Intensive care nurse-led point of care ultrasound in the assessment and management of the critically ill COVID-19 patient: A single centre case series.

Focused ultrasound can be used to rapidly diagnose COVID-19 disease, assess disease severity, and inform management of COVID-19 and associated pathologies, reducing radiation exposure from other imaging modalities and minimizing spread of infection. Ultrasound examinations performed by trained nurses in the intensive care unit (ICU) enable more patients to receive these assessments. This case series evaluates the use of nurse-led focused cardiac and lung ultrasound for clinical management of ICU patients with COVID-19. We describe common pathophysiological findings and how findings were used to inform clinical decision-making. An ultrasound trained ICU nurse performed Focused Ultrasound in Intensive Care (FUSIC) cardiac and lung scans enabling calculation of a lung severity score on adult ICU patients with a confirmed COVID-19 diagnosis in a single-centre setting. Fifteen scans were performed on 15 patients. Thirteen (87%) patients had normal left ventricular function; 12 (80%) normal right ventricular function. All 15 (100%) scans identified abnormal lung findings including irregular thickened pleura, B-lines, sub-pleural consolidation and hepatization. Worse lung severity scores were correlated with higher Acute Physiology and Chronic Health Evaluation (APACHE II) scores (r = 0.70; p = .003). Of the 15 scans, 10 (67%) identified abnormal pathology contributing to a change in clinical management. This included targeted fluid removal (4, 27%), change in respiratory management (3, 20%) and need for formal echocardiographic assessment (3, 20%). Findings from five (33%) scans required no intervention. This case series demonstrates nurse-led ultrasound could be a useful adjunct in the management of the COVID-19 patient.

Updated variant curation expert panel criteria and pathogenicity classifications for 251 variants for RYR1-related malignant hyperthermia susceptibility.

The ClinGen malignant hyperthermia susceptibility (MHS) variant curation expert panel specified the American College of Medical Genetics and Genomics/Association of Molecular Pathologists (ACMG/AMP) criteria for RYR1-related MHS and a pilot analysis of 84 variants was published. We have now classified an additional 251 variants for RYR1-related MHS according to current ClinGen standards and updated the criteria where necessary. Criterion PS4 was modified such that individuals with multiple RYR1 variants classified as pathogenic (P), likely pathogenic (LP), or variant of uncertain significance (VUS) were not considered as providing evidence for pathogenicity. Criteria PS1 and PM5 were revised to consider LP variants at the same amino-acid residue as providing evidence for pathogenicity at reduced strength. Finally, PM1 was revised such that if PS1 or PM5 are used PM1, if applicable, should be downgraded to supporting. Of the 251 RYR1 variants, 42 were classified as P/LP, 16 as B/LB, and 193 as VUS. The primary driver of 175 VUS classifications was insufficient evidence supporting pathogenicity, rather than evidence against pathogenicity. Functional data supporting PS3/BS3 was identified for only 13 variants. Based on the posterior probabilities of pathogenicity and variant frequencies in gnomAD, we estimated the prevalence of individuals with RYR1-related MHS pathogenic variants to be between 1/300 and 1/1075, considerably higher than current estimates. We have updated ACMG/AMP criteria for RYR1-related MHS and classified 251 variants. We suggest that prioritization of functional studies is needed to resolve the large number of VUS classifications and allow for appropriate risk assessment. RYR1-related MHS pathogenic variants are likely to be more common than currently appreciated.

Repair of acute respiratory distress syndrome by stromal cell administration (REALIST): a structured study protocol for an open-label dose-escalation phase 1 trial followed by a randomised, triple-blind, allocation concealed, placebo-controlled phase 2 trial.

BACKGROUND: Mesenchymal stromal cells (MSCs) may be of benefit in ARDS due to immunomodulatory and reparative properties. This trial investigates a novel CD362 enriched umbilical cord derived MSC product (REALIST ORBCEL-C), produced to Good Manufacturing Practice standards, in patients with moderate to severe ARDS due to COVID-19 and ARDS due to other causes. METHODS: Phase 1 is a multicentre open-label dose-escalation pilot trial. Patients will receive a single infusion of REALIST ORBCEL-C (100 × 106 cells, 200 × 106 cells or 400 × 106 cells) in a 3 + 3 design. Phase 2 is a multicentre randomised, triple blind, allocation concealed placebo-controlled trial. Two cohorts of patients, with ARDS due to COVID-19 or ARDS due to other causes, will be recruited and randomised 1:1 to receive either a single infusion of REALIST ORBCEL-C (400 × 106 cells or maximal tolerated dose in phase 1) or placebo. Planned recruitment to each cohort is 60 patients. The primary safety outcome is the incidence of serious adverse events. The primary efficacy outcome is oxygenation index at day 7. The trial will be reported according to the Consolidated Standards for Reporting Trials (CONSORT 2010) statement. DISCUSSION: The development and manufacture of an advanced therapy medicinal product to Good Manufacturing Practice standards within NHS infrastructure are discussed, including challenges encountered during the early stages of trial set up. The rationale to include a separate cohort of patients with ARDS due to COVID-19 in phase 2 of the trial is outlined. TRIAL REGISTRATION: ClinicalTrials.gov NCT03042143. Registered on 3 February 2017. EudraCT Number 2017-000584-33.

