Design and testing of the safety of the SARUS-CPR hood for novice resuscitators.

BACKGROUND AND AIMS: Bystanders should be protected against aerosols, droplets, saliva, blood and vomitus during resuscitation after cardiac arrest The SARUS (safer - airway - resuscitation) CPR airway hood™ is a clear plastic cover and integrated mask that envelopes the head and torso. Our objectives were to test leakage using saline aerosol generation tests, then assess the performance of the hood during mock cardio-pulmonary resuscitation on a manikin. METHODS: A checklist was validated by comparing the performance of 10 novices against 10 experts during mock resuscitation. Thereafter, 15 novices were tested with and without the hood, in a randomised cross-over study, one week apart. RESULTS: Laboratory analysis showed a > 99% reduction of saline particles detected 5 cm, 75 cm and 165 cm above volunteers wearing the hood. On manikins, experts scored better compared to novices, 8.5 (0.7) vs 7.6 (1.2), difference (95%CI) 0.9 (0.4-1.3), P = 0.0004. Novice performance was equivalent using the hood and standard equipment, 7.3 (1.4) vs 7.3 (1.1) respectively, difference (90%CI) 0.0 (-0.3 - 0.3), P = 0.90. CONCLUSION: Aerosol transmission reduced in the breathing zone. Simulated resuscitation by novices was equivalent with and without the hood.

Left ventricular geometry, tissue composition, and residual stress in High Fat Diet Dahl-Salt sensitive rats.

BACKGROUND: Hypertension drives myocardial remodeling, leading to changes in structure, composition and mechanical behavior, including residual stress, which are linked to heart disease progression in a gender-specific manner. Emerging therapies are also targeting constituent-specific pathological features. All previous studies, however, have characterized remodeling in the intact tissue, rather than isolated tissue constituents, and did not include sex as a biological variable. OBJECTIVE: In this study we first identified the contribution of collagen fiber network and myocytes to the myocardial residual stress/strain in Dahl-Salt sensitive rats fed with high fat diet. Then, we quantified the effect of hypertension on the remodeling of the left ventricle (LV), as well as the existence of sex-specific remodeling features. METHODS: We performed mechanical tests (opening angle, ring-test) and histological analysis on isolated constituents and intact tissue of the LV. Based on the measurements from the tests, we performed a stress analysis to evaluate the residual stress distribution. Statistical analysis was performed to identify the effects of constituent isolation, elevated blood pressure, and sex of the animal on the output of both experimental measures and modeling results. RESULTS: Hypertension leads to reduced residual stress/strain intact tissue, isolated collagen fibers, and isolated myocytes in male and female rats. Collagen remains the largest contributor to myocardial residual stress in both normotensive and hypertensive animals. We identified sex-differences in both hypertensive and normotensive animals. CONCLUSIONS: We observed both constituent- and sex-specific remodeling features in the LV of an animal model of hypertension.

Dysregulation of the actin scavenging system and inhibition of DNase activity following severe thermal injury.

BACKGROUND: Circulating cell-free DNA (cfDNA) is not found in healthy subjects, but is readily detected after thermal injury and may contribute to the risk of multiple organ failure. The hypothesis was that a postburn reduction in DNase protein/enzyme activity could contribute to the increase in cfDNA following thermal injury. METHODS: Patients with severe burns covering at least 15 per cent of total body surface area were recruited to a prospective cohort study within 24 h of injury. Blood samples were collected from the day of injury for 12 months. RESULTS: Analysis of blood samples from 64 patients revealed a significant reduction in DNase activity on days 1-28 after injury, compared with healthy controls. DNase protein levels were not affected, suggesting the presence of an enzyme inhibitor. Further analysis revealed that actin (an inhibitor of DNase) was present in serum samples from patients but not those from controls, and concentrations of the actin scavenging proteins gelsolin and vitamin D-binding protein were significantly reduced after burn injury. In a pilot study of ten military patients with polytrauma, administration of blood products resulted in an increase in DNase activity and gelsolin levels. CONCLUSION: The results of this study suggest a novel biological mechanism for the accumulation of cfDNA following thermal injury by which high levels of actin released by damaged tissue cause a reduction in DNase activity. Restoration of the actin scavenging system could therefore restore DNase activity, and reduce the risk of cfDNA-induced host tissue damage and thrombosis.

