A randomised controlled trial of extended brief intervention for alcohol dependent patients in an acute hospital setting (ADPAC)

<p>Abstract</p> <p>Background</p> <p>Alcohol dependence affects approximately 3% of the English population, and accounts for significant medical and psychiatric morbidity. Only 5.6% of alcohol-dependent individuals ever access specialist treatment and only a small percentage ever seek treatment. As people who are alcohol dependent are more likely to have experienced health problems leading to frequent attendance at acute hospitals it would seem both sensible and practical to ensure that this setting is utilised as a major access point for treatment, and to test the effectiveness of these treatments.</p> <p>Methods/Design</p> <p>This is a randomised controlled trial with a primary hypothesis that extended brief interventions (EBI) delivered to alcohol-dependent patients in a hospital setting by an Alcohol Specialist Nurse (ASN) will be effective when compared to usual care in reducing overall alcohol consumption and improving on the standard measures of alcohol dependence. Consecutive patients will be screened for alcohol misuse in the Emergency Department (ED) of a district general hospital. On identification of an alcohol-related problem, following informed written consent, we aim to randomize 130 patients per group. The ASN will discharge to usual clinical care all control group patients, and plan a programme of EBI for treatment group patients. Follow-up interview will be undertaken by a researcher blinded to the intervention at 12 and 24 weeks. The primary outcome measure is level of alcohol dependence as determined by the Severity of Alcohol Dependence Questionnaire (SADQ) score. Secondary outcome measures include; Alcohol Use Disorders Identification Test (AUDIT) score, quantity and frequency of alcohol consumption, health-related quality of life measures, service utilisation, and patient experience. The trial will also allow an assessment of the cost-effectiveness of EBI in an acute hospital setting. In addition, patient experience will be assessed using qualitative methods.</p> <p>Discussion</p> <p>This paper presents a protocol for a RCT of EBI delivered to alcohol dependent patients by an ASN within an ED. Importantly; the trial will also seek to understand patients' perceptions and experiences of being part of a RCT and of receiving this form of intervention.</p> <p>Trial registration number</p> <p>ISRCTN: <a href="http://www.controlled-trials.com/ISRCTN78062794">ISRCTN78062794</a></p

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

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

Improved life cycle performance of mechanical ventilation systems

Includes bibliographical references and indexSIGLEAvailable from British Library Document Supply Centre- DSC:8665. 726(30:2003) / BLDSC - British Library Document Supply CentreGBUnited Kingdo

Abstract 3595: Perfusion imaging predicts Outcome in TIA and Minor Stroke. A Prospective Derivation-Validation Study

Background: Patients presenting with transient or minor ischemic symptoms (TIA/MIS) are at risk for early deterioration. Identification of those at highest risk for progression may justify more aggressive acute reperfusion treatments. We tested the hypothesis that baseline perfusion (PWI)- diffusion (DWI) mismatch predicts clinical deterioration and infarct growth on follow-up imaging in this population. Methods: Patients with TIA/MIS (NIH Stroke Scale ≤ 3) were prospectively enrolled and imaged within 24 hours of symptom onset as part of two sequential prospective imaging studies. All patients had clinical follow-up. Baseline DWI and PWI (tmax+4s delay) and follow-up FLAIR infarct volumes (day 30 (derivation), day 90 (validation) cohort) were measured. Mismatch volumes were calculated as (Tmax+4s delay) - DWI lesion volume. Primary outcome was infarct growth on FLAIR imaging which was defined a priori as growth of at least 2.5 ml. Secondary outcome was clinical progression. Results: 137 patients were included in the derivation and 281 patients in the validation cohorts. The rates of DWI (54% vs 56%, p= 0.67) and PWI lesions (42% vs 34.5%, p=0.16) at baseline were similar between the cohorts. The median time between symptom onset and baseline imaging was significantly shorter in the derivation (9.2 h, IQR=9.4) relative to the validation sets (15.1h, IQR=12.5 p<0.001). More patients had follow-up imaging in the derivation (87%) compared to the validation (76%) cohort (p=0.021). Primary and secondary outcome occurred in 18.5% and 9.5% in the derivation and 5.5% and 4.6% in the validation cohort. In the derivation cohort, baseline mismatch volumes adjusting for age, sex and time from symptom onset to MRI significantly predicted radiographic progression (OR=1.06 [1.03-1.09], p<0.001). The optimal threshold for maximizing sensitivity (Sen) and specificity (Spec) in predicting infarct growth occurred at a mismatch volume of 10ml; which correctly predicted infarct expansion with 82% (Sen) and 91%(Spec) (Area under the curve (AUC)= 0.89 [0.80-0.98]). In the validation cohort, this threshold was highly predictive of radiological progression (p=0.011, McNemars test). Linear regression showed that for every 10ml of mismatch, there would be 2.5ml infarct growth on day 30 FLAIR [R=0.80, p<0.001] (derivation set) and 1.1 ml of growth on day 90 FLAIR (R=0.22, p<0.001) (validation set). Baseline mismatch showed a high discriminative value in predicting clinical deterioration in the derivation (AUC =0.81 [0.67-0.96]) and moderate value in the validation cohort (AUC=0.66 [0.46, 0.85]). Conclusion: In a population of patients with minor stroke and TIA, early MR perfusion-diffusion mismatch predicts infarct growth and clinical progression. These findings suggest that there may be a group of patients with minor symptoms in whom reperfusion strategies may be beneficial

