Early Intravenous Beta-Blockade with Esmolol in Adults with Severe Traumatic Brain Injury: A Phase 2a Intervention Design Study.

BACKGROUND: Targeted beta-blockade after severe traumatic brain injury may reduce secondary brain injury by attenuating the sympathoadrenal response. The potential role and optimal dosage for esmolol, a selective, short-acting, titratable beta-1 beta-blocker, as a safe, putative early therapy after major traumatic brain injury has not been assessed. METHODS: We conducted a single-center, open-label dose-finding study using an adaptive model-based design. Adults (18 years or older) with severe traumatic brain injury and intracranial pressure monitoring received esmolol within 24 h of injury to reduce their heart rate by 15% from baseline of the preceding 4 h while ensuring cerebral perfusion pressure was maintained above 60 mm Hg. In cohorts of three, the starting dosage and dosage increments were escalated according to a prespecified plan in the absence of dose-limiting toxicity. Dose-limiting toxicity was defined as failure to maintain cerebral perfusion pressure, triggering cessation of esmolol infusion. The primary outcome was the maximum tolerated dosage schedule of esmolol, defined as that associated with less than 10% probability of dose-limiting toxicity. Secondary outcomes include 6-month mortality and 6-month extended Glasgow Outcome Scale score. RESULTS: Sixteen patients (6 [37.5%] female patients; mean age 36 years [standard deviation 13 years]) with a median Glasgow Coma Scale score of 6.5 (interquartile range 5-7) received esmolol. The optimal starting dosage of esmolol was 10 µg/kg/min, with increments every 30 min of 5 µg/kg/min, as it was the highest dosage with less than 10% estimated probability of dose-limiting toxicity (7%). All-cause mortality was 12.5% at 6 months (corresponding to a standardized mortality ratio of 0.63). One dose-limiting toxicity event and no serious adverse hemodynamic effects were seen. CONCLUSIONS: Esmolol administration, titrated to a heart rate reduction of 15%, is feasible within 24 h of severe traumatic brain injury. The probability of dose-limiting toxicity requiring withdrawal of esmolol when using the optimized schedule is low. Trial registrationI SRCTN, ISRCTN11038397, registered retrospectively January 7, 2021 ( https://www.isrctn.com/ISRCTN11038397 ).

The fragility index in randomised controlled trials of interventions for aneurysmal subarachnoid haemorrhage: A systematic review.

Background: Fragility analysis supplements the p-value and risk of bias assessment in the interpretation of results of randomised controlled trials. In this systematic review we determine the fragility index (FI) and fragility quotient (FQ) of randomised trials in aneurysmal subarachnoid haemorrhage. Methods: This is a systematic review registered with PROSPERO (ID: CRD42020173604). Randomised controlled trials in adults with aneurysmal subarachnoid haemorrhage were analysed if they reported a statistically significant primary outcome of mortality, function (e.g. modified Rankin Scale), vasospasm or delayed neurological deterioration. Results: We identified 4825 records with 18 randomised trials selected for analysis. The median fragility index was 2.5 (inter-quartile range 0.25-5) and the median fragility quotient was 0.015 (IQR 0.02-0.039). Five of 20 trial outcomes (25%) had a fragility index of 0. In seven trials (39.0%), the number of participants lost to follow-up was greater than or equal to the fragility index. Only 16.7% of trials are at low risk of bias. Conclusion: Randomised controlled trial evidence supporting management of aneurysmal subarachnoid haemorrhage is weaker than indicated by conventional analysis using p-values alone. Increased use of fragility analysis by clinicians and researchers could improve the translation of evidence to practice.

Education in times of restriction: an examination of refugee girls' and young women's access to learning during COVID-19 school closures in Pakistan.

This paper examines the extent to which refugee girls and young women were able to access learning during COVID-19 education closures in Pakistan, and the role that EdTech played in their learning access. It is based on findings from a survey with 403 Afghan refugee students, along with in-depth interviews with six young female refugees. The research shows that, while the majority of female refugee students were able to continue accessing education in some form during school closures, learning access was nevertheless limited, and a sizable minority were not engaged in any learning during this time. Teacher and institutional support was either absent or inadequate for many students, and infrastructure and devices that serve to support remote learning were not always reliable or accessible. Although male respondents were less likely than females to engage in independent study during the closures, refugee girls and young women were significantly less likely than their male counterparts to own the devices they needed for learning. The findings demonstrate how targeted investment in specific types of EdTech and teacher professional development, as well as supporting educational institutions in the establishment of remote learning opportunities, could help sustain learning during future periods of educational restriction.

Early Intravenous Beta-Blockade with Esmolol in Adults with Severe Traumatic Brain Injury (EBB-TBI): Protocol for a Phase 2a Intervention Design Study.

Traumatic brain injury is a leading cause of death and disability worldwide. Interventions that mitigate secondary brain injury have the potential to improve outcomes for patients and reduce the impact on communities and society. Increased circulating catecholamines are associated with worse outcomes and there are supportive animal data and indications in human studies of benefit from beta-blockade after severe traumatic brain injury. Here, we present the protocol for a dose-finding study using esmolol in adults commenced within 24 h of severe traumatic brain injury. Esmolol has practical advantages and theoretical benefits as a neuroprotective agent in this setting, but these must be balanced against the known risk of secondary injury from hypotension. The aim of this study is to determine a dose schedule for esmolol, using the continual reassessment method, that combines a clinically significant reduction in heart rate as a surrogate for catecholamine drive with maintenance of cerebral perfusion pressure. The maximum tolerated dosing schedule for esmolol can then be tested for patient benefit in subsequent randomized controlled trials.Trial registration ISRCTN, ISRCTN11038397, registered retrospectively 07/01/2021 https://www.isrctn.com/ISRCTN11038397.

Hypothermia vs Normothermia in Patients With Cardiac Arrest and Nonshockable Rhythm: A Meta-Analysis.

Importance: International guidelines recommend body temperature control below 37.8 °C in unconscious patients with out-of-hospital cardiac arrest (OHCA); however, a target temperature of 33 °C might lead to better outcomes when the initial rhythm is nonshockable. Objective: To assess whether hypothermia at 33 °C increases survival and improves function when compared with controlled normothermia in unconscious adults resuscitated from OHCA with initial nonshockable rhythm. Data Sources: Individual patient data meta-analysis of 2 multicenter, randomized clinical trials (Targeted Normothermia after Out-of-Hospital Cardiac Arrest [TTM2; NCT02908308] and HYPERION [NCT01994772]) with blinded outcome assessors. Unconscious patients with OHCA and an initial nonshockable rhythm were eligible for the final analysis. Study Selection: The study cohorts had similar inclusion and exclusion criteria. Patients were randomized to hypothermia (target temperature 33 °C) or normothermia (target temperature 36.5 to 37.7 °C), according to different study protocols, for at least 24 hours. Additional analyses of mortality and unfavorable functional outcome were performed according to age, sex, initial rhythm, presence or absence of shock on admission, time to return of spontaneous circulation, lactate levels on admission, and the cardiac arrest hospital prognosis score. Data Extraction and Synthesis: Only patients who experienced OHCA and had a nonshockable rhythm with all causes of cardiac arrest were included. Variables from the 2 studies were available from the original data sets and pooled into a unique database and analyzed. Clinical outcomes were harmonized into a single file, which was checked for accuracy of numbers, distributions, and categories. The last day of follow-up from arrest was recorded for each patient. Adjustment for primary outcome and functional outcome was performed using age, gender, time to return of spontaneous circulation, and bystander cardiopulmonary resuscitation. Main Outcomes and Measures: The primary outcome was mortality at 3 months; secondary outcomes included unfavorable functional outcome at 3 to 6 months, defined as a Cerebral Performance Category score of 3 to 5. Results: A total of 912 patients were included, 490 from the TTM2 trial and 422 from the HYPERION trial. Of those, 442 had been assigned to hypothermia (48.4%; mean age, 65.5 years; 287 males [64.9%]) and 470 to normothermia (51.6%; mean age, 65.6 years; 327 males [69.6%]); 571 patients had a first monitored rhythm of asystole (62.6%) and 503 a presumed noncardiac cause of arrest (55.2%). At 3 months, 354 of 442 patients in the hypothermia group (80.1%) and 386 of 470 patients in the normothermia group (82.1%) had died (relative risk [RR] with hypothermia, 1.04; 95% CI, 0.89-1.20; P = .63). On the last day of follow-up, 386 of 429 in the hypothermia group (90.0%) and 413 of 463 in the normothermia group (89.2%) had an unfavorable functional outcome (RR with hypothermia, 0.99; 95% CI, 0.87-1.15; P = .97). The association of hypothermia with death and functional outcome was consistent across the prespecified subgroups. Conclusions and Relevance: In this individual patient data meta-analysis, including unconscious survivors from OHCA with an initial nonshockable rhythm, hypothermia at 33 °C did not significantly improve survival or functional outcome.

Cognitive remediation therapy - implementation and translation into clinical practice in rural and metropolitan New South Wales mental health services.

OBJECTIVE: Cognitive Remediation Therapy (CRT) is an effective intervention in managing the significant cognitive deficits experienced by those living with psychosis. Given its strong evidence base CRT is recommended in Australian and international guidelines for rehabilitation of people with psychosis, however, access to CRT remains limited. In this commentary, we describe recent efforts to implement CRT programs within NSW mental health services. Development of CRT delivery has been successfully achieved in both rural and metropolitan settings, utilising both face-to-face and telehealth methods. CONCLUSIONS: The delivery of CRT in public mental health services is feasible and adaptable to diverse settings. We strongly advocate for sustainable implementation of CRT into routine clinical practice. This will require policy and practice change to enable resources for CRT training and delivery to become embedded in the roles of the clinical workforce.

Use of historical remote monitoring data to determine predictors of CPAP non-compliance in patients with OSA.

PURPOSE: Continuous positive airway pressure (CPAP) is the gold standard treatment for obstructive sleep apnoea. This study aimed to use complete usage data collected remotely from modern CPAP devices to identify compliance trends and clinical predictors of CPAP usage. METHODS: Group usage data were analysed for a large cohort at a single tertiary sleep-centre before a detailed review of a 90-day reporting window for each patient was conducted. Individual data were collected for a smaller cohort of patients including demographics, past medical history and diagnostic sleep study results. A zero-inflated negative binomial regression model was used to determine associations between patient characteristics and usage days. RESULTS: Of 6450 patients who were prescribed CPAP and included in the initial service analysis, 476 patients were included in the sub-group. Complete usage data revealed that 46% of patients were fully compliant with CPAP therapy. Compliance fell from 55 to 46% by day 90 and remained at this rate going forward. Significant predictors of CPAP non-compliance included being in the lowest quartile of Index of Multiple Deprivation scores (most deprived) compared with the highest quartile (least deprived) (p = .005), and less severe oxygen desaturation index (ODI) on diagnosis (p = .03). CONCLUSIONS: Complete usage data show that compliance at day 90 appears to be a good indicator of future CPAP usage. Predictors of CPAP non-compliance may include lower socioeconomic status, and lower ODI.

The structure of the Hospital Anxiety and Depression Scale: Theoretical and methodological considerations.

The Hospital Anxiety and Depression Scale (HADS; Zigmond - Snaith, 1983) is widely used; however, its factor structure is unclear, with studies reporting differing unidimensional, two-factor and three-factor models. We aimed to address some key theoretical and methodological issues contributing to inconsistencies in HADS structures across samples. We reviewed existing HADS models and compared their fit using confirmatory factor analysis (CFA). We also investigated methodological effects by comparing factor structures derived from Rasch and Principal Components Analysis (PCA) methods, as well as effects of a negative wording factor. An Australian community-dwelling sample consisting of 189 females and 158 males aged 17-86 (M = 35.73, SD = 17.41) completed the 14-item HADS. The Rasch Analysis, PCA and CFA all supported the original two-factor structure. Although some three-factor models had good fit, they had unacceptable reliability. In the CFA, a hierarchical bifactor model with a general distress factor and uncorrelated depression and anxiety subscales produced the best fit, but the general factor was not unidimensional. The addition of a negative wording factor improved model fit. These findings highlight the effects of differing methodologies in producing inconsistent HADS factor structures across studies. Further replication of model fit across samples and refinement of the HADS items is warranted.

Therapeutic potential of IL6R blockade for the treatment of sepsis and sepsis-related death: A Mendelian randomisation study.

BACKGROUND: Sepsis is characterised by dysregulated, life-threatening immune responses, which are thought to be driven by cytokines such as interleukin 6 (IL-6). Genetic variants in IL6R known to down-regulate IL-6 signalling are associated with improved Coronavirus Disease 2019 (COVID-19) outcomes, a finding later confirmed in randomised trials of IL-6 receptor antagonists (IL6RAs). We hypothesised that blockade of IL6R could also improve outcomes in sepsis. METHODS AND FINDINGS: We performed a Mendelian randomisation (MR) analysis using single nucleotide polymorphisms (SNPs) in and near IL6R to evaluate the likely causal effects of IL6R blockade on sepsis (primary outcome), sepsis severity, other infections, and COVID-19 (secondary outcomes). We weighted SNPs by their effect on CRP and combined results across them in inverse variance weighted meta-analysis, proxying the effect of IL6RA. Our outcomes were measured in UK Biobank, FinnGen, the COVID-19 Host Genetics Initiative (HGI), and the GenOSept and GainS consortium. We performed several sensitivity analyses to test assumptions of our methods, including utilising variants around CRP and gp130 in a similar analysis. In the UK Biobank cohort (N = 486,484, including 11,643 with sepsis), IL6R blockade was associated with a decreased risk of our primary outcome, sepsis (odds ratio (OR) = 0.80; 95% confidence interval (CI) 0.66 to 0.96, per unit of natural log-transformed CRP decrease). The size of this effect increased with severity, with larger effects on 28-day sepsis mortality (OR = 0.74; 95% CI 0.47 to 1.15); critical care admission with sepsis (OR = 0.48, 95% CI 0.30 to 0.78) and critical care death with sepsis (OR = 0.37, 95% CI 0.14 to 0.98). Similar associations were seen with severe respiratory infection: OR for pneumonia in critical care 0.69 (95% CI 0.49 to 0.97) and for sepsis survival in critical care (OR = 0.22; 95% CI 0.04 to 1.31) in the GainS and GenOSept consortium, although this result had a large degree of imprecision. We also confirm the previously reported protective effect of IL6R blockade on severe COVID-19 (OR = 0.69, 95% CI 0.57 to 0.84) in the COVID-19 HGI, which was of similar magnitude to that seen in sepsis. Sensitivity analyses did not alter our primary results. These results are subject to the limitations and assumptions of MR, which in this case reflects interpretation of these SNP effects as causally acting through blockade of IL6R, and reflect lifetime exposure to IL6R blockade, rather than the effect of therapeutic IL6R blockade. CONCLUSIONS: IL6R blockade is causally associated with reduced incidence of sepsis. Similar but imprecisely estimated results supported a causal effect also on sepsis related mortality and critical care admission with sepsis. These effects are comparable in size to the effect seen in severe COVID-19, where IL-6 receptor antagonists were shown to improve survival. These data suggest that a randomised trial of IL-6 receptor antagonists in sepsis should be considered.

Presymptomatic diagnosis of postoperative infection and sepsis using gene expression signatures.

PURPOSE: Early accurate diagnosis of infection ± organ dysfunction (sepsis) remains a major challenge in clinical practice. Utilizing effective biomarkers to identify infection and impending organ dysfunction before the onset of clinical signs and symptoms would enable earlier investigation and intervention. To our knowledge, no prior study has specifically examined the possibility of pre-symptomatic detection of sepsis. METHODS: Blood samples and clinical/laboratory data were collected daily from 4385 patients undergoing elective surgery. An adjudication panel identified 154 patients with definite postoperative infection, of whom 98 developed sepsis. Transcriptomic profiling and subsequent RT-qPCR were undertaken on sequential blood samples taken postoperatively from these patients in the three days prior to the onset of symptoms. Comparison was made against postoperative day-, age-, sex- and procedure- matched patients who had an uncomplicated recovery (n =151) or postoperative inflammation without infection (n =148). RESULTS: Specific gene signatures optimized to predict infection or sepsis in the three days prior to clinical presentation were identified in initial discovery cohorts. Subsequent classification using machine learning with cross-validation with separate patient cohorts and their matched controls gave high Area Under the Receiver Operator Curve (AUC) values. These allowed discrimination of infection from uncomplicated recovery (AUC 0.871), infectious from non-infectious systemic inflammation (0.897), sepsis from other postoperative presentations (0.843), and sepsis from uncomplicated infection (0.703). CONCLUSION: Host biomarker signatures may be able to identify postoperative infection or sepsis up to three days in advance of clinical recognition. If validated in future studies, these signatures offer potential diagnostic utility for postoperative management of deteriorating or high-risk surgical patients and, potentially, other patient populations.

A scoping review of the utility of self-report and informant-report prospective memory measures.

There has been increased use of self-report prospective memory (PM) scales in recent years, despite uncertainty about their validity. This study reviewed how self-and informant-report PM questionnaires have been used in the assessment of PM. We evaluated relationships between self-report, informant-report, and performance-based PM measures, and the validity of using self-report measures in detecting PM impairments and monitoring intervention outcomes. The scoping review methodology of Arksey and O'Malley (2005. Scoping studies: Towards a methodological framework. International Journal of Social Research Methodology, 8(1), 19-32) was used. Database searches yielded 488 published studies that used the Prospective Memory Questionnaire (PMQ), Prospective and Retrospective Memory Questionnaire (PRMQ), Comprehensive Assessment of PM (CAPM), and Brief Assessment of PM (BAPM). The self-report and informant-report measures of PM had weak- to moderate-strength relationships with performance-based PM measures. Some self-report PM scales could detect PM impairments and monitor intervention outcomes, however few studies had investigated this. The findings indicated that self- and informant-report scales measure different constructs to performance-based measures of PM. It is recommended that these scales be used alongside performance-based measures to provide complementary and comprehensive assessments of PM. Further research into assessment of PM using self-report measures will aid assessment and treatment choices.

Urgent care for older people.

Geriatric medicine is the clinical specialty that focuses upon the care of older people-especially those with frailty (a state of increased vulnerability). In hospital, older people living with frailty are at high risk of developing a range of unpleasant outcomes such as delirium, falls, fractures, pressure sores and death. Comprehensive geriatric assessment is a form of holistic care that incorporates a specific set of clinical competencies that are able to reduce these adverse outcomes. Over the years, geriatric medicine has moved from being more of a community-based service towards a more acute specialty-encroaching now upon emergency department care. The challenge now is to work out how best to deliver geriatric care across the whole hospital (older people with frailty are not just cared for in geriatric wards!). The themed collection published on the Age & Ageing journal website outlines key articles that are attempting to develop solutions to this challenging conundrum. We hope that you enjoy reading them.

Critical illness-related cardiac arrest: Protocol for an investigation of the incidence and outcome of cardiac arrest within intensive care units in the United Kingdom.

Critical illness-related cardiac arrest (CIRCA) as a distinct entity is not well described epidemiologically. There is currently a knowledge gap regarding how many occur in the UK or the impact on patient outcome. The CIRCA study is a prospective multi-centre observational cohort study of patients in the United Kingdom experiencing a cardiac arrest while in a Critical Care Unit embedded in the Case Mix Programme and National Cardiac Arrest Audit. The duration of data collection is 12 months, with surviving patients and family members receiving questionnaire follow-up at 90 days, 180 days and 12 months. This paper describes the protocol for the CIRCA study which received favourable ethical opinion from South Central - Berkshire Research Ethics Committee and approval from the Health Research Authority. Study registration is on clinicaltrials.gov (NCT04219384).

A Systematic Review of Intravenous ß-Hydroxybutyrate Use in Humans - A Promising Future Therapy?

Therapeutic ketosis is traditionally induced with dietary modification. However, owing to the time delay involved, this is not a practical approach for treatment of acute conditions such as traumatic brain injury. Intravenous administration of ketones would obviate this problem by rapidly inducing ketosis. This has been confirmed in a number of small animal and human studies. Currently no such commercially available product exists. The aim of this systematic review is to review the safety and efficacy of intravenous beta-hydroxybutyrate. The Web of Science, PubMed and EMBASE databases were searched, and a systematic review undertaken. Thirty-five studies were included. The total beta-hydroxybutyrate dose ranged from 30 to 101 g administered over multiple doses as a short infusion, with most studies using the racemic form. Such dosing achieves a beta-hydroxybutyrate concentration >1 mmol/L within 15 min. Infusions were well tolerated with few adverse events. Blood glucose concentrations occasionally were reduced but remained within the normal reference range for all study participants. Few studies have examined the effect of intravenous beta-hydroxybutyrate in disease states. In patients with heart failure, intravenous beta-hydroxybutyrate increased cardiac output by up to 40%. No studies were conducted in patients with neurological disease. Intravenous beta-hydroxybutyrate has been shown to increase cerebral blood flow and reduce cerebral glucose oxidation. Moreover, beta-hydroxybutyrate reduces protein catabolism and attenuates the production of counter-regulatory hormones during induced hypoglycemia. An intravenous beta-hydroxybutyrate formulation is well tolerated and may provide an alternative treatment option worthy of further research in disease states.

Validation of the Prospective Memory Concerns Questionnaire (PMCQ).

Prospective memory (PM), the ability to remember to complete intended tasks, is essential for successfully completing activities of daily living. PM impairments are common in people with neuropathology such as acquired brain injury and dementia. These PM impairments affect individuals' capabilities in key aspects of daily living including their health, safety, and independence. The Prospective Memory Concerns Questionnaire (PMCQ) was designed as a self-report measure to understand individuals' concerns about their memory. This questionnaire may help identify issues with PM which in turn may assist clinicians in the targeted implementation of memory compensation strategies. The PMCQ was developed using Rasch and classical test methodologies, with subscales measuring frequency of forgetting behaviors, memory concerns, and retrieval failures. The current study aimed to confirm the factor structure of the PMCQ for use in adults in the general population. The study also aimed to examine relationships between the PMCQ and naturalistic performance-based measures of PM to determine how the self-report PMCQ could be used in conjunction with performance-based measures. A community dwelling sample of 558 adults completed the PMCQ, an event-based naturalistic PM task, and time-based naturalistic PM task. Confirmatory factor analyses (CFAs) indicated that a higher order model with three subscales containing 35 items produced acceptable fit [RMSEA = 0.056 (90% CI 0.054, 0.060), SRMR = 0.062, CFI = 0.915, TLI = 0.909] The PMCQ demonstrated good internal consistency (total α = 0.95, subscales: α = 0.88-0.89). The Forgetting Behaviors subscale significantly correlated with performance on the event-based naturalistic PM task (r = -0.14, p < 0.01). The Memory Concerns and Retrieval Failures subscales did not correlate significantly with performance-based PM tasks. These findings suggest that the PMCQ may be best suited for assessing individuals' concerns about their forgetting behaviors and identifying appropriate compensation strategies or support services. It is recommended that the PMCQ be used alongside performance-based PM tasks and other cognitive measures to comprehensively assess PM. It was concluded that the PMCQ is a suitable measure for use in adults in the general population. Further validation research of the PMCQ in general population and clinical samples will determine the measures' sensitivity and specificity in identifying PM impairments.

Conservative or liberal oxygen therapy in adults after cardiac arrest: An individual-level patient data meta-analysis of randomised controlled trials.

AIM: The effect of conservative versus liberal oxygen therapy on mortality rates in post cardiac arrest patients is uncertain. METHODS: We undertook an individual patient data meta-analysis of patients randomised in clinical trials to conservative or liberal oxygen therapy after a cardiac arrest. The primary end point was mortality at last follow-up. RESULTS: Individual level patient data were obtained from seven randomised clinical trials with a total of 429 trial participants included. Four trials enrolled patients in the pre-hospital period. Of these, two provided protocol-directed oxygen therapy for 60 min, one provided it until the patient was handed over to the emergency department staff, and one provided it for a total of 72 h or until the patient was extubated. Three trials enrolled patients after intensive care unit (ICU) admission and generally continued protocolised oxygen therapy for a longer period, often until ICU discharge. A total of 90 of 221 patients (40.7%) assigned to conservative oxygen therapy and 103 of 206 patients (50%) assigned to liberal oxygen therapy had died by this last point of follow-up; absolute difference; odds ratio (OR) adjusted for study only; 0.67; 95% CI 0.45 to 0.99; P = 0.045; adjusted OR, 0.58; 95% CI 0.35 to 0.96; P = 0.04. CONCLUSION: Conservative oxygen therapy was associated with a statistically significant reduction in mortality at last follow-up compared to liberal oxygen therapy but the certainty of available evidence was low or very low due to bias, imprecision, and indirectness. PROSPERO REGISTRATION NUMBER: CRD42019138931.