Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

Background: Many patients with COVID-19 have been treated with plasma containing anti-SARS-CoV-2 antibodies. We aimed to evaluate the safety and efficacy of convalescent plasma therapy in patients admitted to hospital with COVID-19. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. The trial is underway at 177 NHS hospitals from across the UK. Eligible and consenting patients were randomly assigned (1:1) to receive either usual care alone (usual care group) or usual care plus high-titre convalescent plasma (convalescent plasma group). The primary outcome was 28-day mortality, analysed on an intention-to-treat basis. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings: Between May 28, 2020, and Jan 15, 2021, 11558 (71%) of 16287 patients enrolled in RECOVERY were eligible to receive convalescent plasma and were assigned to either the convalescent plasma group or the usual care group. There was no significant difference in 28-day mortality between the two groups: 1399 (24%) of 5795 patients in the convalescent plasma group and 1408 (24%) of 5763 patients in the usual care group died within 28 days (rate ratio 1·00, 95% CI 0·93–1·07; p=0·95). The 28-day mortality rate ratio was similar in all prespecified subgroups of patients, including in those patients without detectable SARS-CoV-2 antibodies at randomisation. Allocation to convalescent plasma had no significant effect on the proportion of patients discharged from hospital within 28 days (3832 [66%] patients in the convalescent plasma group vs 3822 [66%] patients in the usual care group; rate ratio 0·99, 95% CI 0·94–1·03; p=0·57). Among those not on invasive mechanical ventilation at randomisation, there was no significant difference in the proportion of patients meeting the composite endpoint of progression to invasive mechanical ventilation or death (1568 [29%] of 5493 patients in the convalescent plasma group vs 1568 [29%] of 5448 patients in the usual care group; rate ratio 0·99, 95% CI 0·93–1·05; p=0·79). Interpretation: In patients hospitalised with COVID-19, high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Background: In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). Findings: Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001). Interpretation: In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Upper Cretaceous biostratigraphy of the Sirte Basin, Northern Libya

Butt Aftab Ahmad. Upper Cretaceous biostratigraphy of the Sirte Basin, Northern Libya. In: Géologie Méditerranéenne. Tome 11, numéro 1-2, 1984. C.A.M. IXe colloque africain de micropaléontologie. Paris, Museum d'Histoire Naturelle, du 3 au 6 octobre 1983. pp. 237-238

The Upper Cretaceous biostratigraphy of Pakistan : A synthesis

The Upper Cretaceous succession of Pakistan covers a time interval from Cenomanian to Turanian but largely, Coniadan to Campanian and Maastrichtian interval. Sediments of Coniacian to Campanian age are known as the Kawagarh Formation in Northern Pakistan and correspondingly the Parh Limestone in Southern Pakistan. The regional distribution of these sediments having lithologic and palaeontologic similarity (micritic sediments and globotmncanid fauna) envisages a major transgression along the northwestern margin of the Indian Plate, whereas the Maastrichtian interval records a major period of regression along the northwestern margin of the Indian Plate marked either by a complete absence of Maastrichtian deposits in Northern Pakistan or by the development of a regional blanket of regressive facies of the shallow-water Pab Sandstone in Southern Pakistan. Uninterrupted succession of argillaceous deposits (Korara Shale), across the Cretaceous-Tertiary boundary in the Kirthar Range (Gaj River section), or the Pab Range containing Maastrichtian and Danian planctonik foraminifera in continued sedimentary environments, is among the very few worldwide examples of a continuous section across the boundary.Synthise biostratigraphique du Crétacé supérieur du Pakistan. La succession stratigraphique du Crétacé supérieur pakistanais concerne les intervalles Cénomanien-Turonien, Coniacien-Campanien et Maastrichtien. Les sédiments coniaciens à campaniens sont connus dans le Nord (Kawagarh Formation) et dans le Sud (Parh Limestone). La distribution régionale et les similitudes de faciès (micrites à globotruncanidés) supposent des phénomènes de transgression sur la marge nord-ouest de la plaque indienne. Au Maastrichtien par contre, des phénomènes de régression sont marqués par l'absence de dépôt au Nord et le développement de faciès peu profonds au Sud (Pab Sandstone). Au passage Crétacé-Tertiaire, on observe une continuité de dépôts argileux (Korara Shale) livrant des foraminifères planctoniques du Maastrichtien et du Danien, dans le Kirthar Range (coupe de la rivière Gaj) ou dans le Pab Range.Butt Aftab Ahmad. The Upper Cretaceous biostratigraphy of Pakistan : A synthesis. In: Géologie Méditerranéenne. Tome 19, numéro 4, 1992. pp. 265-272

Upper Cretaceous biostratigraphy of the Sirte Basin, Northern Libya

Butt Aftab Ahmad. Upper Cretaceous biostratigraphy of the Sirte Basin, Northern Libya. In: Géologie Méditerranéenne. Tome 11, numéro 1-2, 1984. C.A.M. IXe colloque africain de micropaléontologie. Paris, Museum d'Histoire Naturelle, du 3 au 6 octobre 1983. pp. 237-238

