Rotational thromboelastometry values across age groups in all trauma patients presenting to a level 1 trauma centre: An observational study.

OBJECTIVES: To describe rotational thromboelastometry (ROTEM) values (FIBTEM A5, EXTEM A5 and EXTEM CT) across age groups and assess for a statistical trend; and to determine whether any trend in ROTEM values is affected by severity of injury and packed red blood cells (PRBC) requirement. METHODS: Retrospective observational study at a level 1 trauma centre in Queensland, Australia. A total of 1601 consecutive trauma patients presenting to the ED. ROTEM data described included FIBTEM A5, EXTEM A5 and EXTEM CT. These values are described by age group (≤30 years, 31-45 years, 46-60 years, 61-75 years and >75 years), Injury Severity Score (ISS) category (<12, ≥12, <25 and ≥25) and number of PRBCs transfused in the first 24 h of admission (0 units, 1-4 units, 5-9 units and ≥10 units). RESULTS: The median age of participants was 37 years (interquartile range [IQR] 25-54 years), with 48.2% of patients had severe trauma (ISS >12) and 13.2% receiving at least one unit of PRBC in the first 24 h of admission. Median (IQR) values for FIBTEM A5, EXTEM A5 and EXTEM CT were 13 mm (10-16 mm), 45 mm (40-49 mm) and 62 s (56-71 s), respectively. A test for trend over progressive age groups showed an increase in FIBTEM A5 (P < 0.001) and EXTEM A5 values (P < 0.001) and a decrease in EXTEM CT values (P < 0.001). CONCLUSION: The present study demonstrated a pattern of increasing coagulability, as defined by ROTEM, with increasing age group in trauma patients, even among the severely injured. Further investigation is required to determine the clinical impact of these findings on both the ROTEM-guided management and longitudinal outcomes of these patients and whether an age-specific approach is beneficial.

Durable Responses to Anti-PD1 and Anti-CTLA4 in a Preclinical Model of Melanoma Displaying Key Immunotherapy Response Biomarkers.

Immunotherapy has transformed the management of patients with advanced melanoma, with five-year overall survival rates reaching 52% for combination immunotherapies blocking the cytotoxic T-lymphocyte-associated antigen-4 (CTLA4) and programmed cell death-1 (PD1) immune axes. Yet, our understanding of local and systemic determinants of immunotherapy response and resistance is restrained by the paucity of preclinical models, particularly those for anti-PD1 monotherapy. We have therefore generated a novel murine model of melanoma by integrating key immunotherapy response biomarkers into the model development workflow. The resulting YUMM3.3UVRc34 (BrafV600E; Cdkn2a-/-) model demonstrated high mutation burden and response to interferon (IFN)γ, including induced expression of antigen-presenting molecule MHC-I and the principal PD1 ligand PD-L1, consistent with phenotypes of human melanoma biopsies from patients subsequently responding to anti-PD1 monotherapy. Syngeneic immunosufficient mice bearing YUMM3.3UVRc34 tumors demonstrated durable responses to anti-PD1, anti-CTLA4, or combined treatment. Immunotherapy responses were associated with early on-treatment changes in the tumor microenvironment and circulating T-cell subsets, and systemic immunological memory underlying protection from tumor recurrence. Local and systemic immunological landscapes associated with immunotherapy response in the YUMM3.3UVRc34 melanoma model recapitulate immunotherapy responses observed in melanoma patients and identify discrete immunological mechanisms underlying the durability of responses to anti-PD1 and anti-CTLA4 treatments.

Is There an Association Between Untreated Hearing Loss and Psychosocial Outcomes?

Objective: Age-related hearing loss is one of the leading causes of disability in older adults. This cross-sectional study investigated the association between untreated hearing loss, social (perception of quality and quantity of social network) and emotional loneliness (perception of limited emotional support), social isolation (size of the social network), social support (actual or perceived availability of resources from the social network) and psychological discomfort (depression, anxiety, and stress) in older adults. Study Design: Cross-sectional study design. Methods: A total of 202 community derived sample of volunteers, age range 40-89 years, mean age (M) = 65.3 ± 11.0 years were recruited. Of these 115 were females (M = 63.2 ± 12.0 years) and 87 were males (M = 68.2 ± 8.9 years). All participants completed a hearing assessment, social interaction and support questionnaire and a social and emotional loneliness questionnaire. Results: Hearing loss significantly contributed to both moderate [P < 0.001, B (95% CI): 0.01 (0.99-1.02)] and intense levels [P < 0.001, 0.02 (1.00-1.04)] of emotional loneliness. Depression was significantly associated with satisfaction with social support [P < 0.001; -0.17 (-0.23 to -0.11), social interaction [P = 0.01; -0.07 (-0.12 to -0.01)], and moderate [P < 0.001; 0.31 (1.22-1.53)] and intense [P < 0.001; 0.29 (1.20-1.50)] levels of emotional loneliness and intense levels of social loneliness [P = 0.01; 0.12 (1.05-1.21)]. Conclusion: Untreated hearing loss significantly increases the odds of being emotionally lonely. Depression significantly contributes to social and emotional loneliness, satisfaction with social support and social loneliness. Given the higher prevalence of loneliness and psychological discomfort and their associations with untreated hearing loss, hearing-impaired older adults are at significant risk of developing loneliness and psychological discomfort. Therefore, hearing health professionals should be aware of the psychosocial burden that may accompany hearing loss, in order to provide appropriate advice and support.

