Acropolis Educational Resources Repository
Not a member yet
31278 research outputs found
Sort by
Doxycycline for community treatment of suspected COVID-19 in people at high risk of adverse outcomes in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial
No full textBackground
Doxycycline is often used for treating COVID-19 respiratory symptoms in the community despite an absence of evidence from clinical trials to support its use. We aimed to assess the efficacy of doxycycline to treat suspected COVID-19 in the community among people at high risk of adverse outcomes.
Methods
We did a national, open-label, multi-arm, adaptive platform randomised trial of interventions against COVID-19 in older people (PRINCIPLE) across primary care centres in the UK. We included people aged 65 years or older, or 50 years or older with comorbidities (weakened immune system, heart disease, hypertension, asthma or lung disease, diabetes, mild hepatic impairment, stroke or neurological problem, and self-reported obesity or body-mass index of 35 kg/m2 or greater), who had been unwell (for ≤14 days) with suspected COVID-19 or a positive PCR test for SARS-CoV-2 infection in the community. Participants were randomly assigned using response adaptive randomisation to usual care only, usual care plus oral doxycycline (200 mg on day 1, then 100 mg once daily for the following 6 days), or usual care plus other interventions. The interventions reported in this manuscript are usual care plus doxycycline and usual care only; evaluations of other interventions in this platform trial are ongoing. The coprimary endpoints were time to first self-reported recovery, and hospitalisation or death related to COVID-19, both measured over 28 days from randomisation and analysed by intention to treat. This trial is ongoing and is registered with ISRCTN, 86534580.
Findings
The trial opened on April 2, 2020. Randomisation to doxycycline began on July 24, 2020, and was stopped on Dec 14, 2020, because the prespecified futility criterion was met; 2689 participants were enrolled and randomised between these dates. Of these, 2508 (93·3%) participants contributed follow-up data and were included in the primary analysis: 780 (31·1%) in the usual care plus doxycycline group, 948 in the usual care only group (37·8%), and 780 (31·1%) in the usual care plus other interventions group. Among the 1792 participants randomly assigned to the usual care plus doxycycline and usual care only groups, the mean age was 61·1 years (SD 7·9); 999 (55·7%) participants were female and 790 (44·1%) were male. In the primary analysis model, there was little evidence of difference in median time to first self-reported recovery between the usual care plus doxycycline group and the usual care only group (9·6 [95% Bayesian Credible Interval [BCI] 8·3 to 11·0] days vs 10·1 [8·7 to 11·7] days, hazard ratio 1·04 [95% BCI 0·93 to 1·17]). The estimated benefit in median time to first self-reported recovery was 0·5 days [95% BCI −0·99 to 2·04] and the probability of a clinically meaningful benefit (defined as ≥1·5 days) was 0·10. Hospitalisation or death related to COVID-19 occurred in 41 (crude percentage 5·3%) participants in the usual care plus doxycycline group and 43 (4·5%) in the usual care only group (estimated absolute percentage difference −0·5% [95% BCI −2·6 to 1·4]); there were five deaths (0·6%) in the usual care plus doxycycline group and two (0·2%) in the usual care only group.
Interpretation
In patients with suspected COVID-19 in the community in the UK, who were at high risk of adverse outcomes, treatment with doxycycline was not associated with clinically meaningful reductions in time to recovery or hospital admissions or deaths related to COVID-19, and should not be used as a routine treatment for COVID-19.
Funding
UK Research and Innovation, Department of Health and Social Care, National Institute for Health Research
Relationships between psoriatic arthritis composite measures of disease activity with patient-reported outcomes in Phase 3 studies of tofacitinib
No full textBackground: In psoriatic arthritis (PsA), further understanding of relationships between clinical measures and patient-reported outcomes (PROs) is needed. This post hoc analysis evaluated associations between minimal disease activity (MDA) as a continuous outcome (termed ScoreMDA) or Psoriatic Arthritis Disease Activity Score (PASDAS) with selected PROs not included in the composite measures.
Methods: Data from two Phase 3 studies of tofacitinib in PsA (OPAL Broaden [NCT01877668; N=422]; OPAL Beyond [NCT01882439; N=394]) were included. MDA (binary outcome) was defined as meeting ≥5/7 criteria. For ScoreMDA, each criterion was assigned a value (1=true; 0=false; score range, 0–7; scores ≥5 indicated MDA). For PASDAS (score range, 0–10), higher scores indicated worse disease activity. PROs analyzed included Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Patient’s Assessment of Arthritis Pain visual analog scale (Pain VAS), and EuroQoL-Five Dimensions-Three Level Health Questionnaire visual analog scale (EQ-5D-3L VAS) and utility index. Relationships were evaluated using repeated measures regression models.
