The effectiveness and harms of pharmacological interventions for the treatment of delirium in adults admitted into the intensive care unit after cardiac surgery: a systematic review

Background: Patients who undergo cardiac surgery are at high risk of delirium (incidence: 50-90%), increasing the risk of death and adversely affecting recovery. Clinical interventional trials have been conducted to prevent and treat postoperative delirium pharmacologically including antipsychotics and sedatives. These trials have provided some evidence about efficacy and influenced clinical decision making. However, much reporting is incomplete and provides biased assessments of efficacy; benefits are emphasised while harms are inadequately reported. The purpose of this study was to undertake a systematic review using the Joanna Briggs Institute (JBI) methodology that aimed at identifying and synthesising the best available evidence about the effectiveness and harms of pharmacological interventions in the treatment of delirium in adult intensive care patients after cardiac surgery. Inclusion Criteria: Types of participants: Participants were ≥ 16 years, any gender or ethnicity, who were treated postoperatively in a cardiothoracic intensive care unit (ICU) following cardiac surgery and identified as having delirium. Types of interventions: Any pharmacological intervention for the treatment of delirium was included, regardless of drug classification, dosage or frequency of administration. Types of comparators: Studies that compared any pharmacological interventions for the treatment of delirium in patients who were admitted in the ICU after cardiac surgery. No limitations were placed on drug classification, dosage of the medications or frequency of administration. Types of outcomes: This systematic review examined eleven primary and five secondary outcomes of interest. The primary outcomes of interest included: mortality, duration and severity of delirium, use of physical restraints, quality of life, family members satisfaction with delirium management, duration/severity of the aggressive episode, associated falls, severity of accidental self-harm, pharmacological harms, and harms related to over-sedation. Types of studies: Randomised controlled trials (RCTs) were considered first and in their absence, non-RCTs and quasi-experimental would have been considered followed by analytical observational studies. Search Strategy: A comprehensive search was conducted across seven databases, three clinical trial registers and a database for dissertations and theses as well as a hand search for published primary studies. Methodological quality: Two reviewers assessed the methodological quality of the included studies using standardised critical appraisal instruments from JBI and McMaster University. Data extraction: Quantitative data were extracted using the standardised JBI data extraction tool. A meta-analysis was not performed as there was too much clinical and methodological heterogeneity in the included studies. Results have been presented in a narrative form. Standard GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) evidence assessment of outcomes has been reported. Results: Three RCTs investigating morphine vs haloperidol (n=53), ondansetron vs haloperidol (n=72) and dexmedetomidine vs midazolam (n=80) were included. Overall the methodological quality of these studies was found to be low. There is currently insufficient evidence to confirm or refute the effectiveness of morphine compared with haloperidol, ondansetron compared with haloperidol or dexmedetomidine compared with midazolam for reducing the duration or severity of hyperactive delirium in the postoperative cardiac surgical patient treated in the ICU. Additionally, this review found reporting of harms to be inadequate for all three studies and did not meet the required standards for harms reporting. Conclusions: This review was unable to draw any valid conclusions regarding the effectiveness of the included pharmacological interventions in treating delirium after cardiac surgery. This is due to the low number of studies, the poor methodological quality in conducting and reporting and the heterogeneity between the studies. Implications for practice: There is insufficient evidence to support the use of morphine, ondansetron or dexmedetomidine as effective pharmacological agents in treating delirium. It is imperative that clinicians remain vigilant to the known indications, contraindications and harms of the pharmacological agents that are being administered and to understand the implications of such drugs on cardiac performance in the initial postoperative recovery phase after cardiac surgeryThesis (MClinSc) -- University of Adelaide, The Joanna Briggs Institute, 201

Reliability of recommended non-invasive chairside screening tests for diabetes-related peripheral neuropathy : a systematic review with meta-analyses

The objective is to determine, by systematic review, the reliability of testing methods for diagnosis of diabetes-related peripheral neuropathy (DPN) as recommended by the most recent guidelines from the International Diabetes Foundation, International Working Group on the Diabetic Foot and American Diabetes Association. Electronic searches of Cochrane Library, EBSCO Megafile Ultimate and EMBASE were performed to May 2021. Articles were included if they reported on the reliability of recommended chairside tests in diabetes cohorts. Quality appraisal was performed using a Quality Appraisal of Reliability Studies checklist and where possible, meta-analyses, with reliability reported as estimated Cohen's kappa (95% CI). Seventeen studies were eligible for inclusion. Pooled analysis found acceptable inter-rater reliability of vibration perception threshold (VPT) (κ=0.61 (0.50 to 0.73)) and ankle reflex testing (κ=0.60 (0.55 to 0.64)), but weak inter-rater reliability for pinprick (κ=0.45 (0.22 to 0.69)) and 128 Hz tuning fork (κ=0.42 (0.15 to 0.70)), though intra-rater reliability of the 128 Hz tuning fork was moderate (κ=0.54 (0.37 to 0.73)). Inter-rater reliability of the four-site monofilament was acceptable (κ=0.61 (0.45 to 0.77)). These results support the clinical use of VPT, ankle reflexes and four-site monofilament for screening and ongoing monitoring of DPN as recommended by the latest guidelines. The reliability of temperature perception, pinprick, proprioception, three-site monofilament and Ipswich touch test when performed in people with diabetes remains unclear