Machine learning - Predicting Ames mutagenicity of small molecules.

In modern drug discovery, detection of a compound's potential mutagenicity is crucial. However, the traditional method of mutagenicity detection using the Ames test is costly and time consuming as the compounds need to be synthesised and then tested and the results are not always accurate and reproducible. Therefore, it would be advantageous to develop robust in silico models which can accurately predict the mutagenicity of a compound prior to synthesis to overcome the inadequacies of the Ames test. After curation of a previously defined compound mutagenicity library, over 5000 molecules had their chemical fingerprints and molecular properties calculated. Using 8 classification modelling algorithms, including support vector machine (SVM), random forest (RF) and extreme gradient boosting (XGB), a total of 112 predictive models have been constructed. Their performance has been assessed using 10-fold cross validation and a hold-out test set and some of the top performing models have been assessed using the y-randomisation approach. As a result, we have found SVM and XGB models to have good performance during the 10-fold cross validation (AUROC >0.90, sensitivity >0.85, specificity >0.75, balanced accuracy >0.80, Kappa >0.65) and on the test set (AUROC >0.65, sensitivity >0.65, specificity >0.60, balanced accuracy >0.65, Kappa >0.30). We have also identified molecular properties that are the most influential for mutagenicity prediction when combined with chemical molecular fingerprints. Using the Class A mutagenic compounds from the Ames/QSAR International Challenge Project, we were able to verify our models perform better, predicting more mutagens correctly then the StarDrop Ames mutagenicity prediction and TEST mutagenicity prediction.

The Peripheral Hearing and Central Auditory Processing Skills of Individuals With Subjective Memory Complaints.

PURPOSE: This study examined the central auditory processing (CAP) assessment results of adults between 45 and 85 years of age with probable pre-clinical Alzheimer's disease - i.e., individuals with subjective memory complaints (SMCs) as compared to those who were not reporting significant levels of memory complaints (non-SMCs). It was hypothesized that the SMC group would perform significantly poorer on tests of central auditory skills compared to participants with non-SMCs (control group). METHODS: A total of 95 participants were recruited from the larger Western Australia Memory Study and were classified as SMCs (N = 61; 20 males and 41 females, mean age 71.47 ±7.18 years) and non-SMCs (N = 34; 10 males, 24 females, mean age 68.85 ±7.69 years). All participants completed a peripheral hearing assessment, a CAP assessment battery including Dichotic Digits, Duration Pattern Test, Dichotic Sentence Identification, Synthetic Sentence Identification with Ipsilateral Competing Message (SSI-ICM) and the Quick-Speech-in-Noise, and a cognitive screening assessment. RESULTS: The SMCs group performed significantly poorer than the control group on SSI-ICM -10 and -20 dB signal-to-noise conditions. No significant differences were found between the two groups on the peripheral hearing threshold measurements and other CAP assessments. CONCLUSIONS: The results suggest that individuals with SMCs perform poorly on specific CAP assessments in comparison to the controls. The poor CAP in SMC individuals may result in a higher cost to their finite pool of cognitive resources. The CAP results provide yet another biomarker that supports the hypothesis that SMCs may be a primary indication of neuropathological changes in the brain. Longitudinal follow up of individuals with SMCs, and decreased CAP abilities should inform whether this group is at higher risk of developing dementia as compared to non-SMCs and those SMC individuals without CAP difficulties.

When is a Phylogenetic Network Simply an Amalgamation of Two Trees?

Phylogenetic networks generalise phylogenetic (evolutionary) trees by allowing for the representation of reticulation (non-treelike) events. The structure of such networks is often viewed by the phylogenetic trees they embed. In this paper, we determine when a phylogenetic network [Formula: see text] has two phylogenetic tree embeddings which collectively contain all of the edges of [Formula: see text]. This determination leads to a polynomial-time algorithm for recognising such networks and an unexpected characterisation of the class of reticulation-visible networks.

Chemical composition and antimicrobial activity of honeybee (Apis mellifera ligustica) propolis from subtropical eastern Australia.