Regional anesthesia for shoulder surgery.

Regional anesthesia should be the preferred technique for analgesia in shoulder surgery, which is a frequent procedure in the daily practice of anesthesiologists. The use of ultrasound guidance enables the visualization of the relevant nerve structures and the adjacent anatomical details. Low volumes of local anesthetics reduce the incidence of inadvertent blockade of the phrenic nerve with subsequent respiratory impairment. The additional administration of dexmedetomidine to local anesthetics prolonges the duration of analgesia with a minimal increased incidence of haemodynamic side effects. An optimal workflow is associated with economical advantages due to an improved use of operation rooms. Attention have to be paid regarding intraoperative hypotension, cerebral hypoperfusion and complications due to positioning.

Decision rules for determining terrestrial movement and the consequences for filtering high-resolution global positioning system tracks: a case study using the African lion (Panthera leo).

The combined use of global positioning system (GPS) technology and motion sensors within the discipline of movement ecology has increased over recent years. This is particularly the case for instrumented wildlife, with many studies now opting to record parameters at high (infra-second) sampling frequencies. However, the detail with which GPS loggers can elucidate fine-scale movement depends on the precision and accuracy of fixes, with accuracy being affected by signal reception. We hypothesized that animal behaviour was the main factor affecting fix inaccuracy, with inherent GPS positional noise (jitter) being most apparent during GPS fixes for non-moving locations, thereby producing disproportionate error during rest periods. A movement-verified filtering (MVF) protocol was constructed to compare GPS-derived speed data with dynamic body acceleration, to provide a computationally quick method for identifying genuine travelling movement. This method was tested on 11 free-ranging lions (Panthera leo) fitted with collar-mounted GPS units and tri-axial motion sensors recording at 1 and 40 Hz, respectively. The findings support the hypothesis and show that distance moved estimates were, on average, overestimated by greater than 80% prior to GPS screening. We present the conceptual and mathematical protocols for screening fix inaccuracy within high-resolution GPS datasets and demonstrate the importance that MVF has for avoiding inaccurate and biased estimates of movement.

How often should dead-reckoned animal movement paths be corrected for drift?

BACKGROUND: Understanding what animals do in time and space is important for a range of ecological questions, however accurate estimates of how animals use space is challenging. Within the use of animal-attached tags, radio telemetry (including the Global Positioning System, 'GPS') is typically used to verify an animal's location periodically. Straight lines are typically drawn between these 'Verified Positions' ('VPs') so the interpolation of space-use is limited by the temporal and spatial resolution of the system's measurement. As such, parameters such as route-taken and distance travelled can be poorly represented when using VP systems alone. Dead-reckoning has been suggested as a technique to improve the accuracy and resolution of reconstructed movement paths, whilst maximising battery life of VP systems. This typically involves deriving travel vectors from motion sensor systems and periodically correcting path dimensions for drift with simultaneously deployed VP systems. How often paths should be corrected for drift, however, has remained unclear. METHODS AND RESULTS: Here, we review the utility of dead-reckoning across four contrasting model species using different forms of locomotion (the African lion Panthera leo, the red-tailed tropicbird Phaethon rubricauda, the Magellanic penguin Spheniscus magellanicus, and the imperial cormorant Leucocarbo atriceps). Simulations were performed to examine the extent of dead-reckoning error, relative to VPs, as a function of Verified Position correction (VP correction) rate and the effect of this on estimates of distance moved. Dead-reckoning error was greatest for animals travelling within air and water. We demonstrate how sources of measurement error can arise within VP-corrected dead-reckoned tracks and propose advancements to this procedure to maximise dead-reckoning accuracy. CONCLUSIONS: We review the utility of VP-corrected dead-reckoning according to movement type and consider a range of ecological questions that would benefit from dead-reckoning, primarily concerning animal-barrier interactions and foraging strategies.

COVID-19-related acute kidney injury; incidence, risk factors and outcomes in a large UK cohort.

