7 research outputs found
Recommendations for collaborative paediatric research including biobanking in Europe: a Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) initiative
Innovative research in childhood rheumatic diseases mandates international collaborations. However, researchers struggle with significant regulatory heterogeneity; an enabling European Union (EU)-wide framework is missing. The aims of the study were to systematically review the evidence for best practice and to establish recommendations for collaborative research. The Paediatric Rheumatology European Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) project enabled a scoping review and expert discussion, which then informed the systematic literature review. Published evidence was synthesised; recommendations were drafted. An iterative review process and consultations with Ethics Committees and European experts for ethical and legal aspects of paediatric research refined the recommendations. SHARE experts and patient representatives vetted the proposed recommendations at a consensus meeting using Nominal Group Technique. Agreement of 80% was mandatory for inclusion. The systematic literature review returned 1319 records. A total of 223 full-text publications plus 22 international normative documents were reviewed; 85 publications and 16 normative documents were included. A total of 21 recommendations were established including general principles (1-3), ethics (4-7), paediatric principles (8 and 9), consent to paediatric research (10-14), paediatric databank and biobank (15 and 16), sharing of data and samples (17-19), and commercialisation and third parties (20 and 21). The refined recommendations resulted in an agreement of >80% for all recommendations. The SHARE initiative established the first recommendations for Paediatric Rheumatology collaborative research across borders in Europe. These provide strong support for an urgently needed European framework and evidence-based guidance for its implementation. Such changes will promote research in children with rheumatic diseases
Early Evolution of Hepatitis C Virus (HCV) Quasispecies after Liver Transplant for HCVâRelated Disease
International audienceEnd-stage liver disease as a result of chronic hepatitis C virus (HCV) infection is the main indication for liver transplant (LT), but allografts are systematically infected with HCV soon after transplant. Viral quasispecies are poorly described during the early posttransplant period
Hereditary spastic paraplegia type 5 : natural history, biomarkers and a randomized controlled trial
Hereditary spastic paraplegia type 5: natural history, biomarkers and a randomized controlled trial
SPG5 is a rare subtype of Hereditary Spastic Paraplegia caused by
mutations in the oxysterol-7 alpha-hydroxylase gene CYP7B1. Schols et
al. study properties of lipid biomarkers in SPG5 and evaluate a
treatment strategy targeting oxysterol accumulation in a randomized
controlled trial (STOP-SPG5).Spastic paraplegia type 5 (SPG5) is a rare
subtype of hereditary spastic paraplegia, a highly heterogeneous group
of neurodegenerative disorders defined by progressive neurodegeneration
of the corticospinal tract motor neurons. SPG5 is caused by recessive
mutations in the gene CYP7B1 encoding oxysterol-7 alpha-hydroxylase.
This enzyme is involved in the degradation of cholesterol into primary
bile acids. CYP7B1 deficiency has been shown to lead to accumulation of
neurotoxic oxysterols. In this multicentre study, we have performed
detailed clinical and biochemical analysis in 34 genetically confirmed
SPG5 cases from 28 families, studied dose-dependent neurotoxicity of
oxysterols in human cortical neurons and performed a randomized
placebo-controlled double blind interventional trial targeting oxysterol
accumulation in serum of SPG5 patients. Clinically, SPG5 manifested in
childhood or adolescence (median 13 years). Gait ataxia was a common
feature. SPG5 patients lost the ability to walk independently after a
median disease duration of 23 years and became wheelchair dependent
after a median 33 years. The overall cross-sectional progression rate of
0.56 points on the Spastic Paraplegia Rating Scale per year was slightly
lower than the longitudinal progression rate of 0.80 points per year.
Biochemically, marked accumulation of CYP7B1 substrates including
27-hydroxycholesterol was confirmed in serum (n = 19) and cerebrospinal
fluid (n = 17) of SPG5 patients. Moreover, 27-hydroxycholesterol levels
in serum correlated with disease severity and disease duration.
