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Aim: Sotrovimab, an engineered human monoclonal antibody, targets a conserved region of the SARS-CoV-2 spike protein. The phase III COMET-TAIL study evaluated noninferiority of intravenous versus intramuscular sotrovimab for early treatment of high-risk COVID-19 in 973 participants. Materials & methods: We investigated prevalence of variants of concern/interest (VOC/VOI) and characterized baseline, postbaseline and treatment-emergent sotrovimab epitope amino acid substitutions. Results: The Delta variant was predominant; the Alpha, Delta or Mu variants were detected in participants meeting the primary clinical endpoint for progression. Of 82 participants with sotrovimab epitope substitutions, two participants with baseline epitope substitutions met the primary endpoint for progression. Conclusion: Overall, there was no evidence that specific VOC/VOI, or postbaseline and treatment-emergent epitope substitutions, impacted clinical progression. Clinical Trial Registration:NCT04913675 (clinicaltrials.gov) Based on results of a past clinical study, a monoclonal antibody sotrovimab given directly into the vein has been used to treat COVID-19. In another clinical study, a shot of sotrovimab was also able to treat COVID-19. In this study, we looked at the genetics of SARS-CoV-2 viruses after these two ways of treating COVID-19 with sotrovimab. Most participants in the study were infected with the Delta variant of SARS-CoV-2. After treatment with sotrovimab, there were changes in the protein sotrovimab binds to, but these changes did not cause participants in the study to do worse after treatment. Article highlights In the COMET-TAIL resistance analysis, 98.0% (749/764) of participants had VOC/VOI detected. The Delta (B.1.617.2) variant was the predominant VOC/VOI and was detected in 88.2% (674/764) of participants with sequence data available. 26 participants met the primary endpoint for clinical progression and were infected with either the Delta, Alpha, or Mu variants. Sotrovimab epitope amino acid substitutions were detected in 4.7 (35/745) and 14.6% (62/424) of participants at baseline and postbaseline visits, respectively. The P337L and E340A/K/V sotrovimab epitope substitutions were detected as TE in 11.1% (45/405) of treated participants with paired baseline and postbaseline results (500 mg IV: 19.5%, 31/159; 500 mg IM: 6.4%, 11/171; 250 mg IM: 4.0%, 3/75). In a pseudotyped virus assay, substitutions P337L and E340A/K/V resulted in significant EC50 shifts (>100-fold), indicating reduced susceptibility to sotrovimab in vitro. Of the 82 participants with sotrovimab epitope substitutions, two met the primary clinical endpoint for progression. One participant infected with the Mu variant (500 mg IV) carried the characteristic R346K substitution. The second participant infected with the Delta variant (500 mg IM) had P337L and E340K substitutions, which confer resistance to sotrovimab in vitro, detected at baseline (Day 3) but only P337L was detected at Day 8 postbaseline. None of the sotrovimab-treated participants with TE epitope substitutions met the primary clinical endpoint for progression. There was no evidence that the presence of postbaseline or TE epitope substitutions impacted clinical outcomes, or that clinical efficacy was impacted by specific VOC/VOI. [ABSTRACT FROM AUTHOR]

Purpose: Emerging SARS-CoV-2 variants have impacted the in vitro activity of sotrovimab, with variable fold changes in neutralization potency for the Omicron BA.2 sublineage and onward. The correlation between reduced in vitro activity and clinical efficacy outcomes is unknown. A systematic literature review (SLR) evaluated the effectiveness of sotrovimab on severe clinical outcomes during Omicron BA.2 predominance. Methods: Electronic databases were searched for peer-reviewed journals, preprint articles, and conference abstracts published from January 1–November 3, 2022. Results: Five studies were included, which displayed heterogeneity in study design and population. Two UK studies had large samples of patients during BA.2 predominance: one demonstrated clinical effectiveness vs molnupiravir during BA.1 (adjusted hazard ratio [aHR] 0.54, 95% CI 0.33–0.88; p = 0.014) and BA.2 (aHR 0.44, 95% CI 0.27–0.71; p = 0.001); the other reported no difference in the clinical outcomes of sotrovimab-treated patients when directly comparing sequencing-confirmed BA.1 and BA.2 cases (HR 1.17, 95% CI 0.74–1.86). One US study showed a lower risk of 30-day all-cause hospitalization/mortality for sotrovimab compared with no treatment during the BA.2 surge in March (adjusted relative risk [aRR] 0.41, 95% CI 0.27–0.62) and April 2022 (aRR 0.54, 95% CI 0.08–3.54). Two studies from Italy and Qatar reported low progression rates but were either single-arm descriptive or not sufficiently powered to draw conclusions on the effectiveness of sotrovimab. Conclusion: This SLR showed that the effectiveness of sotrovimab was maintained against Omicron BA.2 in both ecological and sequencing-confirmed studies, by demonstrating low/comparable clinical outcomes between BA.1 and BA.2 periods or comparing against an active/untreated comparator. [ABSTRACT FROM AUTHOR]