ANTECEDENTES: El ADN libre de las células circulantes (circulating cell-free DNA, cfDNA) no se encuentra en sujetos sanos, pero se detecta fácilmente después de una lesión térmica y puede contribuir al riesgo de fallo multiorgánico. La hipótesis fue que una disminución en la actividad de la proteína/enzima ADNasa tras la lesión térmica podría contribuir a la elevación del cfDNA que ocurre tras la misma. MÉTODOS: Los pacientes con quemaduras graves con una extensión ≥ 15% del área de superficie corporal total (total body surface area, TBSA) se incluyeron en un estudio prospectivo de cohortes durante las primeras 24 horas posteriores a la lesión. Se recogieron muestras de sangre desde el día de la lesión hasta los 12 meses posteriores a la misma. RESULTADOS: El análisis de muestras de sangre de 64 pacientes reveló una reducción significativa de la actividad de la ADNasa en los días 1 a 28 después de la lesión, en comparación con los controles sanos. Los niveles de proteína ADNasa no se vieron afectados, lo que sugiere la presencia de un inhibidor enzimático. Un análisis adicional reveló que la actina (un inhibidor de la ADNasa) estaba presente en las muestras de suero de los pacientes, pero no en los controles, y las concentraciones de la gelsolina, proteína que causa la disociación de la actina, y la proteína de unión a la vitamina D se redujeron significativamente después de la lesión térmica. En un estudio piloto de 10 pacientes con politrauma por lesiones militares, la administración de hemoderivados produjo un aumento en la actividad de la ADNasa y de los niveles de gelsolina. CONCLUSIÓN: Este estudio sugiere un nuevo mecanismo biológico para la acumulación de cfDNA después de una lesión térmica, por el cual los altos niveles de actina liberada por el tejido dañado causarían una reducción en la actividad de la ADNasa. La restauración del sistema eliminador de actina podría, por lo tanto, restaurar la actividad de la ADNasa y reducir el riesgo de daño tisular y trombosis en el huésped inducido por el cfDNA.

Nebulised recombinant activated factor VII (rFVIIa) does not attenuate the haemorrhagic effects of blast lung injury.

INTRODUCTION: Primary blast lung injury causes intrapulmonary haemorrhage. A number of case reports have suggested the efficacy of recombinant activated factor VII (rFVIIa) in the treatment of diffuse alveolar haemorrhage from a range of medical causes, but its efficacy in blast lung is unknown. The aim of this study was to investigate whether nebulised rFVIIa attenuates the haemorrhagic effects of blast lung injury in an animal model. METHODS: Terminally anaesthetised rabbits subjected to blast lung injury were randomised to receive either rFVIIa or placebo via a nebuliser. The primary outcome was the level of blood iron-transferrin complex, a marker of the extent of blast lung injury, analysed using low temperature electron paramagnetic resonance spectroscopy. RESULTS: Blast exposure led to a significant fall in iron-bound transferrin in both groups of animals (p<0.001), which remained depressed during the study. There were no significant differences in iron-transferrin between the rFVIIa and placebo treatment groups over the duration of the study (p=0.081), and there was no trend towards elevated iron-transferrin in the rFVIIa-treated group once drug treatment had started. There was suggestive evidence of systemic absorption of rFVIIa given via the inhaled route. CONCLUSION: A single dose of nebulised rFVIIa did not attenuate pulmonary haemorrhage in a rabbit model of blast lung injury. As there was some evidence of systemic absorption, the inhaled route does not avoid the concern about potential thromboembolic complications from administration of rFVIIa.

Guidelines for conducting epidemiological studies of blast injury.

Blast injuries are often caused by more than one mechanism, do not occur in isolation, and typically elicit a secondary multi-system response. Research efforts often do not separate blast injuries caused by blast waves from those caused by blunt force trauma and other mechanisms. 15 experts from nine different NATO nations developed in the HFM Research Task Group (RTG; HFM-234 (RTG)) 'Environmental Toxicology of Blast Exposures: Injury Metrics, Modelling, Methods and Standards' Guidelines for Conducting Epidemiological Studies of Blast Injury. This paper describes these guidelines, which are intended to provide blast injury researchers and clinicians with a basic set of recommendations for blast injury epidemiological study design and data collection that need to be considered and described when conducting prospective longitudinal studies of blast injury.

