Viral, bacterial, or fungal infections are suspected of triggering multiple sclerosis (MS) and promoting relapses of the disease and are likely to be promoted by immune-active treatments. This raises ...questions about the infectious workup and preventive treatment of these infections prior to their initiation.
To establish recommendations on infections and MS. Provide information to patients and healthcare professionals on the minimal infectious workup to be performed in an MS patient at diagnosis and prior to initiation of immuno-active therapy in MS.
The recommendation attempts to answer four main questions about infections and MS. The French Group for Recommendations in Multiple Sclerosis (France4MS) did a systematic review of articles from PubMed and universities databases (from January 1975 to June 2020), using the RAND/UCLA formalized consensus method. The RAND/UCLA method has been developed to synthesize the scientific literature and expert opinions on health care topics and was used for reaching a formal agreement. Twenty-three experts contributed to the detailed review and a group of 63 multidisciplinary health professionals validated the final version of 36 recommendations.
It is recommended that MS patients undergo a minimal infectious workup, check their vaccination status at diagnosis, and repeat it during follow-up and before starting immunotherapy. Screening and preventive treatment of viral (group Herpes virus, HPV, JCV, HCV, HBV), bacterial (mycobacteria) and fungal (Cryptococcus) infections is recommended prior to the initiation of certain immuno-active MS therapies.
At diagnosis of MS and prior to the choice of therapeutic strategy, it is recommended to update the vaccination schedule of MS patients in reference to the HCSP vaccination schedule and the SFSEP recommendations. Before starting immunosuppressive treatment, it is recommended to inform patients of the risks of infections and to look for a constitutive or acquired immune deficiency. Health professionals and patients should be informed of the updated recommendations on infections and MS.
The potential of antibody conjugates with high drug loading in anticancer therapy has recently been highlighted by the approval of Trastuzumab deruxtecan and Sacituzumab govitecan. These ...biopharmaceutical approaches have spurred interest in bioconjugation strategies with high and defined degrees of drug‐to‐antibody ratio (DAR), in particular on native antibodies. Here, a glycoengineering methodology was developed to generate antibody drug conjugates with DAR of up to eight, by combining highly selective enzymatic galactosylation and oxidation with biorthogonal tandem Knoevenagel–Michael addition chemistry. This four‐step approach offers a selective route to conjugates from native antibodies with high drug loading, and thus illustrates how biocatalysis can be used for the generation of biopharmaceuticals using mild reaction conditions.
Glycoengineering: The synthesis of antibody–drug conjugates with high drug loading from native antibodies is of great interest for development of biopharmaceuticals. Here, selective biocatalysis using galactose oxidase and tandem Knoevenagel–Michael addition conjugation chemistry are combined to achieve molecular drug‐to‐antibody ratios of up to eight.
The Eocene (56–34 million years ago) is characterized by declining sea surface temperatures (SSTs) in the low latitudes (∼4°C) and high southern latitudes (∼8–11°C), in accord with decreasing CO2 ...estimates. However, in the mid‐to‐high northern latitudes there is no evidence for surface water cooling, suggesting thermal decoupling between northern and southern hemispheres and additional non‐CO2 controls. To explore this further, we present a multi‐proxy (Mg/Ca, δ18O, TEX86) SST record from Bass River in the western North Atlantic. Our compiled multi‐proxy SST record confirms a net decline in SSTs (∼4°C) between the early Eocene Climatic Optimum (53.3–49.1 Ma) and mid‐Eocene (∼44–41 Ma), supporting declining atmospheric CO2 as the primary mechanism of Eocene cooling. However, from the mid‐Eocene onwards, east‐west North Atlantic temperature gradients exhibit different trends, which we attribute to incursion of warmer waters into the eastern North Atlantic and inception of Northern Component Water across the early‐middle Eocene transition.