Oxysterols were found to impair metabolic activity and viability of
human cortical neurons at concentrations found in SPG5 patients,
indicating that elevated levels of oxysterols might be key pathogenic
factors in SPG5. We thus performed a randomized placebo-controlled trial
(EudraCT 2015-000978-35) with atorvastatin 40 mg/day for 9 weeks in 14
SPG5 patients with 27-hydroxycholesterol levels in serum as the primary
outcome measure. Atorvastatin, but not placebo, reduced serum
27-hydroxycholesterol from 853 ng/ml [interquartile range (IQR)
683-1113] to 641 (IQR 507-694) (-31.5%, P = 0.001, Mann-Whitney
U-test). Similarly, 25-hydroxycholesterol levels in serum were reduced.
In cerebrospinal fluid 27-hydroxycholesterol was reduced by 8.4% but
this did not significantly differ from placebo. As expected, no effects
were seen on clinical outcome parameters in this short-term trial. In
this study, we define the mutational and phenotypic spectrum of SPG5,
examine the correlation of disease severity and progression with
oxysterol concentrations, and demonstrate in a randomized controlled
trial that atorvastatin treatment can effectively lower
27-hydroxycholesterol levels in serum of SPG5 patients. We thus
demonstrate the first causal treatment strategy in hereditary spastic
paraplegia
Measurement of the J/ photoproduction cross section over the full near-threshold kinematic region
We report the total and differential cross sections for
J
/
Ï
photoproduction with the large acceptance GlueX spectrometer for photon beam energies from the threshold at 8.2 GeV up to 11.44 GeV and over the full kinematic range of momentum transfer squared,
t
. Such coverage facilitates the extrapolation of the differential cross sections to the forward (
t
=
0
) point beyond the physical region. The forward cross section is used by many theoretical models and plays an important role in understanding
J
/
Ï
photoproduction and its relation to the
J
/
Ï
-proton interaction. These measurements of
J
/
Ï
photoproduction near threshold are also crucial inputs to theoretical models that are used to study important aspects of the gluon structure of the proton, such as the gluon generalized parton distribution of the proton, the mass radius of the proton, and the trace anomaly contribution to the proton mass. We observe possible structures in the total cross section energy dependence and find evidence for contributions beyond gluon exchange in the differential cross section close to threshold, both of which are consistent with contributions from open-charm intermediate states
Risk of COVID-19 after natural infection or vaccinationResearch in context
Summary: Background: While vaccines have established utility against COVID-19, phase 3 efficacy studies have generally not comprehensively evaluated protection provided by previous infection or hybrid immunity (previous infection plus vaccination). Individual patient data from US government-supported harmonized vaccine trials provide an unprecedented sample population to address this issue. We characterized the protective efficacy of previous SARS-CoV-2 infection and hybrid immunity against COVID-19 early in the pandemic over three-to six-month follow-up and compared with vaccine-associated protection. Methods: In this post-hoc cross-protocol analysis of the Moderna, AstraZeneca, Janssen, and Novavax COVID-19 vaccine clinical trials, we allocated participants into four groups based on previous-infection status at enrolment and treatment: no previous infection/placebo; previous infection/placebo; no previous infection/vaccine; and previous infection/vaccine. The main outcome was RT-PCR-confirmed COVID-19 >7â15 days (per original protocols) after final study injection. We calculated crude and adjusted efficacy measures. Findings: Previous infection/placebo participants had a 92% decreased risk of future COVID-19 compared to no previous infection/placebo participants (overall hazard ratio [HR] ratio: 0.08; 95% CI: 0.05â0.13). Among single-dose Janssen participants, hybrid immunity conferred greater protection than vaccine alone (HR: 0.03; 95% CI: 0.01â0.10). Too few infections were observed to draw statistical inferences comparing hybrid immunity to vaccine alone for other trials. Vaccination, previous infection, and hybrid immunity all provided near-complete protection against severe disease. Interpretation: Previous infection, any hybrid immunity, and two-dose vaccination all provided substantial protection against symptomatic and severe COVID-19 through the early Delta period. Thus, as a surrogate for natural infection, vaccination remains the safest approach to protection. Funding: National Institutes of Health