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.

Arhinia, or absence of the nose, is a rare malformation of unknown etiology that is often accompanied by ocular and reproductive defects. Sequencing of 40 people with arhinia revealed that 84% of probands harbor a missense mutation localized to a constrained region of SMCHD1 encompassing the ATPase domain. SMCHD1 mutations cause facioscapulohumeral muscular dystrophy type 2 (FSHD2) via a trans-acting loss-of-function epigenetic mechanism. We discovered shared mutations and comparable DNA hypomethylation patterning between these distinct disorders. CRISPR/Cas9-mediated alteration of smchd1 in zebrafish yielded arhinia-relevant phenotypes. Transcriptome and protein analyses in arhinia probands and controls showed no differences in SMCHD1 mRNA or protein abundance but revealed regulatory changes in genes and pathways associated with craniofacial patterning. Mutations in SMCHD1 thus contribute to distinct phenotypic spectra, from craniofacial malformation and reproductive disorders to muscular dystrophy, which we speculate to be consistent with oligogenic mechanisms resulting in pleiotropic outcomes.

Objective: Frail patients in any age group are more likely to die than those that are not frail. To evaluate the impact of frailty on clinical mortality, readmission rate and length of stay for emergency surgical patients of all ages.Design, setting and participants: A multi-centre prospective cohort study was conducted on adult admissions to acute surgical units. Every patient presenting as a surgical emergency to secondary care, regardless of whether they ultimately underwent a surgical procedure. Participants were included during 2015 and 2016Intervention: Frailty as defined by the 7 point Clinical Frailty Scale Main outcomes and measures: The primary outcome was mortality at Day 90. Secondary outcomes included: Mortality at day 30, readmission at day 30 and length of stay. Results:The cohort included 2,279 patients (median age 54 years ; 56% female). Frailty was documented in patients of all ages: 1% in the under 40's to 45% of those aged 80+. We found that each incremental step of worsening frailty was associated with an 80% increase in mortality at day 90 (95% CI 1.61-2.01) supporting a linear doseresponse relative relationship. In addition, the most frail patients were increasingly likely to be readmitted, stay in hospital longer and die within 30 days. Conclusions:Worsening frailty at any age is associated with significantly poorer patient outcomes, including mortality in unselected acute surgical admissions.

Objective: This study aimed to document the prevalence of frailty in older adults undergoing emergency laparotomy and to explore relationships between frailty and postoperative morbidity and mortality. Summary Background Data: The majority of adults undergoing emergency laparotomy are older adults (≥65 y) that carry the highest mortality. Improved understanding is urgently needed to allow development of targeted interventions. Methods: An observational multicenter (n=49) UK study was performed (March–June 2017). All older adults undergoing emergency laparotomy were included. Preoperative frailty score was calculated using the progressive Clinical Frailty Score (CFS): 1 (very fit) to 7 (severely frail). Primary outcome measures were the prevalence of frailty (CFS 5–7) and its association to mortality at 90 days postoperative. Secondary outcomes included 30-day mortality and morbidity, length of critical care, and overall hospital stay. Results: A total of 937 older adults underwent emergency laparotomy: frailty was present in 20%. Ninety-day mortality was 19.5%. After age and sex adjustment, the risk of 90-day mortality was directly associated with frailty: CFS 5 adjusted odds ratio (aOR) 3.18 [95% confidence interval (CI), 1.24–8.14] and CFS 6/7 aOR 6·10 (95% CI, 2.26–16.45) compared with CFS 1. Similar associations were found for 30-day mortality. Increasing frailty was also associated with increased risk of complications, length of Intensive Care Unit, and overall hospital stay. Conclusions: A fifth of older adults undergoing emergency laparotomy are frail. The presence of frailty is associated with greater risks of postoperative mortality and morbidity and is independent of age. Frailty scoring should be integrated into acute surgical assessment practice to aid decision-making and development of novel postoperative strategies.

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Background: Laparoscopic cholecystectomy is commonly performed, and several factors increase the

ObjectivesMultimorbidity is the presence of 2 or more medical conditions. This increasingly used assessment has not been assessed in a surgical population. The objectives of this study were to assess the prevalence of multimorbidity and its association with common outcome measures.DesignA cross-sectional observational study.SettingA UK-based multicentre study, included participants between July and October 2014.ParticipantsConsecutive emergency (non-elective) general surgical patients admitted to hospital, aged over 65 years.Outcome measuresThe outcome measures were (1) the prevalence of multimorbidity and (2) the association between multimorbidity and frailty; the rate and severity of surgery; length of hospital stay; readmission to hospital within 30 days of discharge; and death at 30 and 90 days.ResultsData were collected on 413 participants aged 65–98 years (median 77 years, (IQR (70–84)). 51.6% (212/413) participants were women. Multimorbidity was present in 74% (95% CI 69.7% to 78.2%) of the population and increased with age (p<0.0001). Multimorbidity was associated with increasing frailty (p for trend <0.0001). People with multimorbidity underwent surgery as often as those without multimorbidity, including major surgery (p=0.03). When comparing multimorbid people with those without multimorbidity, we found no association between length of hospital stay (median 5 days, IQR (1–54), vs 6 days (1–47), (p=0.66)), readmission to hospital (64 (21.1%) vs 18 (16.8%) (p=0.35)), death at 30 days (14 (4.6%) vs 6 (5.6%) (p=0.68)) or 90-day mortality (28 (9.2%) vs 8 (7.6%) (p=0.60)).Conclusions and implicationsMultimorbidity is common. Nearly three-quarters of this older emergency general surgical population had 2 or more chronic medical conditions. It was strongly associated with age and frailty, and was not a barrier to surgical intervention. Multimorbidity showed no associations across a range of outcome measures, as it is currently defined. Multimorbidity should not be relied on as a useful clinical tool in guidelines or policies for older emergency surgical patients.

BackgroundPsoriatic Arthritis (PsA) is estimated to occur in 10-15% of people with psoriasis and accounts for 13% of people attending early arthritis clinics. With an increasing awareness of the poor outcomes associated with PsA and the availability of new effective, but costly, treatments, there is an urgent need to research the optimal treatment for patients with PsA. The aim of the TICOPA study is to establish whether, in treatment naive early PsA patients, “tight control” intensive management with protocol driven therapies and pre-defined objective targets for treatment can improve clinical outcome compared to standard care alone.Methods/designTICOPA is a UK multicentre, open-label, randomised controlled, parallel group trial of 206 patients with early PsA. Patients will be randomised on a 1:1 basis to receive either standard care (12 weekly review) or intensive management (4 weekly review) for a period of 48 weeks. Patients assigned to the intensive management group will follow a strict treatment protocol whereby dose continuation/escalation is determined through the objective assessment of the minimal disease activity (MDA) criteria. Patients assigned to the standard care group will have treatment prescribed as felt appropriate by the treating clinician, with no set protocol. The primary objective of the trial is to compare intensive management with standard care in terms of the proportion of patients achieving an ACR 20 response at 48 weeks post-randomisation, in order to determine whether intensive management has superior clinical efficacy. Key secondary outcomes include ACR 50 and 70, PASI 75 and X-ray Van der Heijde score at 48 weeks post-randomisation along with cost-effectiveness at 12, 24 and 28 weeks.DiscussionThe TICOPA trial will provide direct evidence as to whether the use of early and intensive treatment in PsA in routine clinical care leads to an improvement in patients’ disease activity and a reduction in radiological joint damage.Trial registrationISRCTN30147736, NCT01106079