BACKGROUND: Acute kidney injury (AKI) is common among patients hospitalised with COVID-19 and associated with worse prognosis. The aim of this study was to investigate the epidemiology, risk factors and outcomes of AKI in patients with COVID-19 in a large UK tertiary centre. METHODS: We analysed data of consecutive adults admitted with a laboratory-confirmed diagnosis of COVID-19 across two sites of a hospital in London, UK, from 1st January to 13th May 2020. RESULTS: Of the 1248 inpatients included, 487 (39%) experienced AKI (51% stage 1, 13% stage 2, and 36% stage 3). The weekly AKI incidence rate gradually increased to peak at week 5 (3.12 cases/100 patient-days), before reducing to its nadir (0.83 cases/100 patient-days) at the end the study period (week 10). Among AKI survivors, 84.0% had recovered renal function to pre-admission levels before discharge and none required on-going renal replacement therapy (RRT). Pre-existing renal impairment [odds ratio (OR) 3.05, 95%CI 2.24-4,18; p <  0.0001], and inpatient diuretic use (OR 1.79, 95%CI 1.27-2.53; p <  0.005) were independently associated with a higher risk for AKI. AKI was a strong predictor of 30-day mortality with an increasing risk across AKI stages [adjusted hazard ratio (HR) 1.59 (95%CI 1.19-2.13) for stage 1; p < 0.005, 2.71(95%CI 1.82-4.05); p < 0.001for stage 2 and 2.99 (95%CI 2.17-4.11); p < 0.001for stage 3]. One third of AKI3 survivors (30.7%), had newly established renal impairment at 3 to 6 months. CONCLUSIONS: This large UK cohort demonstrated a high AKI incidence and was associated with increased mortality even at stage 1. Inpatient diuretic use was linked to a higher AKI risk. One third of survivors with AKI3 exhibited newly established renal impairment already at 3-6 months.

Repair of acute respiratory distress syndrome by stromal cell administration (REALIST) trial: A phase 1 trial.

BACKGROUND: Mesenchymal stromal cells (MSCs) may be of benefit in acute respiratory distress syndrome (ARDS) due to immunomodulatory, reparative, and antimicrobial actions. ORBCEL-C is a population of CD362 enriched umbilical cord-derived MSCs. The REALIST phase 1 trial investigated the safety and feasibility of ORBCEL-C in patients with moderate to severe ARDS. METHODS: REALIST phase 1 was an open label, dose escalation trial in which cohorts of mechanically ventilated patients with moderate to severe ARDS received increasing doses (100, 200 or 400 × 106 cells) of a single intravenous infusion of ORBCEL-C in a 3 + 3 design. The primary safety outcome was the incidence of serious adverse events. Dose limiting toxicity was defined as a serious adverse reaction within seven days. Trial registration clinicaltrials.gov NCT03042143. FINDINGS: Nine patients were recruited between the 7th January 2019 and 14th January 2020. Study drug administration was well tolerated and no dose limiting toxicity was reported in any of the three cohorts. Eight adverse events were reported for four patients. Pyrexia within 24 h of study drug administration was reported in two patients as pre-specified adverse events. A further two adverse events (non-sustained ventricular tachycardia and deranged liver enzymes), were reported as adverse reactions. Four serious adverse events were reported (colonic perforation, gastric perforation, bradycardia and myocarditis) but none were deemed related to administration of ORBCEL-C. At day 28 no patients had died in cohort one (100 × 106), three patients had died in cohort two (200 × 106) and one patient had died in cohort three (400 × 106). Overall day 28 mortality was 44% (n = 4/9). INTERPRETATION: A single intravenous infusion of ORBCEL-C was well tolerated in patients with moderate to severe ARDS. No dose limiting toxicity was reported up to 400 × 106 cells.

Natural language word embeddings as a glimpse into healthcare language and associated mortality surrounding end of life.

OBJECTIVES: To clarify real-world linguistic nuances around dying in hospital as well as inaccuracy in individual-level prognostication to support advance care planning and personalised discussions on limitation of life sustaining treatment (LST). DESIGN: Retrospective cross-sectional study of real-world clinical data. SETTING: Secondary care, urban and suburban teaching hospitals. PARTICIPANTS: All inpatients in 12-month period from 1 October 2018 to 30 September 2019. METHODS: Using unsupervised natural language processing, word embedding in latent space was used to generate phrase clusters with most similar semantic embeddings to 'Ceiling of Treatment' and their prognostication value. RESULTS: Word embeddings with most similarity to 'Ceiling of Treatment' clustered around phrases describing end-of-life care, ceiling of care and LST discussions. The phrases have differing prognostic profile with the highest 7-day mortality in the phrases most explicitly referring to end of life-'Withdrawal of care' (56.7%), 'terminal care/end of life care' (57.5%) and 'un-survivable' (57.6%). CONCLUSION: Vocabulary used at end-of-life discussions are diverse and has a range of associations to 7-day mortality. This highlights the importance of correct application of terminology during LST and end-of-life discussions.