Effective communication between ENT and primary care - a survey of outpatient correspondence.

OBJECTIVE: To improve the quality of outpatient clinic communication between Otolaryngology and primary care doctors. DESIGN: Three example outpatient letters with identical content were created using different structure styles - full prose, headline subheadings with full prose and full subheadings throughout. Electronic questionnaires were sent out to 30 randomly selected General Practitioners in the area served by Western Sussex NHS Trust. The electronic mail study invite contained the initial GP referral, the three different letter formats and a link to the Sheffield Assessment for Letters (SAIL) questionnaire, which contained a 18-point checklist, 6 rating subheadings with a 10-point rating scale and a free text comment section. Study participants were asked to read the letters in the time usually afforded to outpatient letters in their routine practice, answer questions and then rate the letters. RESULTS: With a response rate of 66.7%, overall comparison of GP preferences demonstrated a significant variation between the three letter formats (Freidman P value = 0.0001). Post hoc multiple comparisons showed statistically significant preference for the headline subheading and prose letter compared to the full subheaded letter (P < 0.05). In assessing the letters for readability, comprehension, usefulness, informativeness and helpfulness, analysis showed significant preference for both fully subheaded and headline subheaded with full prose structures compared to the full prose letter. CONCLUSION: Although the headline subheadings and prose letter had the highest word count, it scored the highest in almost all the rating categories analysed. This study is the first published work to study primary care physician's preference for the structure of letters from secondary care. Prominent headline subheadings of diagnosis and management improve interpretation of content and comprehension and are helpful to GPs for co-ordinating patient management. Lack of subheadings or conversely an excess of subheadings may be a hindrance to effective communication between healthcare professionals.

Haemodynamic changes in trauma.

Trauma is the leading cause of death during the first four decades of life in the developed countries. Its haemodynamic response underpins the patient's initial ability to survive, and the response to treatment and subsequent morbidity and resolution. Trauma causes a number of insults including haemorrhage, tissue injury (nociception) and, predominantly, in military casualties, blast from explosions. This article discusses aspects of the haemodynamic responses to these insults and subsequent treatment. 'Simple' haemorrhage (blood loss without significant volume of tissue damage) causes a biphasic response: mean arterial blood pressure (MBP) is initially maintained by the baroreflex (tachycardia and increased vascular resistance, Phase 1), followed by a sudden decrease in MAP initiated by a second reflex (decrease in vascular resistance and bradycardia, Phase 2). Phase 2 may be protective. The response to tissue injury attenuates Phase 2 and may cause a deleterious haemodynamic redistribution that compromises blood flow to some vital organs. In contrast, thoracic blast exposure augments Phase 2 of the response to haemorrhage. However, hypoxaemia from lung injury limits the effectiveness of hypotensive resuscitation by augmenting the attendant shock state. An alternative strategy ('hybrid resuscitation') whereby tissue perfusion is increased after the first hour of hypotensive resuscitation by adopting a revised normotensive target may ameliorate these problems. Finally, morphine also attenuates Phase 2 of the response to haemorrhage in some, but not all, species and this is associated with poor outcome. The impact on human patients is currently unknown and is the subject of a current physiological investigation.

Combat Casualty Care research programme.

The Combat Casualty Care research programme is an integrated suite of projects designed to address Defence Medical Services' research needs for casualty care. The programme covers a broad spectrum of topics ranging from the pathophysiological and immunological impact of military relevant injuries to the effects of these disturbances on the response to early treatment. Dstl Porton Down has a long history of studying military injuries and has developed models, both in vivo and physical, to address the research needs. The work is conducted in close collaboration with clinical colleagues at the Royal Centre for Defence Medicine who have direct experience of the clinical issues faced by combat casualties and insights into the potential clinical implications of emerging strategies. This article reviews progress in research areas spanning forward resuscitation, with a particular focus on blast-related injuries, trauma coagulopathy, effects of drugs on the response to haemorrhage and deployed research. A significant 'value added' component has been the underpinning of higher degrees for seconded military clinicians at Dstl Porton Down who have made a valuable contribution to the overall programme.

Evaluation of a portable, lightweight modular system to deliver high inspired oxygen to trauma casualties without the use of pressurised cylinders.