Abstract 2674: DWI Reversal is associated with Small Infarct Volume and Early Reperfusion in Patients with TIA and Minor Stroke. Data from VISION and CATCH study groups

Introduction: One-third of patients with TIA and minor ischemic stroke (MIS) have evidence of ischemic penumbra, defined as hypoperfused regions that have not been irreversibly damaged. Diffusion weighted Imaging (DWI) lesions are thought to represent irreversibly damaged tissue. DWI reversal therefore has implications in accurate estimation of penumbra. We aimed to determine the rate of DWI reversal in this population. Methods: Patients with TIA/MIS (NIH Stroke Scale ≤ 3) were prospectively enrolled and imaged within 24 hours of symptom onset as part of two prospective imaging cohorts. Patients were included if their baseline modified Rankin scale (mRS) score was ≤1. All patients were followed clinically for 3 months and had a repeat MRI either at day 30 or 90. Baseline diffusion and perfusion lesions and follow-up FLAIR final infarct volumes were measured. Results: 418 patients were included; 55.5% had DWI lesions and 37% had PWI (Tmax+2s delay) deficits at baseline. A total of 337 (81%) patients had follow-up imaging. DWI reversal occurred in 22/192 (11.5%) of patients who had a diffusion lesion at baseline. The median time from symptom onset to follow-up imaging was not significantly different between those with or without DWI reversal (78.6 days, IQR=33.3 vs. 79.7 days, IQR= 59.4, p=0.65). The median DWI lesion volume was significantly smaller in those with reversal (0.27ml, IQR=0.75 ml) compared to those who did not reverse (1.45 ml, IQR=3.8 ml, p<0.001). Patients with concurrent perfusion deficits (Tmax+2s) were significantly less likely to have DWI reversal (6%) compared to those without evidence of tissue hypoperfusion (20%; p=0.003). DWI reversal occurred in 4% of patients with penumbral patterns ((Tmax+2s)-DWI) and 18% of those without penumbra (p=0.003).Severity of hypoperfusion defined as greater prolongation of Tmax (+2,+4, +6, +8s) did not affect the likelihood of DWI reversal (linear trend p=0.147). No patient with DWI reversal had a mRS of ≥2 at 90 day, compared to 19% of those with evidence of infarction on follow-up imaging (p= 0.02). Conclusion: DWI reversal is common in patients with TIA/MIS and is more likely to occur in those with smaller baseline lesions without concurrent tissue hypoperfusion. DWI reversal therefore should not have a significant effect on the accuracy of penumbra definition. These data suggest early reperfusion is correlated with DWI reversal and better clinical outcome as measured by mRS

Thrombolysis in the developing world: is there a role for streptokinase?

