we explore genetic influences on long-term disease course and severity; in a unique cohort of clinically isolated syndrome patients with homogenous 30-year disease duration, deep clinical phenotyping and advanced MRI metrics. Sixty-one clinically isolated syndrome patients [41 female (67%): 20 male (33%)] underwent clinical and MRI assessment at baseline, 1-, 5-, 10-, 14-, 20- and 30-year follow-up (mean age ± standard deviation: 60.9 ± 6.5 years). After 30 years, 29 patients developed relapsing-remitting multiple sclerosis, 15 developed secondary progressive multiple sclerosis and 17 still had a clinically isolated syndrome. Twenty-seven genes were investigated for associations with clinical outcomes [including disease course and Expanded Disability Status Scale (EDSS)] and brain MRI (including white matter lesions, cortical lesions, and brain tissue volumes) at the 30-year follow-up. Genetic associations with changes in EDSS, relapses, white matter lesions and brain atrophy (third ventricular and medullary measurements) over 30 years were assessed using mixed-effects models. HLA-DRB1*1501-positive (n = 26) patients showed faster white matter lesion accrual [+1.96 lesions/year (0.64–3.29), P = 3.8 × 10−3], greater 30-year white matter lesion volumes [+11.60 ml, (5.49–18.29), P = 1.27 × 10−3] and higher annualized relapse rates [+0.06 relapses/year (0.005–0.11), P = 0.031] compared with HLA-DRB1*1501-negative patients (n = 35). PVRL2-positive patients (n = 41) had more cortical lesions (+0.83 [0.08–1.66], P = 0.042), faster EDSS worsening [+0.06 points/year (0.02–0.11), P = 0.010], greater 30-year EDSS [+1.72 (0.49–2.93), P = 0.013; multiple sclerosis cases: +2.60 (1.30–3.87), P = 2.02 × 10−3], and greater risk of secondary progressive multiple sclerosis [odds ratio (OR) = 12.25 (1.15–23.10), P = 0.031] than PVRL2-negative patients (n = 18). In contrast, IRX1-positive (n = 30) patients had preserved 30-year grey matter fraction [+0.76% (0.28–1.29), P = 8.4 × 10−3], lower risk of cortical lesions [OR = 0.22 (0.05–0.99), P = 0.049] and lower 30-year EDSS [−1.35 (−0.87,−3.44), P = 0.026; multiple sclerosis cases: −2.12 (−0.87, −3.44), P = 5.02 × 10−3] than IRX1-negative patients (n = 30). In multiple sclerosis cases, IRX1-positive patients also had slower EDSS worsening [−0.07 points/year (−0.01,−0.13), P = 0.015] and lower risk of secondary progressive multiple sclerosis [OR = 0.19 (0.04–0.92), P = 0.042]. These exploratory findings support diverse genetic influences on pathological mechanisms associated with multiple sclerosis disease course. HLA-DRB1*1501 influenced white matter inflammation and relapses, while IRX1 (protective) and PVRL2 (adverse) were associated with grey matter pathology (cortical lesions and atrophy), long-term disability worsening and the risk of developing secondary progressive multiple sclerosis.This study was funded by the Multiple Sclerosis Society of Great Britain and Northern Ireland (20; 984) and supported by the National Institute for Health and Care Research University College London Hospitals (UCLH) Biomedical Research Centre. Funding for extended SNP analysis was supported by a Small Acorns Fund from The National Brain Appeal (NBA/QSQ/SAF/R17)

Lesional Antibody Synthesis and Complement Deposition Associate With De Novo Antineuronal Antibody Synthesis After Spinal Cord Injury