Plain Language Summary
Over the past 541 million years, the Earth has oscillated between warm (greenhouse) and cold (icehouse) climates. The most recent transition between a greenhouse and icehouse climate state occurred during the Eocene (56–34 million years ago). This transition shows a gradual cooling, previously suggested to be driven by a decline in atmospheric carbon dioxide (CO2). However, we know little about this transition in the North Atlantic Ocean. Previous studies show limited cooling of surface waters in this region. This suggests that changes in North Atlantic temperatures are not driven by CO2. To understand how sea surface temperature changes in the western North Atlantic, we analyzed the chemistry of microscopic marine fossils in sediments. Our results show a 4°C decline in temperature from the early (∼53 Ma) to the middle Eocene (∼42 Ma). This matches computer simulations of Eocene climate and confirms CO2 was responsible for the transition. The lack of cooling observed in previous work is probably due to the development of an ancient water mass known as Northern Component Water (observed today as North Atlantic Deep Water) and changes in how the Eocene ocean transported heat.
Key Points
Long‐term (∼4°C) decline in North Atlantic sea surface temperatures (SSTs) between the early (∼53–49 Ma) and middle (∼44–41 Ma) Eocene
This indicates that CO2 was likely responsible for the onset of long‐term Eocene cooling
However, east‐west temperature gradients in the North Atlantic are decoupled, possibly due to additional non‐CO2 forcing mechanisms
A prospective, double blind, randomised, placebo controlled trial over 2 years was performed to test the efficacy of alendronate, an oral aminobisphosphonate, in improving symptoms and arrest disease ...progression in patients with mild to severe ankylosing spondylitis (AS).
180 patients with AS were randomised to receive weekly alendronate 70 mg or placebo (1:1 randomisation). BAS-G was the primary outcome measure with Bath indices as secondary outcomes. Vertebral x-rays were performed at 0 and 24 months. Biomarkers (including CRP, IL-1beta, IL6, VEGF, MMP-1, and MMP-3) were collected during the first 12 months.
There was no significant difference between the placebo and treatment groups in any of the recorded outcomes over the 2 years including clinical indices, biomarkers, and radiology. The change in BAS-G, the primary outcome measure, was -0.21 for the treatment group and -0.42 for the placebo group p=0.57. Change in all other clinical outcome measures were also non-significant; BASDAI p=0.86, BASFI p=0.37, BASMI p=0.021. Sub-group analysis of those subjects with a baseline BASDAI >4 were also non-significant.
This prospective study demonstrates that alendronate 70mg weekly for 2 years was no more efficacious than placebo in improving clinical or laboratory measures of disease activity or measures of physical impact in subjects with mild to severe active AS.
ID SRCTN12308164, registered on 15.12.2015.
Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a multisystem disease, the pathogenesis of which remains undetermined. We set out to determine the precise abnormalities of gene ...expression in the blood of patients with CFS/ME. We analyzed gene expression in peripheral blood from 25 patients with CFS/ME diagnosed according to the Centers for Disease Control and Prevention diagnostic criteria and 50 healthy blood donors, using a microarray with a cutoff fold difference of expression of ⩾2.5. Genes showing differential expression were further analyzed in 55 patients with CFS/ME and 75 healthy blood donors, using quantitative polymerase chain reaction. Differential expression was confirmed for 88 genes; 85 were upregulated, and 3 were downregulated. Highly represented functions were hematological disease and function, immunological disease and function, cancer, cell death, immune response, and infection. Clustering of quantitative polymerase chain reaction data from patients with CFS/ME revealed 7 subtypes with distinct differences in Medical Outcomes Survey Short Form-36 scores, clinical phenotypes, and severity