Intravenous thrombolysis with tissue plasminogen activator is the only proven acute therapy for ischemic stroke. This therapy has not been translated into clinical practice in the developing world primarily due to economic constraints. Streptokinase, a lower cost alternative thrombolytic agent, is widely available in developing countries where it is utilized to treat patients with acute coronary syndromes. Although this drug has previously been found to be ineffective in ischemic stroke, the lack of benefit may have been related to a number of factors related to trial design rather than the drug itself. Specific features of prior trial designs that may have adversely affected outcomes include a prolonged treatment window, inclusion of patients with established infarction on computed tomography scan, failure to treat excessive arterial pressures, a fixed dose of streptokinase, and concomitant use of antithrombotic medications. Given the lack of therapeutic alternatives in developing countries, a new trial of streptokinase in acute stroke, utilizing stricter inclusion criteria similar to those in more recent thrombolytic studies, appears warranted

Movable typing of full‐lumen personalized Vein‐Chips to model cerebral venous sinus thrombosis

Abstract Cerebral venous sinus thrombosis (CVST) is a type of stroke associated with COVID‐19 vaccine‐induced immune thrombotic thrombocytopenia. The precise etiology of CVST often remains elusive due to the highly heterogeneous nature of its governing mechanisms, specifically, Virchow's triad that involves altered blood flow, endothelial dysfunction, and hypercoagulability, which varies substantially amongst individuals. Existing diagnostic and monitoring approaches lack the capability to reflect the combination of these patient‐specific thrombotic determinants. In response to this challenge, we introduce a Vein‐Chip platform that recapitulates the CVST vascular anatomy from magnetic resonance venography and the associated hemodynamic flow profile using the “Chinese Movable Type‐like” soft stereolithography technique. The resultant full‐lumen personalized Vein‐Chips, functionalized with endothelial cells, enable in‐vitro thrombosis assays that can elucidate distinct thrombogenic scenarios between normal vascular conditions and those of endothelial dysfunction. The former displayed minimal platelet aggregation and negligible fibrin deposition, while the latter presented significant fibrin extrusion from platelet aggregations. The low‐cost movable typing technique further enhances the potential for commercialization and broader utilization of personalized Vein‐Chips in surgical labs and at‐home monitoring. Future research and development in this direction will pave the way for improved management and prevention of CVST, ultimately benefiting both patients and healthcare systems

Most endovascular thrombectomy patients have Target Mismatch despite absence of formal CT perfusion selection criteria.

Endovascular thrombectomy (EVT) is the standard of care for large vessel occlusion stroke. Use of Computed Tomographic Perfusion (CTP) to select EVT candidates is variable. The frequency of treatment and outcome in patients with unfavourable CTP patterns is unknown. A retrospective analysis of CTP utilisation prior to EVT was conducted. All CTP data were analysed centrally and a Target Mismatch was defined as an infarct core ≤70 ml, penumbral volume ≥15ml, and a total hypoperfused volume:core volume ratio >1.8. The primary outcome was good functional outcome at 90 days, defined as a modified Rankin Scale (mRS) score 0-2. follow-up infarct volume, core expansion and penumbral salvage volumes were secondary outcomes. Of 572 anterior circulation EVT patients, CTP source image data required to generate objective maps were available in 170, and a Target Mismatch was present in 151 (89%). The rate of 90-day good functional outcome was similar between Target Mismatch (53%) and Large Core Non-Mismatch groups (46%, p = 0.629). Median follow-up infarct volume in the Large Core Non-Mismatch group (104ml [IQR 25ml-189ml]) was larger than that in the Target Mismatch patients (16ml [8ml-47ml], p<0.001). Despite a lack of formal CTP selection criteria, the majority of patients treated at our centres had a Target Mismatch. Patients without Target Mismatch had larger follow-up infarct volumes, but the functional recovery rate was similar to that in Target Mismatch patients. Infarct volumes should be included as objective assessment criteria in the evaluation of the efficacy of EVT in non-Target Mismatch patients