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.

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.

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).

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.

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.

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.

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.

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.

Circannual variability in adrenocorticotropic hormone responses to administration of thyrotropin-releasing hormone in clinically normal horses in Australia.

Thyrotropin releasing hormone (TRH)-stimulation testing for pituitary pars intermedia dysfunction (PPID) in horses is only recommended at certain times of the year. Current diagnostic cut-off values reflect testing in the northern hemisphere during this time. The aims of this study were to evaluate TRH stimulation testing during two different phases of the circannual pituitary cycle and to determine whether diagnostic cut-off values developed in the northern hemisphere are appropriate in Australia. Thirteen clinically normal horses at Perth, Western Australia, and 23 horses at Townsville, Queensland, Australia, had TRH stimulation tests performed at two different time points during the circannual pituitary cycle. At both locations, post-TRH adrenocorticotropic hormone (ACTH) concentrations were significantly different between testing time points (Perth: P=0.001; Townsville: P<0.0001). In Perth, the mean ACTH concentrations 10min post-TRH in September and March were 51.4pg/mL (95% confidence interval, CI, 46.4-56.4pg/mL) and 248.5pg/mL (95% CI 170.2-326.9pg/mL), respectively. The median percentage change in ACTH concentrations in March was 361.9%. In Townsville, the mean ACTH concentrations 30min post-TRH in September and April were 35.3pg/mL (95% CI 29.6-40.9pg/mL) and 112.3pg/mL (95% CI 93.4-131.2pg/mL), respectively. The median percentage change in ACTH concentrations in April was 144.7%. The ACTH cut-off value after TRH stimulation in normal horses in September in Perth and Townsville was similar to the values established in the northern hemisphere. However, TRH stimulation testing in March/April was highly variable at both locations.

Virus-neutralising antibody responses in horses following vaccination with Equivac® HeV: a field study.

OBJECTIVE: To determine the antibody responses to a commercial Hendra virus vaccine (Equivac® HeV) in a field environment. METHODS: A group of 61 horses received a primary vaccination course comprising two doses administered 3-6 weeks apart (V1, V2) and a 3rd dose (V3) given 6 months after the second. This was followed by booster vaccinations at 12 monthly intervals (V4, V5). Antibody titres were assessed using a virus-neutralisation test. RESULTS: Neutralising antibodies against HeV were not detected prior to vaccination. Antibodies were detected in 54/57 horses at 3 weeks after V1 and 51/51 had titres ≥ 32 at 8 weeks after V2. At 6 months after V2, antibody titres decreased in most (31/34) horses and were not detected in three horses. A rapid increase in antibody titres was recorded in 35/36 horses at 1 week following V3. By the first annual booster vaccination (V4), antibodies were still detectable in 29/29 horses, although titres had decreased; in 26/29 horses, titres remained ≥ 32. All horses showed an increase in antibody titres after V4. There was no statistically significant increase in mean antibody titre after V5, compared with after V4. CONCLUSION: Horses administered Equivac® HeV, using a primary vaccination course followed by annual booster vaccinations, mounted an effective secondary immune response and acquired antibody responses that were consistent with protective immunity against HeV in the form of virus-neutralising antibodies. No adverse events were observed after vaccine administration.

Community cognitive interviewing to inform local adaptations of an e-mental health intervention in Lebanon.

BACKGROUND: Lebanon has a need for innovative approaches to increase access to mental health care to meet the country's current high demand. E-mental health has been included in its national mental health strategy while in parallel the World Health Organization has produced an online intervention called 'Step-by-Step' to treat symptoms of depression that is being tested in Lebanon over the coming years. AIM: The primary aim of this study is to conduct bottom-up, community-driven qualitative cognitive interviewing from a multi-stakeholder perspective to inform the cultural adaptation of an Internet-delivered mental health intervention based on behavioural activation in Lebanon. METHODS: National Mental Health Programme staff conducted a total of 11 key informant interviews with three mental health professionals, six front-line workers in primary health care centres (PHCCs) and two community members. Also, eight focus group discussions, one with seven front-line workers and seven others with a total of 66 community members (Lebanese, Syrians and Palestinians) were conducted in several PHCCs to inform the adaptation of Step-by-Step. Results were transcribed and analysed thematically by the project coordinator and two research assistants. RESULTS: Feedback generated from the cognitive interviewing mainly revolved around amending the story, illustrations and the delivery methods to ensure relevance and sensitivity to the local context. The results obtained have informed major edits to the content of Step-by-Step and also to the model of provision. Notably, the intervention was made approximately 30% shorter; it includes additional videos of content alongside the originally proposed comic book-style delivery; there is less emphasis on total inactivity as a symptom of low mood and more focus on enjoyable activities to lift mood; the story and ways to contact participants to provide support were updated in line with local gender norms; and many of the suggested or featured activities have been revised in line with suggestions from community members. CONCLUSIONS: These findings promote and advocate the use of community-driven adaptation of evidence-based psychological interventions. Some of the phenomena recorded mirror findings from other research about barriers to care seeking in the region and so changes made to the intervention should be useful in improving utility and uptake of 'Step-by-Step'.