Background Convenient administration of coronavirus disease 2019 (COVID-19) treatment in community settings is desirable. Sotrovimab is a pan-sarbecovirus dual-action monoclonal antibody formulated for intravenous (IV) or intramuscular (IM) administration for early treatment of mild/moderate COVID-19. Method This multicenter phase 3 study based on a randomized open-label design tested the noninferiority of IM to IV administration according to an absolute noninferiority margin of 3.5%. From June to August 2021, patients aged ≥12 years with COVID-19, who were neither hospitalized nor receiving supplemental oxygen but were at high risk for progression, were randomized 1:1:1 to receive sotrovimab as a single 500-mg IV infusion or a 500- or 250-mg IM injection. The primary composite endpoint was progression to (1) all-cause hospitalization for >24 hours for acute management of illness or (2) all-cause death through day 29. Results Sotrovimab 500 mg IM was noninferior to 500 mg IV: 10 (2.7%) of 376 participants vs 5 (1.3%) of 378 met the primary endpoint, respectively (absolute adjusted risk difference, 1.06%; 95% CI, −1.15% to 3.26%). The 95% CI upper limit was lower than the prespecified noninferiority margin of 3.5%. The 250-mg IM group was discontinued early because of the greater proportion of hospitalizations vs the 500-mg groups. Serious adverse events occurred in <1% to 2% of participants across groups. Four participants experienced serious disease-related events and died (500 mg IM, 2/393, <1%; 250 mg IM, 2/195, 1%). Conclusions Sotrovimab 500-mg IM injection was well tolerated and noninferior to IV administration. IM administration could expand outpatient treatment access for COVID-19. Clinical Trials Registration ClinicalTrials.gov: NCT04913675. [ABSTRACT FROM AUTHOR]

Background Five hundred milligrams of intravenous (IV) sotrovimab has been shown to be well tolerated and efficacious against pre-Omicron strains in treating patients with mild to moderate coronavirus disease 2019 (COVID-19) at high risk for disease progression. Methods This was an open-label, single-arm substudy of phase 3 COMET-TAIL (NCT04913675) assessing the safety and tolerability of a 2000 mg IV dose of sotrovimab. Symptomatic patients (aged ≥18 years) with COVID-19 at high risk for progression were enrolled from June 30 through July 11, 2022, when Omicron BA.5, BA.2.12.1, and BA.4 were the predominant circulating variants in the United States. The primary end point was the occurrence of adverse events (AEs), serious AEs (SAEs), AEs of special interest, and COVID-19 disease-related events (DREs) through day 8. Safety, pharmacokinetics, viral load, and hospitalization >24 hours for acute management of illness or death through day 29 were assessed. Results All participants (n = 81) were Hispanic, 58% were female, and 51% were aged ≥55 years. Through day 8, no AEs, including infusion-related reactions or hypersensitivity, were reported; 2 participants reported DREs (mild cough, n = 2). One SAE (acute myocardial infarction), which was considered unrelated to sotrovimab or COVID-19 by the investigator, occurred on day 27 and was the only hospitalization reported. Maximum serum concentration (geometric mean) was 745.9 µg/mL. Viral load decreased from baseline through day 29; only 2 (3%) participants had a persistently high viral load (≥4.1 log10 copies/mL) at day 8. Conclusions Two thousand milligrams of IV sotrovimab was well tolerated, with no safety signals observed. Trial registration ClinicalTrials.gov Identifier: NCT04913675. [ABSTRACT FROM AUTHOR]