Remarks on the upper cretaceous biostratigraphy of Libya

The marine Upper Cretaceous strata are present in northern Libya among the structural units of the Ghadames Basin, the Sirte Basin, the Cyrenaica Platform and the Jabal A1 Akhdar. In each structural entity, the stratigraphie terminology is unique. The Jabal A1 Akhdar, north of Cyrenaica Platform, contains the mosts valuable though of limited geographical extent Upper Cretaceous marine sequence, where the standard planktonic biostratigraphy can be used from Albian to Maastrichtian among the Hilal Shale (Albian to Coniacian) and the Atrun Limestone (Up. Conaciacian to Maastrichtian) along the coastal area of Marsa A1 Hilal. In the Sirte Basin, both planktonic and benthonic zonation can be established in the Sirte Shale (mainly Campanian) and the Kalash Limestone (Maastrichtian). However, in the shallow-water Maastrichtian Waha Limestone or in theupper part of the Lower Satal Formation, stratigraphically important benthonic larger foraminiferal species Orbitoides apicalatus, Omphalocyclus macroporus and Siderolites calcitrapoides are encountered. TheGhadames Basin comprises Maastrichtian Lower T ar Marl where both planktonic and benthonic biostratigraphy similar to that of the Sirte Basin can be recognised. The Cyrenaica Platform constitutes a single benthonic foraminiferal Bolivina incrassata gigantea Zone in the Maastrichtian "Kalash Limestone" which continues into the neighbouring Sirte Basin.Dans le nord de la Libye, le Crétacé supérieur marin est représenté par les unités structurales du Bassin de Ghadames, du bassin de Sirte, de la Plate-forme de Cyrénaique et du Jabal Al Akhdar. Bien qu'elle soit géographiquement limitée, c'est dans la région du Jabal Al Alkhar, nord de la plate-forme de Cyrénaïque, que se situe la plus importante série marine du Crétacé supérieur. La biostratigraphie basée sur les foraminifères planctoniques peut y être utilisée de l'Albien au Maastrichtien, le long de la zone côtière de Marsa Al Hilal : "Hilal Shale" (Albien à Coniacien), "Atrun Limestone" (Coniacien supérieur à Maastrichtien). Dans le Bassin de Sirte une zonation par foraminifères benthi-ques et plantoniques peut être établie : "Sirte Shale" (Campanien essentiellement), "Kalash Limestone"(Maastichtien). En outre, on observe de grands foraminifères benthiques stratigraphiquement importants (Orbitoides apicalatus, Omphalocycîus macroporus, Sideroiiies caiciirapoides) dans les dépôts peu profonds du Maas¬ trichtien : "Waha Limestone" ou partie supérieure de la "Lower Satal Formation" Dans le Bassin de Ghadames, le Maastrichtien ("Lower Tar Marl") peut être reconnu à l'aide d'une zonation à partir de foramini¬ fères benthiques et planctoniques similaire à celle établie dans le Bas¬ sin de Sirte. La plate-f orme de Cyrénaique représente uniquement la zone à Bolivina incrassata gigantea : Maastrichtien ("Kalash Limestone" ; celle-ci se poursuit dans le Bassin de Sirte voisin.Butt Aftab Ahmad. Remarks on the upper cretaceous biostratigraphy of Libya. In: Géologie Méditerranéenne. Tome 14, numéro 2, 1987. Xe colloque africain de micropaléontologie. B – Le Mesozoique. Rabat – Université Mohamed V – Maroc. 29 septembre-1er octobre 1987. pp. 133-135

Microfacies and foraminiferal assemblages from the Early Tertiary rocks of the Kala Chitta Range (northern Pakistan)

Microfacies analysis and foraminiferal biostratigraphy of the Upper Paleocene (Thanetian) Lockhart Limestone, Patala Formation and the Lower Eocene (Ypresian) Margala Hill Limestone from the Kala Chitta Range, northern Pakistan has been done by studying a large number of thin sections. Most common microfacies of the shelf environment are the bioclas-tic wack.es tone, packstone and grainstone. The biociasts are bentho-nic larger foraminifera including the genera Lockhartia, Ranikothalia, Nummulites, Assilina, Operculina, Alveolina and Discocyclina . The foraminiferal assemblage is age-diagnostic and as well as indicative of shallow shelf (inner shelf or inner neritic) marine environment.Microfaciès et associations de foraminifères du Tertiaire inférieur du "Kala Chitta Range" (Nord Pakistan). L'étude d'un grand nombre de lames minces apporte (tes précisions sur les microfaciès et la biostratigraphie basée sur les foraminifères dans le Paléocène supérieur (Thanétien : Lockhart Limestone, Patala Formation ) et l'Eocène inférieur (Yprésien : Margala Hill Limestone) du "Kala Chitta Range" -Nord Pakistan. Les microfaciès les plus fréquents sont des calcaires bioclastiques de type wackestone, packstone et grainstone dans lesquels les bio-clastes sont représentés par de grands foraminifères benthiques : Lockhartia, Ranikothalia, Nummulites, Assilina, Operculina, Alveolina, Discocyclina. Les associations de forminifères permettent de préciser les âges et indiquent des environnements marins de plate-forme peu profonde (plate-forme intone ou néritique proximale).Akhtar M., Butt Aftab Ahmad. Microfacies and foraminiferal assemblages from the Early Tertiary rocks of the Kala Chitta Range (northern Pakistan). In: Géologie Méditerranéenne. Tome 26, numéro 3-4, 1999. pp. 185-201

The Kala Chitta foreland fold and thrust belt, Northern Pakistan

The present structural framework of the Kala Chitta Range evolved through movement between two detachment surfaces. The Precambrian Attock Slates acted as a basal detachment surface above which large scale horizontal compression took place to produce the main structural framework of the Kala Chitta Range. The Middle Eocene argillaceous and gypsiferous Kuldana Formation behaved as the upper detachment surface giving rise to blind thrusts which were later exposed due to the intense erosion of the overlying folded Miocene strata.</jats:p