Coagulation Profiles in Humans Exposed to Exertional Hypobaric Decompression Stress Determined by Calibrated Automated Thrombogram

Citation: Madden, L.A.; Vince, R.V.; Edwards, V.C.; Lee, V.M.; Connolly, D.M. Coagulation Profiles in Humans Abstract: The blood coagulation response to decompression stress in humans has yet to be fully investigated. Here we utilised calibrated automated thrombogram (CAT) on samples from healthy volunteers exposed to decompression stress to investigate real-time thrombin generation. To induce decompression stress, fifteen apparently healthy males (age 20-50 yr) were exposed to two consecutive ascents to 25,000 ft for 60 min (1st ascent) and then 90 min (2nd ascent) while breathing 100% oxygen. Citrated blood samples were taken prior to exposure (T0), following the 2nd ascent (T8) and at 24 h (T24). Thrombin generation curves were obtained using Thrombinoscope TM. Parameters determined were lag time (LAG), time to peak (TTP), peak thrombin (PEAK), endogenous thrombin potential (ETP) and velocity index (VEL). Of the 15 subjects, 12 had validated coagulation profiles. TTP and ETP showed no significant differences. However, there was a significant increase in VEL from T0 to T8 (p = 0.025) and from T8 to T24 (p = 0.043). A non-significant trend of an overall increase in PEAK was also observed from T0 to T8 (p = 0.069) and from T8 to T24 (p = 0.098). PEAK and VEL were found to be correlated. Taken together, these two parameters suggest an overall shift towards a more procoagulant profile following hypobaric stress

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

Providing a listening ear

The excellent work carried out by the the Pharmacists’ Support Service (PSS) in providing a listening ear to pharmacists in distress has been widely recognised by the pharmacy profession and is reflected in the support it receives from many pharmacy organisation. Vivienne Mak and Emeritus Professor Andrew Gilbert have analysed de‑identified data from call records to provide an informative assessment of the reasons pharmacists used the PSS.

Brain and Lung Biomarker Responses to Hyperoxic Hypobaric Decompression

INTRODUCTION: Biomarker responses to intensive decompression indicate systemic pro-inflammatory responses and possible neurological stress. Twelve additional brain and lungbiomarkers were assayed to further investigate responses. METHODS: Fifteen healthy men (20 to 50 yrs) undertook consecutive same-day ascents to 25,000 ft following denitrogenation,breathing 100% oxygen. Venous blood was sampled at baseline (T0), after the second ascent (T8), and next morning (T24). Soluble protein markers of brain and lung insult were analysedby enzyme-linked immunosorbent assay with plasma microparticles quantified using flow cytometry. RESULTS: Levels of monocyte chemoattractant protein-1 and high mobility group box protein 1 were elevated at T8, by 36% and 16% respectively, before returning to baseline. Levels of soluble receptor for advanced glycation end products fell by 8%, recovering by T24.Brain-derived neurotrophic factor rose by 80% over baseline at T24. Monocyte microparticle levels rose by factors of 3.7 at T8 and 2.7 at T24, due to early and late responses in different subjects. Other biomarkers were unaffected or not detected consistently. CONCLUSIONS:The elevated biomarkers at T8 suggest a neuroinflammatory response, with later elevation of brain-derived neurotrophic factor at T24 indicating an ongoing neurotrophic response and incomplete recovery. A substantial increase at T8 in the ratio of high mobility group box protein 1 to soluble receptor for advanced glycation end products suggests this axis may mediate the systemic inflammatory response to decompression. The mechanism ofneuroinflammation is unclear but elevation of monocyte microparticles and monocyte chemoattractant protein-1 imply a key role for activated monocytes and/or macrophages

Synthesis of pincer-type N-heterocyclic carbene palladium complexes with a hemilabile ligand and their application in cross-coupling catalysis

Benzimidazolium salts containing both a neutral imine and a masked carboxylate functional group for potential metal chelation were prepared. Palladation of the ester-protected ligand afforded a N,C-bidentate carbene complex 4. Subsequent ester hydrolysis preserved the bidentate coordination mode and yielded complex 5 with a pending COOH group exclusively. However, when ester deprotection was carried out prior to metalation, the N,C,O-tridentate pincer-type coordinated palladium complex 7 was obtained. Proton-abstraction of the dangling COOH group in the bidentate ligand of complex 5 by treatment with a base led to the formation of the N,C,O-tridentate coordinated Pd system 7, and inversely, exposure of the tridentate bound Pd complex 7 with acid afforded the N,C-bidentate ligand coordination mode in complex 5, demonstrating hemilability of the oxygen donor site in the pincer ligand. All three palladium(II) complexes 4, 5, and 7 were evaluated in cross-coupling catalysis and revealed distinct activity differences that are dependent on the type of coupling (Suzuki vs. Heck) and the substrate (Ar-Br vs. Ar-Cl). These differences suggest that judicious choice of donor groups in pincer-type complexes is a viable strategy for catalyst optimization.European Research CouncilScience Foundation Irelan