Heterogeneous, modally banded kyanite-bearing and bimineralic eclogites from the lithospheric mantle, collected at the Roberts Victor Diamond mine (South Africa), show a reaction texture in which ...kyanite is consumed. Geothermobarometric calculations using measured mineral compositions in Perple_X allowed the construction of a P-T path showing a steep, cool prograde metamorphic gradient of 2°C/km to reach peak conditions of 5.8GPa and 890°C for the kyanite eclogite. The kyanite-out reaction formed bimineralic eclogite and is probably an integral part of the mineralogical evolution of most archetypal bimineralic eclogites at Roberts Victor and potentially elsewhere. The kyanite-out reaction occured at close to peak pressure (5.3GPa) and was associated with a rise in temperature to 1380°C. Mass balance calculations show that upon breakdown, the kyanite component is fully accommodated in garnet and omphacite via a reaction system with low water fugacity that required restricted fluid influx from metasomatic sources. The δ18O values of garnets are consistently higher than normal mantle values. Each sample has its characteristic trend of δ18O variance between garnets in the kyanite-bearing sections and those in the bimineralic parts covering a range between 5.1‰ and 6.8‰. No systematic change in O-isotope signature exists across the sample population. Differences in garnet trace element signatures between differing lithologies in the eclogites are significant. Grossular-rich garnets coexisting with kyanite have strong positive Eu-anomalies and low Gd/Yb ratios, while more pyrope-rich garnets in the bimineralic sections have lost their positive Eu-anomaly, have higher Gd/Yb ratios and generally higher heavy rare earth element contents. Garnets in the original kyanite-bearing portions thus reflect the provenance of the rocks as metamorphosed gabbros/troctolites. The kyanite-out reaction was most likely triggered by a heating event in the subcratonic lithosphere. As kyanite contains around 100ppm of H2O it is suggested that the kyanite-out reaction, once initiated by heating and restricted metasomatic influx, was promoted by the release of water contained in the kyanite. The steep (high-P low-T) prograde P-T path defining rapid compression at low heating rates is atypical for subduction transport of eclogites into the lithospheric mantle. Such a trajectory is best explained in a model where strong lateral compression forces eclogites downward to higher pressures, supporting models of cratonic lithosphere formation by lateral collision and compression.
Abstract
The Eocene (56–34 million years ago) is characterized by declining sea surface temperatures (SSTs) in the low latitudes (∼4°C) and high southern latitudes (∼8–11°C), in accord with ...decreasing CO
2
estimates. However, in the mid‐to‐high northern latitudes there is no evidence for surface water cooling, suggesting thermal decoupling between northern and southern hemispheres and additional non‐CO
2
controls. To explore this further, we present a multi‐proxy (Mg/Ca, δ
18
O, TEX
86
) SST record from Bass River in the western North Atlantic. Our compiled multi‐proxy SST record confirms a net decline in SSTs (∼4°C) between the early Eocene Climatic Optimum (53.3–49.1 Ma) and mid‐Eocene (∼44–41 Ma), supporting declining atmospheric CO
2
as the primary mechanism of Eocene cooling. However, from the mid‐Eocene onwards, east‐west North Atlantic temperature gradients exhibit different trends, which we attribute to incursion of warmer waters into the eastern North Atlantic and inception of Northern Component Water across the early‐middle Eocene transition.
Plain Language Summary
Over the past 541 million years, the Earth has oscillated between warm (greenhouse) and cold (icehouse) climates. The most recent transition between a greenhouse and icehouse climate state occurred during the Eocene (56–34 million years ago). This transition shows a gradual cooling, previously suggested to be driven by a decline in atmospheric carbon dioxide (CO
2
). However, we know little about this transition in the North Atlantic Ocean. Previous studies show limited cooling of surface waters in this region. This suggests that changes in North Atlantic temperatures are not driven by CO
2
. To understand how sea surface temperature changes in the western North Atlantic, we analyzed the chemistry of microscopic marine fossils in sediments. Our results show a 4°C decline in temperature from the early (∼53 Ma) to the middle Eocene (∼42 Ma). This matches computer simulations of Eocene climate and confirms CO
2
was responsible for the transition. The lack of cooling observed in previous work is probably due to the development of an ancient water mass known as Northern Component Water (observed today as North Atlantic Deep Water) and changes in how the Eocene ocean transported heat.
Key Points
Long‐term (∼4°C) decline in North Atlantic sea surface temperatures (SSTs) between the early (∼53–49 Ma) and middle (∼44–41 Ma) Eocene
This indicates that CO
2
was likely responsible for the onset of long‐term Eocene cooling
However, east‐west temperature gradients in the North Atlantic are decoupled, possibly due to additional non‐CO
2
forcing mechanisms
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