Sotrovimab is a recombinant human monoclonal antibody that has been shown to prevent progression to hospitalization or death in non‐hospitalized high‐risk patients with mild to moderate coronavirus disease 2019 following either intravenous (i.v.) or intramuscular (i.m.) administration. Population pharmacokinetic (PopPK) and exposure‐response (ER) analyses were performed to characterize single dose sotrovimab pharmacokinetics (PK) and the relationship between exposure and response (probability of progression), as well as covariates that may contribute to between‐participant variability in sotrovimab PK and efficacy following i.v. or i.m. administration. Sotrovimab PK was described by a two‐compartment model with linear elimination; i.m. absorption was characterized by a sigmoid absorption model. PopPK covariate analysis led to the addition of the effect of body weight on systemic clearance and peripheral volume of distribution, sex on i.m. bioavailability and first‐order absorption rate (KA), and body mass index on KA. However, the magnitude of covariate effect was not pronounced and was therefore not expected to be clinically relevant based on available data to date. For ER analysis, sotrovimab exposure measures were predicted using the final PopPK model. An ER model was developed using the exposure measure of sotrovimab concentration at 168 h that described the relationship between exposure and probability of progression within the ER dataset for COMET‐TAIL. The number of risk factors (≤1 vs. >1) was incorporated as an additive shift on the model‐estimated placebo response but had no impact on overall drug response. Limitations in the ER model may prevent generalization of these results to describe the sotrovimab exposure‐progression relationship across severe acute respiratory syndrome‐coronavirus 2 variants. [ABSTRACT FROM AUTHOR]

Background: HIV treatment guidelines have traditionally recommended that all HIV-positive individuals are tested for evidence of drug resistance prior to starting ART. Testing for resistance to reverse transcriptase inhibitors and PIs is well established in routine care. However, testing for integrase strand transfer inhibitor (InSTI) resistance is less consistent.Objectives: To inform treatment guidelines by determining the prevalence of InSTI resistance in a national cohort of recently infected individuals.Patients and Methods: Recent (within 4 months) HIV-1 infections were identified using a Recent Infection Testing Algorithm of new HIV-1 diagnoses in the UK. Resistance-associated mutations (RAMs) in integrase, protease and reverse transcriptase were detected by ultradeep sequencing, which allows for the sensitive estimation of the frequency of each resistant variant in a sample.Results: The analysis included 655 randomly selected individuals (median age = 33 years, 95% male, 83% MSM, 78% white) sampled in the period 2014 to 2016 and determined to have a recent infection. These comprised 320, 138 and 197 samples from 2014, 2015 and 2016, respectively. None of the samples had major InSTI RAMs occurring at high variant frequency (≥20%). A subset (25/640, 3.9%) had major InSTI RAMs occurring only as low-frequency variants (2%-20%). In contrast, 47/588 (8.0%) had major reverse transcriptase inhibitor and PI RAMs at high frequency.Conclusions: Between 2014 and 2016, major InSTI RAMs were uncommon in adults with recent HIV-1 infection, only occurring as low-frequency variants of doubtful clinical significance. Continued surveillance of newly diagnosed patients for evidence of transmitted InSTI resistance is recommended to inform clinical practice. [ABSTRACT FROM AUTHOR]

Background: Timely linkage to care after HIV diagnosis is crucial as delayed access can result in poor patient outcomes. The aim of this systematic review was to synthesise the evidence to achieve a better understanding of what proportion of patients are linked to care and what factors impact linkage. Methods: Systematic searches were run in six databases up to the end of February 2017. The grey literature was also reviewed. Inclusion criteria were: sample size ≥50 people (aged ≥15), from the WHO European Region, published 2006–2017 and in English. Linkage to care was defined as a patient seen for HIV care after diagnosis. Study selection, data extraction and quality assurance were performed by two independent reviewers. Random-effects meta-analysis was carried out to summarise linkage to care within three months of diagnosis. Results: Twenty-four studies were included; 22 presented linkage to care data and seven examined factors for linkage. Linkage among 89,006 people in 19 countries was captured. Meta-analysis, restricted to 12 studies and measuring prompt linkage within three months, gave a pooled estimate of 85% (95% CI: 75%-93%). Prompt linkage was higher in studies including only people in care (94%; 95% CI: 91%-97%) than in those of all new diagnoses (71%; 95% CI: 50%-87%). Heterogeneity was high across and within strata (>99%). Factors associated with delaying or not linking to care included: acquiring HIV through heterosexual contact/injecting drug use, younger age at diagnosis, lower levels of education, feeling well at diagnosis and diagnosis outside an STI clinic. Conclusion: Overall, linkage to care was high, though estimates were lower in studies with a high proportion of people who inject drugs. The high heterogeneity between studies made it challenging to synthesise findings. Studies should adopt a standardised definition with a three month cut-off to measure prompt linkage to care to ensure comparability. [ABSTRACT FROM AUTHOR]

