Evaluation of lightweight fibreglass heel casts in the management of ulcers of the heel in diabetes: study protocol for a randomised controlled trial

BackgroundUlcers of the heel in diabetes are the source of considerable suffering and cost. In the absence of specific treatments, it has been suggested that removable, lightweight fibreglass heel casts may both promote healing and reduce discomfort and pain. The aim of the study is to assess the effectiveness and cost-effectiveness of fibreglass heel casts in the management of heel ulcers.Methods/DesignThis is an observer-blind, randomised controlled trial in which participants with diabetes and heel ulcers (NPUAP/EPUAP grades 2, 3 or 4 and present for 2 or more weeks) are randomised to receive either usual care plus lightweight fibreglass heel casts or usual care alone. Randomisation is undertaken by random number sequence generation incorporated as part of the electronic case record form, and is stratified by both ulcer area (less than versus equal to or greater than 1 cm2) and NPUAP/EPUAP grade. Participants are followed every two weeks until healing or for 24 weeks. The primary outcome measure is healing at or before 24 weeks and maintained for 4 weeks. Secondary outcomes include (i) ulcer-related outcomes: time to healing, change in ulcer area, minor and major amputation, secondary infection and (ii) patient-related outcomes: local pain, mood and function (EQ-5D), impact of the ulcer (Cardiff Wound Impact Schedule) and survival. Cost-effectiveness will be assessed using a decision analytic model to estimate costs from the perspective of the UK NHS and personal social services and health outcomes, including percent healing and Quality Adjusted Life Years gained.Safety will be documented as adverse and serious adverse device effects.DiscussionIf it is possible to confirm significant clinical benefit and/or cost-effectiveness, this would have direct implications for the management of this distressing and costly complication of diabete

Mapping the human genetic architecture of COVID-19

Matters Arising to this article was published on 03 August 2022, available online at: https://doi.org/10.1038/s41586-022-04826-7 . A second Matters Arising to this article was published on 06 September 2023, available online at: https://doi.org/10.1038/s41586-023-06355-3 .Data availability: Summary statistics generated by the COVID-19 HGI are available at https://www.covid19hg.org/results/r5/ and are available in the GWAS Catalog (study code GCST011074). The analyses described here include the freeze-5 data. COVID-19 HGI continues to regularly release new data freezes. Summary statistics for non-European ancestry samples are not currently available due to the small individual sample sizes of these groups, but results for lead variants of 13 loci are reported in Supplementary Table 3. Individual level data can be requested directly from contributing studies, listed in Supplementary Table 1. We used publicly available data from GTEx (https://gtexportal.org/home/), the Neale lab (https://www.nealelab.is/uk-biobank/), Finucane lab (https://www.finucanelab.org), the FinnGen Freeze 4 cohort (https://www.finngen.fi/en/access_results) and the eQTL catalogue release 3 (https://www.ebi.ac.uk/eqtl/).Code availability: The code for summary statistics lift-over, the projection PCA pipeline including precomputed loadings and meta-analyses are available on GitHub (https://github.com/covid19-hg/) and the code for the Mendelian randomization and genetic correlation pipeline is available on GitHub at https://github.com/marcoralab/MRcovid.Reporting summary: Further information on research design is available in the Nature Research Reporting Summary linked to this paper online at: https://www.nature.com/articles/s41586-021-03767-x#MOESM2 .Supplementary information is available onlne at: https://www.nature.com/articles/s41586-021-03767-x#Sec24 .Extended data figures and tables are available online at: https://www.nature.com/articles/s41586-021-03767-x#Sec23 .Copyright © The Author(s) 2021. The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3–7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease

Safety, immunogenicity, and reactogenicity of BNT162b2 and mRNA-1273 COVID-19 vaccines given as fourth-dose boosters following two doses of ChAdOx1 nCoV-19 or BNT162b2 and a third dose of BNT162b2 (COV-BOOST): a multicentre, blinded, phase 2, randomised trial

