Dipeptidyl peptidase-1 inhibition in patients hospitalised with COVID-19: a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial

Background Neutrophil serine proteases are involved in the pathogenesis of COVID-19 and increased serine protease activity has been reported in severe and fatal infection. We investigated whether brensocatib, an inhibitor of dipeptidyl peptidase-1 (DPP-1; an enzyme responsible for the activation of neutrophil serine proteases), would improve outcomes in patients hospitalised with COVID-19. Methods In a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial, across 14 hospitals in the UK, patients aged 16 years and older who were hospitalised with COVID-19 and had at least one risk factor for severe disease were randomly assigned 1:1, within 96 h of hospital admission, to once-daily brensocatib 25 mg or placebo orally for 28 days. Patients were randomly assigned via a central web-based randomisation system (TruST). Randomisation was stratified by site and age (65 years or ≥65 years), and within each stratum, blocks were of random sizes of two, four, or six patients. Participants in both groups continued to receive other therapies required to manage their condition. Participants, study staff, and investigators were masked to the study assignment. The primary outcome was the 7-point WHO ordinal scale for clinical status at day 29 after random assignment. The intention-to-treat population included all patients who were randomly assigned and met the enrolment criteria. The safety population included all participants who received at least one dose of study medication. This study was registered with the ISRCTN registry, ISRCTN30564012. Findings Between June 5, 2020, and Jan 25, 2021, 406 patients were randomly assigned to brensocatib or placebo; 192 (47·3%) to the brensocatib group and 214 (52·7%) to the placebo group. Two participants were excluded after being randomly assigned in the brensocatib group (214 patients included in the placebo group and 190 included in the brensocatib group in the intention-to-treat population). Primary outcome data was unavailable for six patients (three in the brensocatib group and three in the placebo group). Patients in the brensocatib group had worse clinical status at day 29 after being randomly assigned than those in the placebo group (adjusted odds ratio 0·72 [95% CI 0·57–0·92]). Prespecified subgroup analyses of the primary outcome supported the primary results. 185 participants reported at least one adverse event; 99 (46%) in the placebo group and 86 (45%) in the brensocatib group. The most common adverse events were gastrointestinal disorders and infections. One death in the placebo group was judged as possibly related to study drug. Interpretation Brensocatib treatment did not improve clinical status at day 29 in patients hospitalised with COVID-19

Questions of 'h' in Northern Ireland: Breathing New Life on the Aspiration Theory

This paper considers existing ideas concerning pronunciation of the letter name for "h" (LNH) in Northern Irish English (NIE). Traditionally, the status of LNH realisation as an ethnic marker has gone unquestioned : Catholics are thought to say [hetf] while the Protestant norm is assumed to be [et f]. The phonetic difference between these realisations is consistendy described as word-initial aspiration versus non-aspiration, with aspiration attributed exclusively to Irish language influence. Here, we show that an explanation based on aspiration alone is phonologically unsatisfying and question whether aspiration is, in fact, an Irish language or ethnically dictated phenomenon. It is further suggested here that the overwhelming stigmatisation of LNH realisation may be responsible for blocking a potential sound change in NIE. While this paper is not intended as a detailed account of ethnolinguistic differences in NI phonology, it engages critically with the over-simplistic and widespread notion that LNH realisation is a result of transfer from the Irish language to the English used by Catholics in Northern Ireland.Cet article examine les idées couramment admises sur la prononciation du nom de la lettre "h" (LNH) dans l'anglais parlé en Irlande du Nord. Son statut de marqueur d'appartenance à une communauté donnée n'a, de manière générale, jamais été remis en question. Il est admis que les Catholiques prononcent [het f] tandis que les Protestants diraient [etf]. La différence phonétique entre ces deux réalisations est constamment décrite comme d'un côté une aspiration à l'initiale du mot, de l'autre une non aspiration, l'aspiration étant exclusivement attribuée à l'influence du gaélique. Nous montrons donc qu'une explication fondée seulement sur l 'aspiration n'est pas satisfaisante d'un point de vue phonologique et nous avançons l'idée que cette stigmatisation massive de la réalisation phonétique de LNH est peut-être responsable du blocage d'un changement phonétique potentiel dans l'anglais du nord de l'Irlande. Cet article ne cherche pas à rendre compte de façon détaillée des différences phonologiques ethnolinguistiques en Irlande du Nord mais aborde de façon critique l'idée reçue et simpliste que la réalisation de la lettre "h" est la conséquence d'un transfert du gaélique vers l'anglais parlé par les Catholiques en Irlande du Nord.Rahilly Joan. Questions of 'h' in Northern Ireland : Breathing New Life on the Aspiration Theory. In: Études irlandaises, n°31 n°2, 2006. Irish English : variétés et variations / Irish English, Varieties and Variations sous la direction de Maryvonne Boisseau et Françoise Canon-Roger. pp. 47-61