The Effect of Geographic Location on Circannual Adrenocorticotropic Hormone Plasma Concentrations in Horses in Australia.

BACKGROUND: Longitudinal evaluation of plasma endogenous ACTH concentration in clinically normal horses has not been investigated in the Southern Hemisphere. OBJECTIVES: To longitudinally determine monthly upper reference limits for plasma ACTH in 2 disparate Australian geographic locations and to examine whether location affected the circannual rhythm of endogenous ACTH in the 2 groups of horses over a 12-month period. ANIMALS: Clinically normal horses <20 years of age from 4 properties (institutional herd and client owned animals) in Perth (n = 40) and Townsville (n = 41) were included in the study. METHODS: A prospective longitudinal descriptive study to determine the upper reference limit and confidence intervals for plasma ACTH in each geographic location using the ASVCP reference interval (RI) guidelines, for individual months and monthly groupings for 12 consecutive months. RESULTS: Plasma endogenous ACTH concentrations demonstrated a circannual rhythm. The increase in endogenous ACTH was not confined to the autumnal months but was associated with changes in photoperiod. During the quiescent period, plasma ACTH concentrations were lower, ≤43 pg/mL (upper limit of the 90% confidence interval (CI)) in horses from Perth and ≤67 pg/mL (upper limit of the 90% CI) in horses from Townsville, than at the acrophase, ≤94 pg/mL (upper limit of the 90% CI) in horses from Perth, ≤101 pg/mL (upper limit of the 90% CI) in horses from Townsville. CONCLUSIONS AND CLINICAL IMPORTANCE: Circannual rhythms of endogenous ACTH concentrations vary between geographic locations, this could be due to changes in photoperiod or other unknown factors, and upper reference limits should be determined for specific locations.

Discriminant ability of the Eating Assessment Tool-10 to detect aspiration in individuals with amyotrophic lateral sclerosis.

BACKGROUND: Oropharyngeal dysphagia is prevalent in individuals with amyotrophic lateral sclerosis (ALS) leading to malnutrition, aspiration pneumonia, and death. These factors necessitate early detection of at-risk patients to prolong maintenance of safe oral intake and pulmonary function. This study aimed to evaluate the discriminant ability of the Eating Assessment Tool (EAT-10) to identify ALS patients with unsafe airway protection during swallowing. METHODS: Seventy ALS patients completed the EAT-10 survey and underwent a standardized videofluoroscopic evaluation of swallowing. Two blinded raters determined airway safety using the Penetration Aspiration Scale (PAS). A between groups anova (safe vs penetrators vs aspirators) was conducted and sensitivity, specificity, area under the curve (AUC), and likelihood ratios calculated. KEY RESULTS: Mean EAT-10 scores for safe swallowers, penetrators, and aspirators (SEM) were: 4.28 (0.79) vs 7.10 (1.79) vs 20.50 (3.19), respectively, with significant differences noted for aspirators vs safe swallowers and aspirators vs penetrators (p < 0.001). The EAT-10 demonstrated good discriminant ability to accurately identify ALS penetrator/aspirators (PAS ≥3) with a cut off score of 3 (AUC: 0.77, sensitivity: 88%, specificity: 57%). The EAT-10 demonstrated excellent accuracy at identifying aspirators (PAS ≥6) utilizing a cut off score of 8 (AUC: 0.88, sensitivity: 86%, specificity: 72%, likelihood ratio: 3.1, negative predictive value: 95.5%). CONCLUSIONS & INFERENCES: The EAT-10 differentiated safe vs unsafe swallowing in ALS patients. This patient self-report scale could represent a quick and meaningful aide to dysphagia screening in busy ALS clinics for the identification and referral of dysphagic patients for further instrumental evaluation.

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.