Substantial amounts of data have been generated from patient management and academic exercises designed to better understand the human immunodeficiency virus (HIV) epidemic and design interventions to control it. A number of specialized databases have been designed to manage huge data sets from HIV cohort, vaccine, host genomic and drug resistance studies. Besides databases from cohort studies, most of the online databases contain limited curated data and are thus sequence repositories. HIV drug resistance has been shown to have a great potential to derail the progress made thus far through antiretroviral therapy. Thus, a lot of resources have been invested in generating drug resistance data for patient management and surveillance purposes. Unfortunately, most of the data currently available relate to subtype B even though >60% of the epidemic is caused by HIV-1 subtype C. A consortium of clinicians, scientists, public health experts and policy markers working in southern Africa came together and formed a network, the Southern African Treatment and Resistance Network (SATuRN), with the aim of increasing curated HIV-1 subtype C and tuberculosis drug resistance data. This article describes the HIV-1 data curation process using the SATuRN Rega database. The data curation is a manual and time-consuming process done by clinical, laboratory and data curation specialists. Access to the highly curated data sets is through applications that are reviewed by the SATuRN executive committee. Examples of research outputs from the analysis of the curated data include trends in the level of transmitted drug resistance in South Africa, analysis of the levels of acquired resistance among patients failing therapy and factors associated with the absence of genotypic evidence of drug resistance among patients failing therapy. All these studies have been important for informing first- and second-line therapy. [ABSTRACT FROM AUTHOR]

Objective: To determine the frequency and patterns of acquired antiretroviral drug resistance in a rural primary health care programme in South Africa. Design: Cross-sectional study nested within HIV treatment programme. Methods: Adult (≥18 years) HIV-infected individuals initially treated with a first-line stavudine- or zidovudine-based antiretroviral therapy (ART) regimen and with evidence of virological failure (one viral load >1000 copies/ml) were enrolled from 17 rural primary health care clinics. Genotypic resistance testing was performed using the in-house SATuRN/Life Technologies system. Sequences were analysed and genotypic susceptibility scores (GSS) for standard second-line regimens were calculated using the Stanford HIVDB 6.0.5 algorithms. Results: A total of 222 adults were successfully genotyped for HIV drug resistance between December 2010 and March 2012. The most common regimens at time of genotype were stavudine, lamivudine and efavirenz (51%); and stavudine, lamivudine and nevirapine (24%). Median duration of ART was 42 months (interquartile range (IQR) 32–53) and median duration of antiretroviral failure was 27 months (IQR 17–40). One hundred and ninety one (86%) had at least one drug resistance mutation. For 34 individuals (15%), the GSS for the standard second-line regimen was <2, suggesting a significantly compromised regimen. In univariate analysis, individuals with a prior nucleoside reverse-transcriptase inhibitor (NRTI) substitution were more likely to have a GSS <2 than those on the same NRTIs throughout (odds ratio (OR) 5.70, 95% confidence interval (CI) 2.60–12.49). Conclusions: There are high levels of drug resistance in adults with failure of first-line antiretroviral therapy in this rural primary health care programme. Standard second-line regimens could potentially have had reduced efficacy in about one in seven adults involved. [ABSTRACT FROM AUTHOR]

Background: Previous studies have suggested that there may be an association between some immune-mediated diseases and risk of tuberculosis (TB). Methods: We analyzed a database of linked statistical records of hospital admissions and death certificates for the whole of England (1999 to 2011), and a similar database (the Oxford Record Linkage Study (ORLS)) for a region of southern England in an earlier period. Rate ratios for TB were determined, comparing immune-mediated disease cohorts with comparison cohorts. Results: In the all-England dataset, there were significantly elevated risks of TB after hospital admission for the following individual immune-mediated diseases: Addison's disease, ankylosing spondylitis, autoimmune hemolytic anemia, chronic active hepatitis, coeliac disease, Crohn's disease, dermatomyositis, Goodpasture's syndrome, Hashimoto's thyroiditis, idiopathic thrombocytopenia purpura (ITP), myasthenia gravis, myxedema, pemphigoid, pernicious anemia, polyarteritis nodosa, polymyositis, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, scleroderma, Sjögren's syndrome, systemic lupus erythematosus (SLE), thyrotoxicosis and ulcerative colitis. Particularly high levels of risk were found for Addison's disease (rate ratio (RR) = 11.9 (95% CI 9.5 to 14.7)), Goodpasture's syndrome (RR = 10.8 (95% CI 4.0 to 23.5)), SLE (RR = 9.4 (95% CI 7.9 to 11.1)), polymyositis (RR = 8.0 (95% CI 4.9 to 12.2)), polyarteritis nodosa (RR = 6.7 (95% CI 3.2 to 12.4)), dermatomyositis (RR = 6.6 (95% CI 3.0 to 12.5)), scleroderma (RR = 6.1 (95% CI 4.4 to 8.2)) and autoimmune hemolytic anemia (RR = 5.1 (95% CI 3.4 to 7.4)). Conclusions: These two databases show that patients with some immune-mediated diseases have an increased risk of TB, although we cannot explicitly state the direction of risk or exclude confounding. Further study of these associations is warranted, and these findings may aid TB screening, control and treatment policies. [ABSTRACT FROM AUTHOR]

