Summary Background The effect of different classes of antihypertensive drugs on incident diabetes mellitus is controversial because traditional meta-analyses are hindered by heterogeneity across ...trials and the absence of trials comparing angiotensin-converting-enzyme (ACE) inhibitors with angiotensin-receptor blockers (ARB). We therefore undertook a network meta-analysis, which accounts for both direct and indirect comparisons to assess the effects of antihypertensive agents on incident diabetes. Methods We undertook a systematic review up to Sept 15, 2006, and identified 48 randomised groups of 22 clinical trials with 143 153 participants who did not have diabetes at randomisation and so were eligible for inclusion in our analysis. 17 trials enrolled patients with hypertension, three enrolled high-risk patients, and one enrolled those with heart failure. The main outcome was the proportion of patients who developed diabetes. Findings Intitial drug therapy used in the trials (and the number of patients with diabetes of the total number at risk) included: an ARB (1189 of 14 185, or 8·38%), ACE inhibitor (1618 of 22 941, or 7·05%), calcium-channel blocker (CCB, 2791 of 38 607, or 7·23%), placebo (1686 of 24 767, or 6·81%), β blocker (2705 of 35 745, or 7·57%), or diuretic (998 of 18 699, or 5·34%). With an initial diuretic as the standard of comparison (eight groups), the degree of incoherence (a measure of how closely the entire network fits together) was small (ω=0·000017, eight degrees of freedom). The odds ratios were: ARB (five groups) 0·57 (95% CI 0·46–0·72, p<0·0001); ACE inhibitor (eight groups) 0·67 (0·56–0·80, p<0·0001); CCB (nine groups): 0·75 (0·62–0·90, p=0·002); placebo (nine groups) 0·77 (0·63-0·94, p = 0·009); β blocker (nine groups) 0·90 (0·75-1·09, p=0·30). These estimates changed little in many sensitivity analyses. Interpretation The association of antihypertensive drugs with incident diabetes is therefore lowest for ARB and ACE inhibitors followed by CCB and placebo, β blockers and diuretics in rank order.
Summary
B‐cell depletion induced by anti‐cluster of differentiation 20 (CD20) monoclonal antibody (mAb) therapy of patients with lymphoma is expected to impair humoral responses to severe acute ...respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) vaccination, but effects on CD8 T‐cell responses are unknown. Here, we investigated humoral and CD8 T‐cell responses following two vaccinations in patients with lymphoma undergoing anti‐CD20‐mAb therapy as single agent or in combination with chemotherapy or other anti‐neoplastic agents during the last 9 months prior to inclusion, and in healthy age‐matched blood donors. Antibody measurements showed that seven of 110 patients had antibodies to the receptor‐binding domain of the SARS‐CoV‐2 Spike protein 3–6 weeks after the second dose of vaccination. Peripheral blood CD8 T‐cell responses against prevalent human leucocyte antigen (HLA) class I SARS‐CoV‐2 epitopes were determined by peptide‐HLA multimer analysis. Strong CD8 T‐cell responses were observed in samples from 20/29 patients (69%) and 12/16 (75%) controls, with similar median response magnitudes in the groups and some of the strongest responses observed in patients. We conclude that despite the absence of humoral immune responses in fully SARS‐CoV‐2‐vaccinated, anti‐CD20‐treated patients with lymphoma, their CD8 T‐cell responses reach similar frequencies and magnitudes as for controls. Patients with lymphoma on B‐cell depleting therapies are thus likely to benefit from current coronavirus disease 2019 (COVID‐19) vaccines, and development of vaccines aimed at eliciting T‐cell responses to non‐Spike epitopes might provide improved protection.
Green thumbs…︁up? We look at the current state‐of‐the‐art use of biocatalysis and biotechnology to deliver more sustainable manufacturing across a range of industries that use applied chemistry. This ...is the output from a series of presentations and a workshop held at EcoChem 2013 with contributors from pharmaceuticals, bulk chemicals, and flavor and fragrances industries, biocatalyst suppliers, synthetic biology innovator companies, and leading academics.
One of the fundamental questions about human language is whether all languages are equally complex. Here, we approach this question from an information-theoretic perspective. We present a large scale ...quantitative cross-linguistic analysis of written language by training a language model on more than 6500 different documents as represented in 41 multilingual text collections consisting of ~ 3.5 billion words or ~ 9.0 billion characters and covering 2069 different languages that are spoken as a native language by more than 90% of the world population. We statistically infer the entropy of each language model as an index of what we call average prediction complexity. We compare complexity rankings across corpora and show that a language that tends to be more complex than another language in one corpus also tends to be more complex in another corpus. In addition, we show that speaker population size predicts entropy. We argue that both results constitute evidence against the equi-complexity hypothesis from an information-theoretic perspective.
Where are Europe's last primary forests? Sabatini, Francesco Maria; Burrascano, Sabina; Keeton, William S. ...
Diversity & distributions,
October 2018, Volume:
24, Issue:
9/10
Journal Article
Peer reviewed
Open access
Aim: Primary forests have high conservation value but are rare in Europe due to historic land use. Yet many primary forest patches remain unmapped, and it is unclear to what extent they are ...effectively protected. Our aim was to (1) compile the most comprehensive European-scale map of currently known primary forests, (2) analyse the spatial determinants characterizing their location and (3) locate areas where so far unmapped primary forests likely occur. Location: Europe. Methods: We aggregated data from a literature review, online questionnaires and 32 datasets of primary forests. We used boosted regression trees to explore which biophysical, socio-economic and forest-related variables explain the current distribution of primary forests. Finally, we predicted and mapped the relative likelihood of primary forest occurrence at a 1-km resolution across Europe. Results: Data on primary forests were frequently incomplete or inconsistent among countries. Known primary forests covered 1.4 Mha in 32 countries (0.7% of Europe's forest area). Most of these forests were protected (89%), but only 46% of them strictly. Primary forests mostly occurred in mountain and boreal areas and were unevenly distributed across countries, biogeographical regions and forest types. Unmapped primary forests likely occur in the least accessible and populated areas, where forests cover a greater share of land, but wood demand historically has been low. Main conclusions: Despite their outstanding conservation value, primary forests are rare and their current distribution is the result of centuries of land use and forest management. The conservation outlook for primary forests is uncertain as many are not strictly protected and most are small and fragmented, making them prone to extinction debt and human disturbance. Predicting where unmapped primary forests likely occur could guide conservation efforts, especially in Eastern Europe where large areas of primary forest still exist but are being lost at an alarming pace.
Cleavage of membrane-anchored proteins by ADAM (a disintegrin and metalloproteinase) endopeptidases plays a key role in a wide variety of biological signal transduction and protein turnover ...processes. Among ADAM family members, ADAM10 stands out as particularly important because it is both responsible for regulated proteolysis of Notch receptors and catalyzes the non-amyloidogenic α-secretase cleavage of the Alzheimer’s precursor protein (APP). We present here the X-ray crystal structure of the ADAM10 ectodomain, which, together with biochemical and cellular studies, reveals how access to the enzyme active site is regulated. The enzyme adopts an unanticipated architecture in which the C-terminal cysteine-rich domain partially occludes the enzyme active site, preventing unfettered substrate access. Binding of a modulatory antibody to the cysteine-rich domain liberates the catalytic domain from autoinhibition, enhancing enzymatic activity toward a peptide substrate. Together, these studies reveal a mechanism for regulation of ADAM activity and offer a roadmap for its modulation.
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•We report an X-ray structure of the ectodomain of the α-secretase ADAM10•Access to the active site is partially occluded by a C-terminal regulatory domain•A modulatory antibody that binds the regulatory region liberates the active site•Catalytically inactive forms of ADAM10 exhibit dominant-negative activity
The X-ray structure of the ADAM10 ectodomain, together with biochemical and cell-based studies, reveals mechanistic insights into its enzymatic function in Notch signaling and in processing of the Alzheimer's precursor protein APP.
•Single crystals of Li2FeSiO4 have been successfully grown by the FZ method with optical heating at high Ar pressure.•Different polymorphs of Li2FeSiO4 are obtained at the same conditions from ...different starting materials.•The steep temperature gradient at the solid-liquid interface stabilizes the formation of the Pmnb phase.•Relevant parameters for successful growth are discussed.
The high-pressure optical floating-zone method enables single crystal growth of the Pmnb high-temperature phase of Li2FeSiO4. The influence of growth conditions on crystal quality, phase homogeneity, and impurity formation in Li2FeSiO4 is studied. The use of different starting materials, i.e., either the P121/n1 or the Pmn21 polymorph, as well as optimization of various growth conditions is investigated. Several mm3-sized high-quality single crystals are obtained by the choice of the Pmn21 polymorph as the starting material. A general challenge of Li2FeSiO4 crystal growth is polymorph control during crystallization. While the temperature gradient at the solid-liquid interface seems to have significant impact on stabilizing the Pmnb high-temperature phase, growth velocity has no evident effect.
Background: literature on last mile logistic electrification has primarily focused either on the stakeholder interactions defining urban rules and policies for urban freight or on the technical ...aspects of the logistic EVs. Methods: the article incorporates energy sourcing, vehicles, logistics operation, and digital cloud environment, aiming at economic and functional viability. Using a combination of engineering and business modeling combined with the unique opportunity of the actual insights from Europe’s largest tender in the automotive aftermarket electrification. Results: the Last Mile Logistics (LML) electrification is possible and profitable without jeopardizing the high-tempo deliveries. Critical asset identification for a viable transition to EVs leads to open new lines of research for future logistic dynamics rendered possible by the digital dimensions of the logistic ecosystem. Conclusions: beyond the unquestionable benefits for the environment, the electrification of the LML constitutes an opportunity to enhance revenue and diversify income.
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