INTRODUCTION: Administering supplemental oxygen is a standard of care for trauma casualties to minimise the deleterious effects of hypoxaemia. Forward deployment of oxygen using pressurised cylinders is challenging, for example, logistics (weight and finite resource) and environmental risk (fire and explosion). Oxygen concentrators may overcome these challenges. Although previous studies successfully demonstrated fractional inspired oxygen (FiO2) >0.8 using oxygen concentrators and ventilators, the systems did not fulfil the size, weight and power requirements of agile military medical units. This study evaluated whether a modular system of commercially available clinical devices could supply high FiO2 to either ventilated or spontaneously breathing casualties. METHODS: As a proof of principle, we configured an Inogen One G5 oxygen concentrator, Ventway Sparrow ventilator and Wenoll rebreather system to ventilate a simulated lung (tidal volume 500 mL). Casualty oxygen consumption (gas withdrawal inspiratory limb) and carbon dioxide (CO2) production (CO2 added expiratory limb) were simulated (respiratory quotient of 0.7-0.8). Three circuit configurations were evaluated: open (supplementary oxygen introduced into air inlet of ventilator); semiclosed (ventilator replaces rebreather bag of Wenoll, oxygen connected to either ventilator or Wenoll); and semiclosed with reservoir tubing (addition of 'deadspace' tube between ventilator patient circuit and Wenoll). Data presented as mean and 95% reference range. RESULTS: There were modest increases in FiO2 with increasing Inogen settings in 'open' configuration 0.23 (0.23-0.24) and 0.30 (0.28-0.32) (Inogen output 420 and 1260 mL/min, respectively). With the 'semiclosed' configuration and oxygen added directly into rebreather circuit, FiO2 increased to 0.36 (0.36-0.37). The addition of the 'reservoir tubing' elevated FiO2 to 0.78 (0.71-0.85). FiO2 remained stable over a 4-hour evaluation period. Fractional inspired carbon dioxide CO2 increased over time, reaching 0.005 after 170 (157-182) min. CONCLUSION: Combining existing lightweight devices can deliver high (>0.8) FiO2 and offers a potential solution for the forward deployment of oxygen without needing pressurised cylinders.

Internet cognitive behavioural therapy for mixed anxiety and depression: a randomized controlled trial and evidence of effectiveness in primary care.

BACKGROUND: Major depressive disorder (MDD) and generalized anxiety disorder (GAD) have the highest co-morbidity rates within the internalizing disorders cluster, yet no Internet-based cognitive behavioural therapy (iCBT) programme exists for their combined treatment. METHOD: We designed a six-lesson therapist-assisted iCBT programme for mixed anxiety and depression. Study 1 was a randomized controlled trial (RCT) comparing the iCBT programme (n = 46) versus wait-list control (WLC; n = 53) for patients diagnosed by structured clinical interview with MDD, GAD or co-morbid GAD/MDD. Primary outcome measures were the Patient Health Questionnaire nine-item scale (depression), Generalized Anxiety Disorder seven-item scale (generalized anxiety), Kessler 10-item Psychological Distress scale (distress) and 12-item World Health Organization Disability Assessment Schedule II (disability). The iCBT group was followed up at 3 months post-treatment. In study 2, we investigated the adherence to, and efficacy of the same programme in a primary care setting, where patients (n = 136) completed the programme under the supervision of primary care clinicians. RESULTS: The RCT showed that the iCBT programme was more effective than WLC, with large within- and between-groups effect sizes found (>0.8). Adherence was also high (89%), and gains were maintained at 3-month follow-up. In study 2 in primary care, adherence to the iCBT programme was low (41%), yet effect sizes were large (>0.8). Of the non-completers, 30% experienced benefit. CONCLUSIONS: Together, the results show that iCBT is effective and adherence is high in research settings, but there is a problem of adherence when translated into the 'real world'. Future efforts need to be placed on developing improved adherence to iCBT in primary care settings.

Modelling for conflict: the legacy of ballistic research and current extremity in vivo modelling.