This first-time-in-human (FTIH) study evaluated the safety, tolerability, pharmacokinetics, and food effect of single and repeat oral doses of GSK3036656, a leucyl-tRNA synthetase inhibitor. In part A, GSK3036656 single doses of 5 mg (fed and fasted), 15 mg, and 25 mg and placebo were administered. In part B, repeat doses of 5 and 15 mg and placebo were administered for 14 days once daily. GSK3036656 showed dose-proportional increase following single-dose administration and after dosing for 14 days. The maximum concentration of drug in serum ( C max ) and area under the concentration-time curve from 0 h to the end of the dosing period (AUC 0-τ ) showed accumulation with repeated administration of approximately 2- to 3-fold. Pharmacokinetic parameters were not altered in the presence of food. Unchanged GSK3036656 was the only drug-related component detected in plasma and accounted for approximately 90% of drug-related material in urine. Based on total drug-related material detected in urine, the minimum absorbed doses after single (25 mg) and repeat (15 mg) dosing were 50 and 78%, respectively. Unchanged GSK3036656 represented at least 44% and 71% of the 25- and 15-mg doses, respectively. Clinical trial simulations were performed to guide dose escalation during the FTIH study and to predict the GSK3036656 dose range that produces the highest possible early bactericidal activity (EBA 0-14 ) in the prospective phase II trial, with consideration of the predefined exposure limit. GSK3036656 was well tolerated after single and multiple doses, with no reports of serious adverse events. (This study has been registered at ClinicalTrials.gov under identifier NCT03075410.)., (Copyright © 2019 Tenero et al.)

Background: We and others have shown a significant proportion of interventional trials registered on ClinicalTrials.gov have their primary outcomes altered after the listed study start and completion dates. The objectives of this study were to investigate whether changes made to primary outcomes are associated with the likelihood of reporting a statistically significant primary outcome on ClinicalTrials.gov., Methods: A cross-sectional analysis of all interventional clinical trials registered on ClinicalTrials.gov as of 20 November 2014 was performed. The main outcome was any change made to the initially listed primary outcome and the time of the change in relation to the trial start and end date., Findings: 13,238 completed interventional trials were registered with ClinicalTrials.gov that also had study results posted on the website. 2555 (19.3%) had one or more statistically significant primary outcomes. Statistical analysis showed that registration year, funding source and primary outcome change after trial completion were associated with reporting a statistically significant primary outcome ., Conclusions:  Funding source and primary outcome change after trial completion are associated with a statistically significant primary outcome report on clinicaltrials.gov.

Background: An important principle in the good conduct of clinical trials is that a summary of the trial protocol, with a pre-defined primary outcome, should be freely available before the study commences. The clinical trials registry ClinicalTrials.gov provides one method of doing this, and once the trial is registered, any changes made to the primary outcome are documented. The objectives of this study were: to assess the proportion of registered trials on ClinicalTrials.gov that had the primary outcome changed; to assess when the primary outcome was changed in relation to the listed study start and end dates and to assess whether the primary outcome change had any relation to the study sponsor., Methods: A cross-sectional analysis of all interventional clinical trials registered on ClinicalTrials.gov as of 25 October 2012 was performed. The main outcome was any change made to the initially listed primary outcome and the time of the change in relation to the trial start and end date., Findings: Our analysis showed that 28229 of 89204 (31.7%) registered studies had their primary outcome changed.  Industry funding was associated with all primary outcome changes, odds ratio (OR)= 1.36, 95% confidence interval (CI)=1.31-1.41, p<0.001; with primary outcome changes after study start date OR=1.37, 95% CI=1.32-1.42, p<0.001; with primary outcome changes after primary completion date OR=1.84, 95% CI=1.75-1.94, p<0.001 and with primary outcome changes after study completion date OR=1.82, 95% CI=1.73-1.91, p<0.001.  Conclusions A significant proportion of interventional trials registered on ClinicalTrials.gov have their primary outcomes altered after the listed study start and completion dates. These changes are associated with funding source.