Results: Similar, approximately linear relationships were confirmed between PASDAS or ScoreMDA and PROs in both studies. In OPAL Broaden and OPAL Beyond, respectively, a one-point difference in PASDAS was associated with clinically relevant differences in PROs, including EQ-5D-3L VAS (-6.7 mm, -6.9 mm), Pain VAS (9.9 mm, 10.7 mm), and FACIT-F (-2.8, -3.3). A one-point difference in ScoreMDA was associated with clinically relevant
differences in PROs, including EQ-5D-3L VAS (5.0 mm, 5.5 mm) and FACIT-F (1.9, 2.7) in OPAL Broaden and OPAL Beyond, respectively.
Conclusions: Linear associations between PASDAS or ScoreMDA and PROs provide interpretable and quantifiable metrics between composite clinical measures and PROs, highlighting the importance of these measures in understanding the relevance of treat-to-target goals in PsA
Safety and immunogenicity of heterologous versus homologous prime-boost schedules with an adenoviral vectored and mRNA COVID-19 vaccine (Com-COV): a single-blind, randomised, non-inferiority trial
No full textBackground
Use of heterologous prime-boost COVID-19 vaccine schedules could facilitate mass COVID-19 immunisation. However, we have previously reported that heterologous schedules incorporating an adenoviral vectored vaccine (ChAdOx1 nCoV-19, AstraZeneca; hereafter referred to as ChAd) and an mRNA vaccine (BNT162b2, Pfizer–BioNTech; hereafter referred to as BNT) at a 4-week interval are more reactogenic than homologous schedules. Here, we report the safety and immunogenicity of heterologous schedules with the ChAd and BNT vaccines.
Methods
Com-COV is a participant-blinded, randomised, non-inferiority trial evaluating vaccine safety, reactogenicity, and immunogenicity. Adults aged 50 years and older with no or well controlled comorbidities and no previous SARS-CoV-2 infection by laboratory confirmation were eligible and were recruited at eight sites across the UK. The majority of eligible participants were enrolled into the general cohort (28-day or 84-day prime-boost intervals), who were randomly assigned (1:1:1:1:1:1:1:1) to receive ChAd/ChAd, ChAd/BNT, BNT/BNT, or BNT/ChAd, administered at either 28-day or 84-day prime-boost intervals. A small subset of eligible participants (n=100) were enrolled into an immunology cohort, who had additional blood tests to evaluate immune responses; these participants were randomly assigned (1:1:1:1) to the four schedules (28-day interval only). Participants were masked to the vaccine received but not to the prime-boost interval. The primary endpoint was the geometric mean ratio (GMR) of serum SARS-CoV-2 anti-spike IgG concentration (measured by ELISA) at 28 days after boost, when comparing ChAd/BNT with ChAd/ChAd, and BNT/ChAd with BNT/BNT. The heterologous schedules were considered non-inferior to the approved homologous schedules if the lower limit of the one-sided 97·5% CI of the GMR of these comparisons was greater than 0·63. The primary analysis was done in the per-protocol population, who were seronegative at baseline. Safety analyses were done among participants receiving at least one dose of a study vaccine. The trial is registered with ISRCTN, 69254139.
Findings
Between Feb 11 and Feb 26, 2021, 830 participants were enrolled and randomised, including 463 participants with a 28-day prime-boost interval, for whom results are reported here. The mean age of participants was 57·8 years (SD 4·7), with 212 (46%) female participants and 117 (25%) from ethnic minorities. At day 28 post boost, the geometric mean concentration of SARS-CoV-2 anti-spike IgG in ChAd/BNT recipients (12 906 ELU/mL) was non-inferior to that in ChAd/ChAd recipients (1392 ELU/mL), with a GMR of 9·2 (one-sided 97·5% CI 7·5 to ∞). In participants primed with BNT, we did not show non-inferiority of the heterologous schedule (BNT/ChAd, 7133 ELU/mL) against the homologous schedule (BNT/BNT, 14 080 ELU/mL), with a GMR of 0·51 (one-sided 97·5% CI 0·43 to ∞). Four serious adverse events occurred across all groups, none of which were considered to be related to immunisation.
Interpretation
Despite the BNT/ChAd regimen not meeting non-inferiority criteria, the SARS-CoV-2 anti-spike IgG concentrations of both heterologous schedules were higher than that of a licensed vaccine schedule (ChAd/ChAd) with proven efficacy against COVID-19 disease and hospitalisation. Along with the higher immunogenicity of ChAd/BNT compared with ChAD/ChAd, these data support flexibility in the use of heterologous prime-boost vaccination using ChAd and BNT COVID-19 vaccines.