BACKGROUND AND OBJECTIVES: Spinal cord injury (SCI) disrupts the fine-balanced interaction between the CNS and immune system and can cause maladaptive aberrant immune responses. The study examines emerging autoantibody synthesis after SCI with binding to conformational spinal cord epitopes and surface peptides located on the intact neuronal membrane. METHODS: This is a prospective longitudinal cohort study conducted in acute care and inpatient rehabilitation centers in conjunction with a neuropathologic case-control study in archival tissue samples ranging from acute injury (baseline) to several months thereafter (follow-up). In the cohort study, serum autoantibody binding was examined in a blinded manner using tissue-based assays (TBAs) and dorsal root ganglia (DRG) neuronal cultures. Groups with traumatic motor complete SCI vs motor incomplete SCI vs isolated vertebral fracture without SCI (controls) were compared. In the neuropathologic study, B cell infiltration and antibody synthesis at the spinal lesion site were examined by comparing SCI with neuropathologically unaltered cord tissue. In addition, the CSF in an individual patient was explored. RESULTS: Emerging autoantibody binding in both TBA and DRG assessments was restricted to an SCI patient subpopulation only (16%, 9/55 sera) while being absent in vertebral fracture controls (0%, 0/19 sera). Autoantibody binding to the spinal cord characteristically detected the substantia gelatinosa, a less-myelinated region of high synaptic density involved in sensory-motor integration and pain processing. Autoantibody binding was most frequent after motor complete SCI (grade American Spinal Injury Association impairment scale A/B, 22%, 8/37 sera) and was associated with neuropathic pain medication. In conjunction, the neuropathologic study demonstrated lesional spinal infiltration of B cells (CD20, CD79a) in 27% (6/22) of patients with SCI, the presence of plasma cells (CD138) in 9% (2/22). IgG and IgM antibody syntheses colocalized to areas of activated complement (C9neo) deposition. Longitudinal CSF analysis of an additional single patient demonstrated de novo (IgM) intrathecal antibody synthesis emerging with late reopening of the blood-spinal cord barrier. DISCUSSION: This study provides immunologic, neurobiological, and neuropathologic proof-of-principle for an antibody-mediated autoimmunity response emerging approximately 3 weeks after SCI in a patient subpopulation with a high demand of neuropathic pain medication. Emerging autoimmunity directed against specific spinal cord and neuronal epitopes suggests the existence of paratraumatic CNS autoimmune syndromes

Genetic influences on disease course and severity, 30 years after a clinically isolated syndrome

Multiple sclerosis risk has a well-established polygenic component, yet the genetic contribution to disease course and severity remains unclear and difficult to examine. Accurately measuring disease progression requires long-term study of clinical and radiological outcomes with sufficient follow-up duration to confidently confirm disability accrual and multiple sclerosis phenotypes. In this retrospective study, we explore genetic influences on long-term disease course and severity; in a unique cohort of clinically isolated syndrome patients with homogenous 30-year disease duration, deep clinical phenotyping and advanced MRI metrics. Sixty-one clinically isolated syndrome patients [41 female (67%): 20 male (33%)] underwent clinical and MRI assessment at baseline, 1-, 5-, 10-, 14-, 20- and 30-year follow-up (mean age ± standard deviation: 60.9 ± 6.5 years). After 30 years, 29 patients developed relapsing-remitting multiple sclerosis, 15 developed secondary progressive multiple sclerosis and 17 still had a clinically isolated syndrome. Twenty-seven genes were investigated for associations with clinical outcomes [including disease course and Expanded Disability Status Scale (EDSS)] and brain MRI (including white matter lesions, cortical lesions, and brain tissue volumes) at the 30-year follow-up. Genetic associations with changes in EDSS, relapses, white matter lesions and brain atrophy (third ventricular and medullary measurements) over 30 years were assessed using mixed-effects models. HLA-DRB1*1501-positive (n = 26) patients showed faster white matter lesion accrual [+1.96 lesions/year (0.64-3.29), P = 3.8 × 10-3], greater 30-year white matter lesion volumes [+11.60 ml, (5.49-18.29), P = 1.27 × 10-3] and higher annualized relapse rates [+0.06 relapses/year (0.005-0.11), P = 0.031] compared with HLA-DRB1*1501-negative patients (n = 35). PVRL2-positive patients (n = 41) had more cortical lesions (+0.83 [0.08-1.66], P = 0.042), faster EDSS worsening [+0.06 points/year (0.02-0.11), P = 0.010], greater 30-year EDSS [+1.72 (0.49-2.93), P = 0.013; multiple sclerosis cases: +2.60 (1.30-3.87), P = 2.02 × 10-3], and greater risk of secondary progressive multiple sclerosis [odds ratio (OR) = 12.25 (1.15-23.10), P = 0.031] than PVRL2-negative patients (n = 18). In contrast, IRX1-positive (n = 30) patients had preserved 30-year grey matter fraction [+0.76% (0.28-1.29), P = 8.4 × 10-3], lower risk of cortical lesions [OR = 0.22 (0.05-0.99), P = 0.049] and lower 30-year EDSS [-1.35 (-0.87,-3.44), P = 0.026; multiple sclerosis cases: -2.12 (-0.87, -3.44), P = 5.02 × 10-3] than IRX1-negative patients (n = 30). In multiple sclerosis cases, IRX1-positive patients also had slower EDSS worsening [-0.07 points/year (-0.01,-0.13), P = 0.015] and lower risk of secondary progressive multiple sclerosis [OR = 0.19 (0.04-0.92), P = 0.042]. These exploratory findings support diverse genetic influences on pathological mechanisms associated with multiple sclerosis disease course. HLA-DRB1*1501 influenced white matter inflammation and relapses, while IRX1 (protective) and PVRL2 (adverse) were associated with grey matter pathology (cortical lesions and atrophy), long-term disability worsening and the risk of developing secondary progressive multiple sclerosis