Background Some high-income countries have deployed fourth doses of COVID-19 vaccines, but the clinical need, effectiveness, timing, and dose of a fourth dose remain uncertain. We aimed to investigate the safety, reactogenicity, and immunogenicity of fourth-dose boosters against COVID-19.Methods The COV-BOOST trial is a multicentre, blinded, phase 2, randomised controlled trial of seven COVID-19 vaccines given as third-dose boosters at 18 sites in the UK. This sub-study enrolled participants who had received BNT162b2 (Pfizer-BioNTech) as their third dose in COV-BOOST and randomly assigned them (1:1) to receive a fourth dose of either BNT162b2 (30 µg in 0·30 mL; full dose) or mRNA-1273 (Moderna; 50 µg in 0·25 mL; half dose) via intramuscular injection into the upper arm. The computer-generated randomisation list was created by the study statisticians with random block sizes of two or four. Participants and all study staff not delivering the vaccines were masked to treatment allocation. The coprimary outcomes were safety and reactogenicity, and immunogenicity (antispike protein IgG titres by ELISA and cellular immune response by ELISpot). We compared immunogenicity at 28 days after the third dose versus 14 days after the fourth dose and at day 0 versus day 14 relative to the fourth dose. Safety and reactogenicity were assessed in the per-protocol population, which comprised all participants who received a fourth-dose booster regardless of their SARS-CoV-2 serostatus. Immunogenicity was primarily analysed in a modified intention-to-treat population comprising seronegative participants who had received a fourth-dose booster and had available endpoint data. This trial is registered with ISRCTN, 73765130, and is ongoing.Findings Between Jan 11 and Jan 25, 2022, 166 participants were screened, randomly assigned, and received either full-dose BNT162b2 (n=83) or half-dose mRNA-1273 (n=83) as a fourth dose. The median age of these participants was 70·1 years (IQR 51·6–77·5) and 86 (52%) of 166 participants were female and 80 (48%) were male. The median interval between the third and fourth doses was 208·5 days (IQR 203·3–214·8). Pain was the most common local solicited adverse event and fatigue was the most common systemic solicited adverse event after BNT162b2 or mRNA-1273 booster doses. None of three serious adverse events reported after a fourth dose with BNT162b2 were related to the study vaccine. In the BNT162b2 group, geometric mean anti-spike protein IgG concentration at day 28 after the third dose was 23 325 ELISA laboratory units (ELU)/mL (95% CI 20 030–27 162), which increased to 37 460 ELU/mL (31 996–43 857) at day 14 after the fourth dose, representing a significant fold change (geometric mean 1·59, 95% CI 1·41–1·78). There was a significant increase in geometric mean anti-spike protein IgG concentration from 28 days after the third dose (25 317 ELU/mL, 95% CI 20 996–30 528) to 14 days after a fourth dose of mRNA-1273 (54 936 ELU/mL, 46 826–64 452), with a geometric mean fold change of 2·19 (1·90–2·52). The fold changes in anti-spike protein IgG titres from before (day 0) to after (day 14) the fourth dose were 12·19 (95% CI 10·37–14·32) and 15·90 (12·92–19·58) in the BNT162b2 and mRNA-1273 groups, respectively. T-cell responses were also boosted after the fourth dose (eg, the fold changes for the wild-type variant from before to after the fourth dose were 7·32 [95% CI 3·24–16·54] in the BNT162b2 group and 6·22 [3·90–9·92] in the mRNA-1273 group).Interpretation Fourth-dose COVID-19 mRNA booster vaccines are well tolerated and boost cellular and humoral immunity. Peak responses after the fourth dose were similar to, and possibly better than, peak responses after the third dose

Lexical priming of function words and content words with children who do, and do not, stutter

The specific mechanisms that underlie childhood stuttering are not fully understood. The current study investigated these mechanisms by comparing the effect on fluency of priming different components of a short sentence. The main findings were that: (1) both children who stutter (CWS) (n = 12, M age = 6;3) and children who do not stutter (CWNS) (n = 12, M age = 6;6) were more fluent after function word (FW) priming than content word (CW) priming, (2) this effect was significantly greater for CWS than for CWNS, and (3) after FW priming, CWS produced CWs with significantly longer duration than did CWNS. These findings are discussed in relation to two competing theories of stuttering: the covert repair hypothesis (CRH) [Kolk, H., & Postma, A. (1997). Stuttering as a covert repair phenomenon. In R. F. Curlee & G. M. Siegel (Eds.), Nature and treatments of stuttering: New directions (pp. 182–203). Needham Heights, MA: Allyn & Bacon] and the developmentally focused model of Howell and Au-Yeung [Howell, P., & Au-Yeung, J. (2002). The EXPLAN theory of fluency control and the diagnosis of stuttering. In E. Fava (Ed.), Current issues in linguistic theory series: Pathology and therapy of speech disorders (pp. 75–94). Amsterdam: John Benjamins]

Lexical priming of function words and content words with children who do, and do not, stutter

Abstract The specific mechanisms that underlie childhood stuttering are not fully understood. The current study investigated these mechanisms by comparing the effect on fluency of priming different components of a short sentence. The main findings were that: (1) both children who stutter (CWS) (n = 12, M age = 6;3) and children who do not stutter (CWNS) (n = 12, M age = 6;6) were more fluent after function word (FW) priming than content word (CW) priming, (2) this effect was significantly greater for CWS than for CWNS, and (3) after FW priming, CWS produced CWs with significantly longer duration than did CWNS. These findings are discussed in relation to two competing theories of stuttering: the covert repair hypothesi

Can the usage-based approach to language development be applied to analysis of developmental stuttering?

The usage-based approach to language development suggests that children initially build up their language through very concrete constructions based around individual words or frames on the basis of the speech they hear and use. These constructions gradually become more general and more abstract during the third and fourth year of life. We outline this approach and suggest that it may be applied to problems of fluency control in early child language development

Intérêt de la spectrométrie de masse par désorption-ionisation laser assistée par matrice dans la comparaison de souches de staphylocoques à coagulase négative

Les staphylocoques à coagulase négative (SCN) sont les espèces majoritaires de la flore commensale cutanée. Dans des situations d immuno-dépression ou en présence de matériels étrangers, les SCN sont à l origine d infections caractérisées par une morbidité et une mortalité importantes. La distinction entre les situations de contamination et celles d infections n est pas toujours aisée et seule la mise en évidence d un lien de clonalité entre les souches est en faveur d une infection. Pour cela, les techniques de biologie moléculaire, dont la méthodologie est lourde et coûteuse, sont souvent utilisées. Récemment, la spectrométrie de masse par Désorption/Ionisation assistée par matrice (MALDI-TOF) a été utilisée comme méthode d identification bactérienne. Dans notre étude, nous avons évalué la capacité de cette technique à comparer les souches de SCN provenant de patients hospitalisés à l hôpital Necker entre 2005 et 2006 et les résultats ont été confrontés à ceux de l électrophorèse en champ pulsé, technique génotypique de comparaison des souches. Les résultats ont montré qu il est possible par MALDI-TOF de différencier les souches génotypiquement liées des autres. Néanmoins, ces résultats nécessitent l analyse d une plus grande série de souches de SCN. Répondre rapidement au clinicien à la question de l existence d un lien de clonalité entre les souches de SCN et donc à la question d une infection éventuelle peut contribuer à améliorer la prise en charge thérapeutique des patientsPARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF