Cumulative sum (CUSUM) analysis: A 10 year experience of outcome monitoring in a regional burn centre.

INTRODUCTION: Outcome monitoring can identify fluctuations in healthcare. Cumulative sum (CUSUM) analysis can detect when mortality deviates from expected, allowing early intervention through targeted audit. We present a 10-year experience of the prospective use of CUSUM methodology in a regional burn centre. METHOD: Prospective outcome monitoring was conducted for all admissions to the intensive care unit between 2012 and 2022. The revised Baux score was used for mortality risk prediction. Risk-adjusted CUSUM charts tracked mortality against that predicted by the revised Baux score. Deviations from expected outcomes triggered detailed structured analysis. Learning outcomes were identified from internal and external governance groups. RESULTS: CUSUM analysis was triggered on eight occasions: one paediatric (excess deaths), six adult (four excess survivors, two excess deaths) and one elderly (excess survivors). Detailed analysis identified areas for continuous improvement and positive themes from excess survivors. CONCLUSION: The use of CUSUM as an early warning trigger stimulates assessment of practice and critical appraisal of factors contributing to unexpected mortality or survival. The revised Baux score at its foundation needs to be carefully considered but remains a valid model. One benefit is positive reinforcement of team cohesion and morale during periods of care excellence leading to excess survivors.

Recovery of functional independence following major burn: A systematic review.

BACKGROUND: Major burn injury, despite advancements in care and prevention, can have a profound impact on long-term morbidity, affecting quality of life and socioeconomic standing. We aim to explore factors predicting recovery of independence, the expected rate and time in majorly burned patients, and the measures of progress used. METHOD: A systematic search of four databases (MEDLINE, EMBASE, COCHRANE, CINAHL) was conducted for studies reporting outcomes pertaining to physical ability indicative of independent function in adult (>15 y) cohorts who had suffered a major burn (>20% TBSA) up to 30 years after treatment in a developed specialised burn service. Data extracted included factors affecting rate of and time to achievement of function in five independence domains, as well as the outcome measures used. RESULTS: 21 eligible studies were included comprising 1298 major burns survivors with a combined mean age of 39.6 y and a mean TBSA of 25.8%. The most significant recurring factors impacting recovery of independent function were older age, female gender, burn severity, prolonged ICU and hospital admission, preceding mental health conditions, and post-acute psychological issues. Exercise-based rehabilitation conferred benefits on major burn patients even over 2 years following injury. Discharge to independent living from hospital occurred in 27% to 97% of patients, while reported return to work rates varied from 52% to 80%. Burns Specific Health Scale-Brief, Functional Independence Measure, and Physical Composite Score (SF-36) were the most widely used outcome scoring systems. CONCLUSION: Major burn survivors have protracted recovery with potential for persistent chronic impairments, remaining consistently below baseline levels of function. Non-modifiable factors such as age and gender, and disease characteristics such as burn size with associated physical, physiological and psychosocial sequelae are contributory. Further research is required to explore achievement of specific milestones of major burn and polytrauma critical care patients, while early targeted rehabilitation addressing physical, psychological, and vocational needs has promising potential benefit.

An eighteen-year review of intensive care requirements for paediatric burns in a regional burns service.

INTRODUCTION: Advances in burns management have reduced mortality. Consequently, efficient resource management plays an increasingly important role in improving paediatric burns care. This study aims to assess the support requirements and outcomes of paediatric burns patients admitted to a burns centre intensive care unit in comparison to established benchmarks in burns care. METHOD: A retrospective review of burns patients under the age of 16 years old, admitted to a regional burns service intensive care unit between March 1998 and March 2016 was conducted. RESULTS: Our analysis included 234 patients, with the percentage of TBSA affected by burn injury ranging from 1.5% to 95.0%. The median (IQR) %TBSA was 20.0% (11.0-30.0), and the observed mortality rate was 2.6% (6/234). The median (IQR) length of stay was 0.7 days/%TBSA burn (0.4-1.2), 17.9% (41/229) required circulatory support and 2.6% (6/234) required renal replacement. Mortality correlated with smoke inhalation injury (P < 0.001), %TBSA burn (P = 0.049) and complications (P = 0.004) including infections (P = 0.013). CONCLUSIONS: Among children with burn injuries who require intensive care, the presence of inhalational injury and the diagnosis of infection are positively correlated with mortality. Understanding the requirements for organ support can facilitate a more effective allocation of resources within a burns service.

Aldehyde Dehydrogenase, a Marker of Normal and Malignant Stem Cells, Typifies Mesenchymal Progenitors in Perivascular Niches.

Innate mesenchymal stem cells exhibiting multilineage differentiation and tissue (re)generative-or pathogenic-properties reside in perivascular niches. Subsets of these progenitors are committed to either osteo-, adipo-, or fibrogenesis, suggesting the existence of a developmental organization in blood vessel walls. We evaluated herein the activity of aldehyde dehydrogenase, a family of enzymes catalyzing the oxidation of aldehydes into carboxylic acids and a reported biomarker of normal and malignant stem cells, within human adipose tissue perivascular areas. A progression of ALDHLow to ALDHHigh CD34+ cells was identified in the tunica adventitia. Mesenchymal stem cell potential was confined to ALDHHigh cells, as assessed by proliferation and multilineage differentiation in vitro of cells sorted by flow cytometry with a fluorescent ALDH substrate. RNA sequencing confirmed and validated that ALDHHigh cells have a progenitor cell phenotype and provided evidence that the main isoform in this fraction is ALDH1A1, which was confirmed by immunohistochemistry. This demonstrates that ALDH activity, which marks hematopoietic progenitors and stem cells in diverse malignant tumors, also typifies native, blood vessel resident mesenchymal stem cells.

Early tracheostomy and active exercise programmes in adult intensive care patients with severe burns.

BACKGROUND: Tracheostomy is a strategy often employed in patients requiring prolonged intubation in ICU settings. Evidence suggests that earlier tracheostomy and early active exercise are associated with better patient centered outcomes. Severe burn patients often require prolonged ventilatory support due to their critical condition, complex sedation management and multiple operating room visits. It is still unclear the optimal timing for tracheostomy in this population. METHODS: We conducted a service evaluation where we compared Early Tracheostomy (≤10 days) with Late Tracheostomy (>10 days) in 41 severely burned patients that required prolonged respiratory support. RESULTS: Early Tracheostomy cohort was associated with fewer days of mechanical ventilation (16 vs 33, p = 0.001), shorter hospital length of stay (65 vs 88 days, p = 0.018), earlier first day of active exercise (day 8 vs day 25, p < 0.0001) and higher Functional Assessment for Burns scores upon discharge (32 vs 28, p = 0.016). CONCLUSION: Early tracheostomy in patients with severe burns is associated with earlier active exercise, fewer days of ventilation, shorter length of hospital stay and better physical functional independence upon discharge from hospital.

Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance.

To identify approaches to target DNA repair vulnerabilities in cancer, we discovered nanomolar potent, selective, low molecular weight (MW), allosteric inhibitors of the polymerase function of DNA polymerase Polθ, including ART558. ART558 inhibits the major Polθ-mediated DNA repair process, Theta-Mediated End Joining, without targeting Non-Homologous End Joining. In addition, ART558 elicits DNA damage and synthetic lethality in BRCA1- or BRCA2-mutant tumour cells and enhances the effects of a PARP inhibitor. Genetic perturbation screening revealed that defects in the 53BP1/Shieldin complex, which cause PARP inhibitor resistance, result in in vitro and in vivo sensitivity to small molecule Polθ polymerase inhibitors. Mechanistically, ART558 increases biomarkers of single-stranded DNA and synthetic lethality in 53BP1-defective cells whilst the inhibition of DNA nucleases that promote end-resection reversed these effects, implicating these in the synthetic lethal mechanism-of-action. Taken together, these observations describe a drug class that elicits BRCA-gene synthetic lethality and PARP inhibitor synergy, as well as targeting a biomarker-defined mechanism of PARPi-resistance.

Abdominal compartment syndrome in burns patients: Introduction of an evidence-based management guideline and algorithm.

ABSTRACT: Abdominal compartment syndrome is a serious potential complication of burn injury, and carries high morbidity and mortality. Although there are generalised published guidelines on managing the condition, to date no management algorithm has yet been published tailored specifically to the burn injury patient. We set out to examine the literature on the subject in order to produce an evidence based management guideline, with the aim of improving outcomes for these patients. The guideline covers early detection and assessment of the condition as well as optimum medical, surgical and postoperative management. We believe that this guideline provides a much needed benchmark for managing burns patients with raised intra-abdominal pressure, as well as providing a template for further research and improvements in care.

WITHDRAWN: Burns first aid practices amongst paediatric caregivers following secondary advice.

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Frailty: an independent predictor of burns mortality following in-patient admission.

INTRODUCTION: Burn injury in the elderly is associated with increased morbidity and mortality. It is not uncommon for biological age, or frailty, to differ from chronological age in this patient group and thus predicting individual clinical outcomes remains challenging. It has been previously shown that Rockwood's Clinical Frailty Scale, a global clinical measure of fitness and frailty in older people, can be a useful adjunct for predicting outcomes for elderly patients with burns >10% TBSA. We refine our previous work to investigate the impact of frailty on mortality of elderly patients with thermal burns of any size admitted to a burns unit and explore its role as a meaningful adjunct to the modified Baux score. METHODS: A retrospective analysis of case notes for all patients ≥65years admitted to our burns centre as an in-patient during an 8-year period was performed with standard demographics, burn injury parameters, length of stay and mortality outcomes collected. Measures of frailty were reviewed and statistically analysed to assess the impact of biological aging on clinical outcome in order to assess how the modified Baux score may be developed for the elderly using Frailty Score. RESULTS: 239 patients met the inclusion criteria. Mean age was 77years (range: 65-99years) and mean burn size was 14.46% TBSA (Range: 0.1-98% TBSA). The modified Baux and Frailty Score were both independent predictors of mortality (p<0.0001). Increased premorbid Frailty Score was associated with increased in-hospital (OR: 2.33, 95% CI: 1.63-3.34) and one-year mortality (OR: 3.13, 95% CI: 2.22-4.41) independent of burn size compared to the modified Baux Score (IHM OR: 1.09; 95% CI: 1.07-1.13, 1yr M: OR 1.08; 95% CI: 1.05-1.11). The Frailty Score (>3) was a much more sensitive predictor of one-year mortality (Sensitivity: 83.9%; Specificity: 66.4%) than the modified Baux (>97) (Sensitivity: 59.8%; Specificity: 82.9%). A Frailty Score >3 when combined with the modified Baux score demonstrated increased area under ROC curve for both in-hospital (0.89 (95% CI: 0.85-0.94); p=0.02) and one-year (0.88 (95% CI: 0.84-0.92); p=0.02) mortality when compared to the modified Baux alone. CONCLUSION: We demonstrate that Frailty Score can be used to independently predict in-hospital and one-year mortality for thermal burns of any size in the elderly admitted as an in-patient to a burns unit. We also find that the Frailty Score can be employed in combination with the modified Baux score to improve mortality prediction. We recommend that Frailty Score is integrated into the modified Baux score and used to focus burn care resources appropriately.

Deubiquitylating enzymes and drug discovery: emerging opportunities.

More than a decade after a Nobel Prize was awarded for the discovery of the ubiquitin-proteasome system and clinical approval of proteasome and ubiquitin E3 ligase inhibitors, first-generation deubiquitylating enzyme (DUB) inhibitors are now approaching clinical trials. However, although our knowledge of the physiological and pathophysiological roles of DUBs has evolved tremendously, the clinical development of selective DUB inhibitors has been challenging. In this Review, we discuss these issues and highlight recent advances in our understanding of DUB enzymology and biology as well as technological improvements that have contributed to the current interest in DUBs as therapeutic targets in diseases ranging from oncology to neurodegeneration.

How Well Do We Know the Future of CO2 Emissions? Projecting Fleet Emissions from Light Duty Vehicle Technology Drivers.

While the UK has committed to reduce CO2 emissions to 80% of 1990 levels by 2050, transport accounts for nearly a fourth of all emissions and the degree to which decarbonization can occur is highly uncertain. We present a new methodology using vehicle and powertrain parameters within a Bayesian framework to determine the impact of engineering vehicle improvements on fuel consumption and CO2 emissions. Our results show how design changes in vehicle parameters (e.g., mass, engine size, and compression ratio) result in fuel consumption improvements from a fleet-wide mean of 5.6 L/100 km in 2014 to 3.0 L/100 km by 2030. The change in vehicle efficiency coupled with increases in vehicle numbers and fleet-wide activity result in a total fleet-wide reduction of 41 ± 10% in 2030, relative to 2012. Concerted internal combustion engine improvements result in a 48 ± 10% reduction of CO2 emissions, while efforts to increase the number of diesel vehicles within the fleet had little additional effect. Increasing plug-in and all-electric vehicles reduced CO2 emissions by less (42 ± 10% reduction) than concerted internal combustion engines improvements. However, if the grid decarbonizes, electric vehicles reduce emissions by 45 ± 9% with further reduction potential to 2050.

The PARP Inhibitor AZD2461 Provides Insights into the Role of PARP3 Inhibition for Both Synthetic Lethality and Tolerability with Chemotherapy in Preclinical Models.

The PARP inhibitor AZD2461 was developed as a next-generation agent following olaparib, the first PARP inhibitor approved for cancer therapy. In BRCA1-deficient mouse models, olaparib resistance predominantly involves overexpression of P-glycoprotein, so AZD2461 was developed as a poor substrate for drug transporters. Here we demonstrate the efficacy of this compound against olaparib-resistant tumors that overexpress P-glycoprotein. In addition, AZD2461 was better tolerated in combination with chemotherapy than olaparib in mice, which suggests that AZD2461 could have significant advantages over olaparib in the clinic. However, this superior toxicity profile did not extend to rats. Investigations of this difference revealed a differential PARP3 inhibitory activity for each compound and a higher level of PARP3 expression in bone marrow cells from mice as compared with rats and humans. Our findings have implications for the use of mouse models to assess bone marrow toxicity for DNA-damaging agents and inhibitors of the DNA damage response. Finally, structural modeling of the PARP3-active site with different PARP inhibitors also highlights the potential to develop compounds with different PARP family member specificity profiles for optimal antitumor activity and tolerability. Cancer Res; 76(20); 6084-94. ©2016 AACR.

Nasal reconstruction in panfacial burns: useful techniques in challenging cases.

Nasal reconstruction after severe panfacial burns can be challenging to correct because of scarring, loss of suitable donor sites, and variably limited blood supply of local flaps. We describe 2 cases of subtotal nasal reconstruction in which we overcame these difficulties. Both cases had alar subunit loss, which had left significant functional and esthetic deformities. However, both cases were managed very differently because of availability of donor sites.The first patient had 70% total body surface area burns with bilateral alar subunit loss: nasal reconstruction required a meticulous multistaged forehead flap. The second patient required nasal reconstruction using a turn-down flap to maximize take of a composite graft from previously burned ear donor sites.A number of surgical techniques have been described to manage subtotal burns nasal reconstruction, foremost of which are the nasolabial and paramedian forehead flaps. Cartilage grafts from the septum and the conchal bowl can be integrated into these flaps. Composite grafts can be unpredictable and are often used with caution.Such cases demonstrate that large composite grafts can be an extremely robust method of reconstruction even in a subset of patients with extensively scarred recipient and donor sites. In our second case, composite grafting avoided multistaged procedures such as the forehead flap and can be considered as a first-line procedure in large alar subunit loss.