A new direction for differentiating animal activity based on measuring angular velocity about the yaw axis.

The use of animal-attached data loggers to quantify animal movement has increased in popularity and application in recent years. High-resolution tri-axial acceleration and magnetometry measurements have been fundamental in elucidating fine-scale animal movements, providing information on posture, traveling speed, energy expenditure, and associated behavioral patterns. Heading is a key variable obtained from the tandem use of magnetometers and accelerometers, although few field investigations have explored fine-scale changes in heading to elucidate differences in animal activity (beyond the notable exceptions of dead-reckoning).This paper provides an overview of the value and use of animal heading and a prime derivative, angular velocity about the yaw axis, as an important element for assessing activity extent with potential to allude to behaviors, using "free-ranging" Loggerhead turtles (Caretta caretta) as a model species.We also demonstrate the value of yaw rotation for assessing activity extent, which varies over the time scales considered and show that various scales of body rotation, particularly rate of change of yaw, can help resolve differences between fine-scale behavior-specific movements. For example, oscillating yaw movements about a central point of the body's arc implies bouts of foraging, while unusual circling behavior, indicative of conspecific interactions, could be identified from complete revolutions of the longitudinal axis.We believe this approach should help identification of behaviors and "space-state" approaches to enhance our interpretation of behavior-based movements, particularly in scenarios where acceleration metrics have limited value, such as for slow-moving animals.

Repair of Acute Respiratory Distress Syndrome by Stromal Cell Administration in COVID-19 (REALIST-COVID-19): A structured summary of a study protocol for a randomised, controlled trial.

OBJECTIVES: The primary objective of the study is to assess the safety of a single intravenous infusion of Mesenchymal Stromal Cells (MSCs) in patients with Acute Respiratory Distress Syndrome (ARDS) due to COVID-19. Secondary objectives are to determine the effects of MSCs on important clinical outcomes, as described below. TRIAL DESIGN: REALIST COVID 19 is a randomised, placebo-controlled, triple blinded trial. PARTICIPANTS: The study will be conducted in Intensive Care Units in hospitals across the United Kingdom. Patients with moderate to severe ARDS as defined by the Berlin definition, receiving invasive mechanical ventilation and with a diagnosis of COVID-19 based on clinical diagnosis or PCR test will be eligible. Patients will be excluded for the following reasons: more than 72 hours from the onset of ARDS; age < 16 years; patient known to be pregnant; major trauma in previous 5 days; presence of any active malignancy (other than non-melanoma skin cancer); WHO Class III or IV pulmonary hypertension; venous thromboembolism currently receiving anti-coagulation or within the past 3 months; patient receiving extracorporeal life support; severe chronic liver disease (Child-Pugh > 12); Do Not Attempt Resuscitation order in place; treatment withdrawal imminent within 24 hours; prisoners; declined consent; non-English speaking patients or those who do not adequately understand verbal or written information unless an interpreter is available; previously enrolled in the REALIST trial. INTERVENTION AND COMPARATOR: Intervention: Allogeneic donor CD362 enriched human umbilical cord derived mesenchymal stromal cells (REALIST ORBCEL-C) supplied as sterile, single-use cryopreserved cell suspension of a fixed dose of 400 x106 cells in 40ml volume, to be diluted in Plasma-Lyte 148 to a total volume of 200mls for administration. Comparator (placebo): Plasma-Lyte 148 Solution for Infusion (200mls). The cellular product (REALIST ORBCEL-C) was developed and patented by Orbsen Therapeutics. MAIN OUTCOMES: The primary safety outcome is the incidence of serious adverse events. The primary efficacy outcome is Oxygenation Index (OI) at day 7. Secondary outcomes include: OI at days 4 and 14; respiratory compliance, driving pressure and PaO2/FiO2 ratio (PF ratio) at days 4, 7 and 14; Sequential Organ Failure Assessment (SOFA) score at days 4, 7 and 14; extubation and reintubation; ventilation free days at day 28; duration of mechanical ventilation; length of ICU and hospital stay; 28-day and 90-day mortality. RANDOMISATION: After obtaining informed consent, patients will be randomised via a centralised automated 24-hour telephone or web-based randomisation system (CHaRT, Centre for Healthcare Randomised Trials, University of Aberdeen). Randomisation will be stratified by recruitment centre and by vasopressor use and patients will be allocated to REALIST ORBCEL-C or placebo control in a 1:1 ratio. BLINDING (MASKING): The investigator, treating physician, other members of the site research team and participants will be blinded. The cell therapy facility and clinical trials pharmacist will be unblinded to facilitate intervention and placebo preparation. The unblinded individuals will keep the treatment information confidential. The infusion bag will be masked at the time of preparation and will be administered via a masked infusion set. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A sample size of 60 patients with 30 patients randomised to the intervention and 30 to the control group. If possible, recruitment will continue beyond 60 patients to provide more accurate and definitive trial results. The total number of patients recruited will depend on the pandemic and be guided by the data monitoring and ethics committee (DMEC). TRIAL STATUS: REALIST Phase 1 completed in January 2020 prior to the COVID-19 pandemic. This was an open label dose escalation study of REALIST ORBCEL-C in patients with ARDS. The COVID-19 pandemic emerged as REALIST Phase 2 was planned to commence and the investigator team decided to repurpose the Phase 2 trial as a COVID-19 specific trial. This decision was discussed and approved by the Trial Steering Committee (TSC) and DMEC. Submissions were made to the Research Ethics Committee (REC) and MHRA to amend the protocol to a COVID-19 specific patient population and the protocol amendment was accepted by the REC on 27th March 2020 and MHRA on 30th March 2020 respectively. Other protocol changes in this amendment included an increase in the time of onset of ARDS from 48 to 72 hours, inclusion of clinical outcomes as secondary outcomes, the provision of an option for telephone consent, an indicative sample size and provision to continue recruitment beyond this indicative sample size. The current protocol in use is version 4.0 23.03.2020 (Additional file 1). Urgent Public Health status was awarded by the NIHR on 2 April 2020 and the trial opened to recruitment and recruited the first participant the same day. At the time of publication the trial was open to recruitment at 5 sites across the UK (Belfast Health and Social Care Trust, King's College London, Guys and St Thomas' Hospital London, Birmingham Heartlands Hospital and the Queen Elizabeth Hospital Birmingham) and 12 patients have been recruited across these sites. Additional sites are planned to open and appropriate approvals for these are being obtained. It is estimated recruitment will continue for 6 months. TRIAL REGISTRATION: ClinicalTrials.gov NCT03042143 (Registered 3 Feb 2017). EudraCT 2017-000585-33 (Registered 28 Nov 2017). FULL PROTOCOL: The full protocol (version 4.0 23.03.2020) is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

Comparative epidemiology of suspected perioperative hypersensitivity reactions.

Suspected perioperative hypersensitivity reactions are rare but contribute significantly to the morbidity and mortality of surgical procedures. Recent publications have highlighted the differences between countries concerning the respective risk of different drugs, and changes in patterns of causal agents and the emergence of new allergens. This review summarises recent information on the epidemiology of perioperative hypersensitivity reactions, with specific consideration of differences between geographic areas for the most frequently involved offending agents.

Dexamethasone as an adjuvant for peripheral nerve blockade: a randomised, triple-blinded crossover study in volunteers.

BACKGROUND: The efficacy of dexamethasone in extending the duration of local anaesthetic block is uncertain. In a randomised controlled triple blind crossover study in volunteers, we tested the hypothesis that neither i.v. nor perineurally administered dexamethasone prolongs the sensory block achieved with ropivacaine. METHODS: Ultrasound-guided ulnar nerve blocks (ropivacaine 0.75% wt/vol, 3 ml, with saline 1 ml with or without dexamethasone 4 mg) were performed on three occasions in 24 male volunteers along with an i.v. injection of saline 1 ml with or without dexamethasone 4 mg. The combinations of saline and dexamethasone were as follows: control group, perineural and i.v. saline; perineural group, perineural dexamethasone and i.v. saline; i.v. group, perineural saline and i.v. dexamethasone. Sensory block was measured using a VAS in response to pinprick testing. The duration of sensory block was the primary outcome and time to onset of sensory block the secondary outcome. RESULTS: All 24 subjects completed the trial. The median [inter-quartile range (IQR)] duration of sensory block was 6.87 (5.85-7.62) h in the control group, 7.37 (5.78-7.93) h in the perineural group and 7.37 (6.10-7.97) h in the i.v. group (P=0.61). There was also no significant difference in block onset time between the three groups. CONCLUSION: Dexamethasone 4 mg has no clinically relevant effect on the duration of sensory block provided by ropivacaine applied to the ulnar nerve. CLINICAL TRIAL REGISTRATION: DRKS, 00014604; EudraCT, 2018-001221-98.