Differentiating Multiple Sclerosis From AQP4-Neuromyelitis Optica Spectrum Disorder and MOG-Antibody Disease With Imaging

Background and objectives: Relapsing remitting multiple sclerosis (RRMS), aquaporin4 antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) may have overlapping clinical features. There is an unmet need for imaging markers that differentiate between them when serologic testing is unavailable or ambiguous. We assessed whether imaging characteristics typical of MS discriminate RRMS from AQP4-NMOSD and MOGAD, alone and in combination. Methods: Adult, non-acute patients with RRMS, APQ4-NMOSD, MOGAD and healthy controls, were prospectively recruited at the National Hospital for Neurology and Neurosurgery (London, UK), and the Walton Centre (Liverpool, UK) between 2014 and 2019. They underwent conventional and advanced brain, cord and optic nerve MRI, and optical coherence tomography. Results: A total of 91 consecutive patients (31 RRMS, 30 APQ4-NMOSD, 30 MOGAD) and 34 healthy controls were recruited. The most accurate measures differentiating RRMS from AQP4-NMOSD were the proportion of lesions with the central vein sign (CVS) (84% vs. 33%, accuracy/specificity/sensitivity: 91/88/93%, p<0.001), followed by cortical lesions (median: 2 [range: 1-14] vs. 1 [0-1], accuracy/specificity/sensitivity: 84/90/77%, p=0.002), and white matter lesions (mean: 39.07 [±25.8] vs. 9.5 [±14], accuracy/specificity/sensitivity: 78/84/73%, p=0.001). The combination of higher proportion of CVS, cortical lesions and optic nerve magnetization transfer ratio reached the highest accuracy in distinguishing RRMS from AQP4-NMOSD (accuracy/specificity/sensitivity: 95/92/97%, p<0.001).The most accurate measures favouring RRMS over MOGAD were: white matter lesions (39.07 [±25.8] vs. 1 [±2.3], accuracy/specificity/sensitivity: 94/94/93%, p=0.006), followed by cortical lesions (2 [1-14] vs. 1 [0-1], accuracy/specificity/sensitivity: 84/97/71%, p=0.004), and retinal nerve fibre layer thickness (RNFL) (mean: 87.54 [±13.83] vs 75.54 [±20.33], accuracy/specificity/sensitivity: 80/79/81%, p=0.009). Higher cortical lesion number combined with higher RNFL thickness best differentiated RRMS from MOGAD (accuracy/specificity/sensitivity: 84/92/77%, p<0.001). Discussion: Cortical lesions, CVS and optic nerve markers achieve a high accuracy in distinguishing RRMS from APQ4-NMOSD and MOGAD. This information may be useful in clinical practice, especially outside the acute phase and when serologic testing is ambiguous or not promptly available. Classification of evidence: This study provides Class II evidence that selected conventional and advanced brain, cord, and optic nerve MRI and OCT markers distinguish adult patients with RRMS from APQ4-NMOSD and MOGAD

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy