29 research outputs found
Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial
Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome
Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial
Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome
Enthalpy and Heat Capacity Changes for Formation of an Oligomeric DNA Duplex: Interpretation in Terms of Coupled Processes of Formation and Association of Single-Stranded Helices â€
Thermodynamic Characterization of Interactions of Native Bovine Serum Albumin with Highly Excluded (Glycine Betaine) and Moderately Accumulated (Urea) Solutes by a Novel Application of Vapor Pressure Osmometry â€
Quantifying Additive Interactions of the Osmolyte Proline with Individual Functional Groups of Proteins: Comparisons with Urea and Glycine Betaine, Interpretation of <i>m</i>‑Values
To quantify interactions of the osmolyte l-proline with
protein functional groups and predict their effects on protein processes,
we use vapor pressure osmometry to determine chemical potential derivatives
dμ<sub>2</sub>/d<i>m</i><sub>3</sub> = μ<sub>23</sub>, quantifying the preferential interactions of proline (component
3) with 21 solutes (component 2) selected to display different combinations
of aliphatic or aromatic C, amide, carboxylate, phosphate or hydroxyl
O, and amide or cationic N surface. Solubility data yield μ<sub>23</sub> values for four less-soluble solutes. Values of μ<sub>23</sub> are dissected using an ASA-based analysis to test the hypothesis
of additivity and obtain α-values (proline interaction potentials)
for these eight surface types and three inorganic ions. Values of
μ<sub>23</sub> predicted from these α-values agree with
the experiment, demonstrating additivity. Molecular interpretation
of α-values using the solute partitioning model yields partition
coefficients (<i>K</i><sub>p</sub>) quantifying the local
accumulation or exclusion of proline in the hydration water of each
functional group. Interactions of proline with native protein surfaces
and effects of proline on protein unfolding are predicted from α-values
and ASA information and compared with experimental data, with results
for glycine betaine and urea, and with predictions from transfer free
energy analysis. We conclude that proline stabilizes proteins because
of its unfavorable interactions with (exclusion from) amide oxygens
and aliphatic hydrocarbon surfaces exposed in unfolding and that proline
is an effective in vivo osmolyte because of the osmolality increase
resulting from its unfavorable interactions with anionic (carboxylate
and phosphate) and amide oxygens and aliphatic hydrocarbon groups
on the surface of cytoplasmic proteins and nucleic acids
Fluorescence Resonance Energy Transfer Characterization of DNA Wrapping in Closed and Open <i>Escherichia coli</i> RNA Polymerase−λP<sub>R</sub> Promoter Complexes
Initial
recognition of promoter DNA by RNA polymerase (RNAP) is
proposed to trigger a series of conformational changes beginning with
bending and wrapping of the 40–50 bp of DNA immediately upstream
of the −35 region. Kinetic studies demonstrated that the presence
of upstream DNA facilitates bending and entry of the downstream duplex
(to +20) into the active site cleft to form an advanced closed complex
(CC), prior to melting of ∼13 bp (−11 to +2), including
the transcription start site (+1). Atomic force microscopy and footprinting
revealed that the stable open complex (OC) is also highly wrapped
(−60 to +20). To test the proposed bent-wrapped model of duplex
DNA in an advanced RNAP−λP<sub>R</sub> CC and compare
wrapping in the CC and OC, we use fluorescence resonance energy transfer
(FRET) between cyanine dyes at far-upstream (−100) and downstream
(+14) positions of promoter DNA. Similarly large intrinsic FRET efficiencies
are observed for the CC (0.30 ± 0.07) and the OC (0.32 ±
0.11) for both probe orientations. Fluorescence enhancements at +14
are observed in the single-dye-labeled CC and OC. These results demonstrate
that upstream DNA is extensively wrapped and the start site region
is bent into the cleft in the advanced CC, reducing the distance between
positions −100 and +14 on promoter DNA from >300 to <100
Ã…. The proximity of upstream DNA to the downstream cleft in the
advanced CC is consistent with the proposed mechanism for facilitation
of OC formation by upstream DNA
Is there more than one proctitis syndrome? A revisitation using data from the TROG 96.01 trial
Purpose: We sought to categorize longitudinal radiation-induced rectal toxicity data obtained from men participating in a randomised controlled trial for locally advanced prostate cancer. Materials and methods: Data from self-assessed questionnaires of rectal symptoms and clinician recorded remedial interventions were collected during the TROG 96.01 trial. In this trial, volunteers were randomised to radiation with or without neoadjuvant androgen deprivation. Characterization of longitudinal variations in symptom intensity was achieved using prevalence data. An integrated visualization and clustering approach based on memetic algorithms was used to define the compositions of symptom clusters occurring before, during and after radiation. The utility of the CTC grading system as a means of identifying specific injury profiles was evaluated using concordance analyses. Results: Seven well-defined clusters of rectal symptoms were present prior to treatment, 25 were seen immediately following radiation and 7 at years 1, 2 and 3 following radiation. CTC grading did not concord with the degree of rectal ‘distress’ and ‘problems’ at all time points. Concordance was not improved by adding urgency to the CTC scale. Conclusions: The CTC scale has serious shortcomings. A powerful new technique for non-hierarchical clustering may contribute to the categorization of rectal toxicity data for genomic profiling studies and detailed patho-physiological studies