Funding
UK Vaccine Task Force and National Institute for Health Research
A common space approach to comparative neuroscience
No full textComparative neuroscience is entering the era of big data. New high-throughput methods and data-sharing initiatives have resulted in the availability of large, digital data sets containing many types of data from ever more species. Here, we present a framework for exploiting the new possibilities offered. The multimodality of the data allows vertical translations, which are comparisons of different aspects of brain organization within a single species and across scales. Horizontal translations compare particular aspects of brain organization across species, often by building abstract feature spaces. Combining vertical and horizontal translations allows for more sophisticated comparisons, including relating principles of brain organization across species by contrasting horizontal translations, and for making formal predictions of unobtainable data based on observed results in a model species
‘One must know how to dance’: Vicki Baum’s Menschen im Hotel (1929), Edmund Goulding’s Grand Hotel (1932), and a choreography of social responses
No full textResearch priorities for Long Covid: refined through an international multi-stakeholder forum
No full textCoronavirus disease 2019 (COVID-19) can lead to a diverse range of clinical manifestations, ranging from an asymptomatic infection to an acute respiratory distress syndrome, and multiorgan failure with high mortality rates. It is established that SARS-CoV-2 not only infects the respiratory tract but that the ensuing viral replication and immune response also affects multiple organ systems, in addition to an acute systemic inflammatory response and in some cases accompanying tissue hypoxia and shock.
While many who have been infected have uncomplicated recoveries, some have prolonged illness. Prolonged course of illness has been reported in adults and children and is affecting both those who were hospitalised with COVID-19 and those who were not.
In December 2020 ISARIC (the International Severe Acute Respiratory and emerging Infection Consortium), the research funders group GloPID-R (The Global Research Collaboration for Infectious Disease Preparedness) and global group, Long Covid Support, jointly organised a ‘Long Covid Forum’. This public forum aimed to gain a better understanding of ‘Long Covid’ and to define research priorities for funders and researchers to take forward
Panderodus from the Waukesha Lagerstätte of Wisconsin, USA – a primitive macrophagous vertebrate predator
No full textConodonts are an extinct group of early vertebrates. Articulated fossils of their feeding apparatus (‘natural assemblages’) are rare, and preserved soft tissues vanishingly so. Here, a primitive conodont with preserved soft tissues is redescribed from the Waukesha Lagerstätte of Wisconsin, USA. Although the feeding apparatus of derived prioniodontid conodonts is well understood, together with the homologies between taxa, the same is not true of more primitive conodonts that have apparatuses composed entirely of coniform elements. The new data provide insights into the long-term problem of determining homology across different types of conodont feeding apparatus. The Waukesha Panderodus preserves an almost complete apparatus, consisting of two parallel rows of elements that occluded across the sagittal plane. A pair of M elements lies at the rostral end of the apparatus, with four pairs of S elements located immediately caudal to them. Three pairs of P elements are identified at the caudal end of the apparatus, for the first time in a primitive conodont with coniform elements. A symmetrical S0 element is located on the midline between the M–S and P suites and provides the key for establishing homology with more derived ramiform–pectiniform apparatuses. The exceptional preservation reveals cartilaginous supports for the elements that inserted into their basal cavities. The trunk of the animal is poorly preserved but was dorsoventrally flattened in life with transverse myomeres containing muscle fibrils. Overall, the specimen shows that Panderodus was a macrophagous feeder and provides an insight into the functional anatomy of early vertebrate predation
A haemagglutination test for rapid detection of antibodies to SARS-CoV-2
No full textSerological detection of antibodies to SARS-CoV-2 is essential for establishing rates of seroconversion in populations, and for seeking evidence for a level of antibody that may be protective against COVID-19 disease. Several high-performance commercial tests have been described, but these require centralised laboratory facilities that are comparatively expensive, and therefore not available universally. Red cell agglutination tests do not require special equipment, are read by eye, have short development times, low cost and can be applied at the Point of Care. Here we describe a quantitative Haemagglutination test (HAT) for the detection of antibodies to the receptor binding domain of the SARS-CoV-2 spike protein. The HAT has a sensitivity of 90% and specificity of 99% for detection of antibodies after a PCR diagnosed infection. We will supply aliquots of the test reagent sufficient for ten thousand test wells free of charge to qualified research groups anywhere in the world
COVID‐19 and education: restructuring after the pandemic
No full textCOVID‐19 challenges to keep a valuable educational offer with lockdown measures and social distancing are reviewed. Scientific Societies had to think of new alternatives to maintain meetings with conversion to a virtual format and development of online resources, rapidly available and broadly accessible. Other in person activities as face‐to‐face clinics have been substituted by telemedicine; the same happened with surgical training in theatre, given the suspension of most of the operations. Finally, the need to share and communicate in a continuous evolving scenario, has impacted negatively the integrity of peer review process, not following the normal procedures to ensure scientific integrity and reproducibility in the earliest phases of the pandemic