Extremity ballistic injury is unique and the literature intended to guide its management is commonly misinterpreted. In order to care for those injured in conflict and conduct appropriate research, clinicians must be able to identify key in vivo studies, understand their weaknesses and desist the propagation of miscited and misunderstood ballistic dogma. This review provides the only inclusive critical overview of key studies of relevance to military extremity injury. In addition, the non-ballistic studies of limb injury, stabilisation and contamination that will form the basis from which future small animal extremity studies are constructed are presented. With an awareness of the legacy of military wound models and an insight into available generic models of extremity injury and contamination, research teams are well placed to optimise future military extremity injury management.

Optimisation of mitochondrial function as a novel target for resuscitation in haemorrhagic shock: a systematic review.

INTRODUCTION: Traumatic injury is one of the leading causes of death worldwide, and despite significant improvements in patient care, survival in the most severely injured patients remains unchanged. There is a crucial need for innovative approaches to improve trauma patient outcomes; this is particularly pertinent in remote or austere environments with prolonged evacuation times to definitive care. Studies suggest that maintenance of cellular homeostasis is a critical component of optimal trauma patient management, and as the cell powerhouse, it is likely that mitochondria play a pivotal role. As a result, therapies that optimise mitochondrial function could be an important future target for the treatment of critically ill trauma patients. METHODS: A systematic review of the literature was undertaken in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol to determine the potential role of mitochondria in traumatic injury and haemorrhagic shock (HS) and to identify current evidence for mitochondrial optimisation therapies in trauma. Articles were included if they assessed a mitochondrial targeted therapy in comparison to a control group, used a model of traumatic injury and HS and reported a method to assess mitochondrial function. RESULTS: The search returned 918 articles with 37 relevant studies relating to mitochondrial optimisation identified. Included studies exploring a range of therapies with potential utility in traumatic injury and HS. Therapies were categorised into the key mitochondrial pathways impacted following traumatic injury and HS: ATP levels, cell death, oxidative stress and reactive oxygen species. CONCLUSION: This systematic review provides an overview of the key cellular functions of the mitochondria following traumatic injury and HS and identifies why mitochondrial optimisation could be a viable and valuable target in optimising outcome in severely injured patients in the future.

Baricitinib improves symptoms in patients with moderate-to-severe atopic dermatitis and inadequate response to topical corticosteroids: patient-reported outcomes from two randomized monotherapy phase III trials.

BACKGROUND: Itch, skin pain, and sleep disturbance are burdensome symptoms in atopic dermatitis (AD) that negatively influence a patient's quality of life (QoL). OBJECTIVE: To evaluate the impact of baricitinib on patient-reported outcomes (PROs) in adult patients with moderate-to-severe AD, and explore the association between improvement in key signs and symptoms of AD with improvements in QoL and patient's assessment of disease severity. METHODS: Data were analyzed from two phase III monotherapy trials (BREEZE-AD1/BREEZE-AD2) in which patients were randomized 2:1:1:1 to once-daily placebo, baricitinib 1-mg, 2-mg, or 4-mg for 16 weeks and assessed using PRO measures. RESULTS: At week 16, baricitinib 4-mg and 2-mg significantly reduced itch severity (Itch Numeric Rating Scale (NRS) (BREEZE-AD1: percent change from baseline -36.6% and -29.4% vs. placebo (-12.0%), p≤.001 and p≤.05; BREEZE-AD2: -47.2% and -46.9% vs. placebo (-16.6%), p≤.001). Baricitinib significantly reduced SCORing AD (SCORAD) pruritus (4-mg in BREEZE-AD1 and 2-mg in BREEZE-AD2) and Patient Oriented Eczema Measure (POEM) itch (both doses). Improvements in skin pain severity and sleep disturbance were also observed. Improvements in AD symptoms showed higher correlations with patients' assessment of AD severity and QoL than improvements in skin inflammation. CONCLUSIONS: Baricitinib significantly improved symptoms in patients with moderate-to-severe AD. CLINICALTRIALS.GOV IDENTIFIERS: NCT03334396 (BREEZE-AD1) and NCT03334422 (BREEZE-AD2).

Interleukin-10 does not contribute to the anti-contractile nature of PVAT in health.