Background: Antiretroviral drug resistance is becoming increasingly common with the expansion of human immunodeficiency virus (HIV) treatment programmes in high prevalence settings. Genotypic resistance testing could have benefit in guiding individual-level treatment decisions but successful models for delivering resistance testing in low- and middle-income countries have not been reported., Methods: An HIV Treatment Failure Clinic model was implemented within a large primary health care HIV treatment programme in northern KwaZulu-Natal, South Africa. Genotypic resistance testing was offered to adults (≥16 years) with virological failure on first-line antiretroviral therapy (one viral load >1000 copies/ml after at least 12 months on a standard first-line regimen). A genotypic resistance test report was generated with treatment recommendations from a specialist HIV clinician and sent to medical officers at the clinics who were responsible for patient management. A quantitative process evaluation was conducted to determine how the model was implemented and to provide feedback regarding barriers and challenges to delivery., Results: A total of 508 specimens were submitted for genotyping between 8 April 2011 and 31 January 2013; in 438 cases (86.2%) a complete genotype report with recommendations from the specialist clinician was sent to the medical officer. The median turnaround time from specimen collection to receipt of final report was 18 days (interquartile range (IQR) 13-29). In 114 (26.0%) cases the recommended treatment differed from what would be given in the absence of drug resistance testing. In the majority of cases (n = 315, 71.9%), the subsequent treatment prescribed was in line with the recommendations of the report., Conclusions: Genotypic resistance testing was successfully implemented in this large primary health care HIV programme and the system functioned well enough for the results to influence clinical management decisions in real time. Further research will explore the impact and cost-effectiveness of different implementation models in different settings.

Substantial amounts of data have been generated from patient management and academic exercises designed to better understand the human immunodeficiency virus (HIV) epidemic and design interventions to control it. A number of specialized databases have been designed to manage huge data sets from HIV cohort, vaccine, host genomic and drug resistance studies. Besides databases from cohort studies, most of the online databases contain limited curated data and are thus sequence repositories. HIV drug resistance has been shown to have a great potential to derail the progress made thus far through antiretroviral therapy. Thus, a lot of resources have been invested in generating drug resistance data for patient management and surveillance purposes. Unfortunately, most of the data currently available relate to subtype B even though >60% of the epidemic is caused by HIV-1 subtype C. A consortium of clinicians, scientists, public health experts and policy markers working in southern Africa came together and formed a network, the Southern African Treatment and Resistance Network (SATuRN), with the aim of increasing curated HIV-1 subtype C and tuberculosis drug resistance data. This article describes the HIV-1 data curation process using the SATuRN Rega database. The data curation is a manual and time-consuming process done by clinical, laboratory and data curation specialists. Access to the highly curated data sets is through applications that are reviewed by the SATuRN executive committee. Examples of research outputs from the analysis of the curated data include trends in the level of transmitted drug resistance in South Africa, analysis of the levels of acquired resistance among patients failing therapy and factors associated with the absence of genotypic evidence of drug resistance among patients failing therapy. All these studies have been important for informing first- and second-line therapy. This database is a free password-protected open source database available on www.bioafrica.net. Database URL: http://www.bioafrica.net/regadb/

Objectives: Weekend admissions have been shown to be associated with an increased risk of mortality compared with weekday admissions for many diagnoses. We analysed emergency department admissions within the Scottish National Health Service to investigate whether mortality is increased in case of weekend emergency department admissions., Design: A cohort study., Setting: Scotland National Health Service (NHS) emergency departments., Participants: 5 271 327 emergency department admissions between 1999 and 2009. We included all patients admitted via emergency departments recorded in the Scottish Morbidity Records (SMR01) in NHS, Scotland for whom complete demographic data were available., Primary Outcome Measures: Death as recorded by the General Register Office (GRO)., Results: There was a significantly increased probability of death associated with a weekend emergency admission compared with admission on a weekday (unadjusted OR 1.27, 95% CI 1.26 to 1.28, p<0.0001; adjusted for year of admission, gender, age, deprivation quintile and number of comorbidities OR 1.42, 95% CI 1.40 to 1.43, p<0.0001)., Conclusions: Despite a general reduction in mortality over the last 11 years, there is still a significant excess mortality associated with weekend emergency admissions. Further research should be undertaken to identify the precise mechanisms underlying this effect so that measures can be put in place to reduce patient mortality.