Perivascular adipose tissue (PVAT) is protective and reduces contraction of blood vessels in health. PVAT is composed of adipocytes, multiple types of immune cells and stromal cells. Interleukin (IL)-10, an anti-inflammatory cytokine usually produced by T cells, B cells and macrophages, was identified as one of the highly expressed (mRNA) cytokines in the mesenteric PVAT of healthy rats. One report suggested that exogenous IL-10 causes relaxation of mouse mesenteric arteries, also suggesting that IL-10 maybe a potential anti-contractile factor. Hence, we hypothesized that PVAT-derived IL-10 causes vasorelaxation and/or reduces vasoconstriction, thus contributing to the anti-contractile nature of PVAT in health. Mesenteric arteries from rats and mice expressed the receptor for IL-10 (in tunica intima and media) as determined by immunohistochemistry. Mesenteric resistance arteries for rats and superior mesenteric artery for mice were used for isometric contractility studies. Increasing concentrations [0.4-100 ng/mL] of recombinant rat/mouse (rr/mr) IL-10 or vehicle was directly added to half-maximally constricted (phenylephrine, PE) vessels (without PVAT, with endothelium). IL-10 did not cause a direct vasorelaxation. Further, the ability of rrIL-10 to cause a rightward or downward shift of a vasoconstriction-response curve was tested in the rat. The vessels were incubated with rrIL-10 [100 ng/mL or 10 ng/mL] or vehicle for 1.5 h in the tissue bath followed by a cumulative PE [10-8-10-4 M] or U46619 [10-10-10-5 M] response curve. The maximal contractions and EC50 values were similar in IL-10 incubated vessels vs vehicle. Thus, acute exposure of exogenous IL-10 did not reduce local vasoconstriction. To further test if endogenous IL-10 from PVAT was anti-contractile, superior mesenteric arteries from IL-10 WT and KO mice, with and without PVAT, were subjected to increasing concentrations of PE. The anti-contractile nature of PVAT was preserved with both short-term and prolonged depletion (using younger and older mice, respectively) of endogenous IL-10 in males and females. Contrary to our hypothesis, PVAT-derived IL-10 neither caused vasorelaxation nor reduced local vasoconstriction directly/indirectly. Therefore, IL-10 does not contribute to the anti-contractile nature of PVAT in healthy rodents.

The tumor-rejection antigens of the 1591 ultraviolet fibrosarcoma. Potential origin and evolutionary implications.

Previously, we cloned and sequenced the three novel MHC class I genes expressed by the C3H UV fibrosarcoma, 1591. We have extended the analysis of the polymorphic nature of these genes relative to the C3H strain. Scattered nucleotide differences among the tumor genes as compared with the C3H H-2 and Qa sequences make it highly unlikely that the novel tumor genes were generated by recombination between endogenous C3H sequences. Given that two of the tumor clones, A149 and A166, are remarkably similar in amino acid and DNA sequence to H-2Lq and H-2Dq, respectively, we also examined the 1591 RP2 and GUS loci for evidence of polymorphism. Compared with C3H and B10.AKM, 1591 appears to be heterozygous at each of these loci, consistent with an H-2q origin for the two novel 1591 class I genes. Interestingly, the third tumor gene, designated A216, shares certain characteristics with the H-2Ks antigen, reminiscent of the naturally occurring combination of H-2Ks, H-2Dq, and H-2Lq antigens found in some Swiss mouse strains. As a result, we propose that the non-C3H/HeN characteristics displayed by the 1591 tumor point to a non-C3H origin for the novel tumor class I genes of 1591.

An approach for the assessment of risk from chronic radiation to populations of phytoplankton and zooplankton.

A conceptual model of the effects of chronic radiation on a population of phytoplankton and zooplankton in an oceanic nutrient layer is presented. The model shows that there are distinct threshold dose rates at which the different plankton populations become unsustainable. These are 10,400 microGy h(-1) for phytoplankton and 125 microGy h(-1) for zooplankton. Both these values are considerably greater than the current screening values for protection of 10 microGy h(-1). The model highlights the effects of predator-prey dynamics in predicting that when the zooplankton is affected by the radiation dose, the phytoplankton population can increase. In addition, the model was altered to replicate the dose rates to the plankton of a previous ERICA Irish Sea assessment (24 microGy h(-1) for zooplankton and 430 microGy h(-1) to phytoplankton). The results showed only a 10% decrease in the zooplankton population and a 15% increase in the phytoplankton population. Therefore, at this level of dose, the model predicts that although the dose rate exceeds the guideline value, populations are not significantly affected. This result highlights the limitations of a single screening value for different groups of organisms.