Propolis is a material manufactured by bees and contains beeswax, bee salivary secretions and plant resins. Propolis preparations have been used for millennia by humans in food, cosmetics and medicines due to its antibacterial effects. Within the hive, propolis plays an important role in bees' health, with much of its bioactivity largely dependent on the plant resins the bees select for its production. Few chemical studies are available on the chemistry of propolis produced by Australian honeybees (Apis mellifera, Apidae). This study aimed to determine the chemical composition as well as in vitro antimicrobial effects of propolis harvested from honeybees in subtropical eastern Australia. Honeybee propolis was produced using plastic frames and multiple beehives in two subtropical sites in eastern Australia. Methanolic extracts of propolis were analysed by liquid chromatography with ultraviolet detection and high-resolution mass spectrometry (ultra-high-pressure liquid chromatography (UHPLC)-UV-high-resolution tandem mass spectrometry (HR-MS/MS)) and by gas chromatography mass spectrometry (GC-MS). The resulting chemical data were dereplicated for compound characterisation. The two crude extracts in abs. ethanol were tested in vitro by the agar diffusion and broth dilution methods, using a phenol standard solution as the positive control and abs. ethanol as the negative control. Chemical constituents were identified to be pentacyclic triterpenoids and C-prenylated flavonoids, including Abyssinoflavanone VII, Propolin C and Nymphaeol C. The two propolis crude extracts showed bactericidal effects at the minimal inhibitory concentrations of 0.37-2.04 mg mL(-1) against Staphylococcus aureus ATCC 25923. However, the extracts were inactive against Klebsiella pneumoniae ATCC 13883 and Candida albicans ATCC 10231. The antistaphylococcal potential of propolis was discussed, also in relation to honeybees' health, as it warrants further investigations on the social and individual immunities of Australian honeybees.

Appropriateness of probit-9 in the development of quarantine treatments for timber and timber commodities.

Following the increasing international phasing out of methyl bromide for quarantine purposes, the development of alternative treatments for timber pests becomes imperative. The international accreditation of new quarantine treatments requires verification standards that give confidence in the effectiveness of a treatment. Probit-9 mortality is a standard for treatment effectiveness that has its origin in fruit fly research, and has been adopted by the United States Department of Agriculture for fruit flies and several other pests. Following this, the probit-9 standard has been adopted as a benchmark for many quarantine treatments worldwide. This article discusses aspects of the application of this concept for a range of timber pests. Problematic issues include the often small pest populations available for testing, the limits of modeling pest responses to a treatment in the absence of sufficient numbers for treatment verification, the species diversity of pests and host materials and the physical and chemical conditions of host material or treatment conditions. Where treatment verification by killing large numbers of individuals is impossible, data collected from small populations or under specific conditions must be interpreted with caution. We discuss possible alternative approaches to probit-9 as a treatment efficacy standard.

A survey of Daldinia species with large ascospores.

Specimens of Daldinia (Xylariaceae) from around the world possessing large ascospores were studied for teleomorphic and anamorphic morphological characters and compared with authentic material of D. grandis. A culture made from a specimen of D. grandis collected from Ecuador produced stromatic structures, but no conidiogenous structures referable to known xylariaceous anamorphs were observed. D. grandis is reconsidered and viewed as a species of warmer climates in the Americas. Three new species are recognised from new combinations of anamorphic and teleomorphic characters: (1) D. novaezelandiae sp. nov. from New Zealand, a fungus obviously related to D. bakeri, which is also reported from that country; (2) D. dennisii sp. nov., from Australia and New Zealand, of which two varieties are erected; and (3) D. loculatoides sp. nov., from the UK and Canada with affinities to D. loculata. The type of Sphaeria durissima was identified as D. loculata. Notes on further Daldinia spp. are included.

Comparative analyses of a small molecule/enzyme interaction by multiple users of Biacore technology.

To gauge the experimental variability associated with Biacore analysis, 36 different investigators analyzed a small molecule/enzyme interaction under similar conditions. Acetazolamide (222 g/mol) binding to carbonic anhydrase II (CAII; 30000 Da) was chosen as a model system. Both reagents were stable and their interaction posed a challenge to measure because of the low molecular weight of the analyte and the fast association rate constant. Each investigator created three different density surfaces of CAII and analyzed an identical dilution series of acetazolamide (ranging from 4.1 to 1000 nM). The greatest variability in the results was observed during the enzyme immobilization step since each investigator provided their own surface activating reagents. Variability in the quality of the acetazolamide binding responses was likely a product of how well the investigators' instruments had been maintained. To determine the reaction kinetics, the responses from the different density surfaces were fit globally to a 1:1 interaction model that included a term for mass transport. The averaged association and dissociation rate constants were 3.1+/-1.6 x 10(6)M(-1)s(-1) and 6.7+/-2.5 x 10(-2)s(-1), respectively, which corresponded to an average equilibrium dissociation constant (K(D) of 2.6+/-1.4 x 10(-8)M. The results provide a benchmark of variability in interpreting binding constants from the biosensor and highlight keys areas that should be considered when analyzing small molecule interactions.

Phylogenetic significance of morphological characters in the taxonomy of Pestalotiopsis species.

There has been considerable disagreement regarding the relationships among Pestalotiopsis species and their delimitations. A molecular phylogenetic analysis was conducted on 32 species of Pestalotiopsis in order to evaluate the utility of morphological characters currently used in their taxonomy. Phylogenetic relationships were inferred from nucleotide sequences in the ITS regions and 5.8S gene of the rDNA under four optimality criteria: maximum parsimony, weighted parsimony, maximum likelihood, and neighbor joining. Phylogenies estimated from all analyses yielded trees of essentially similar topology and revealed 3 major groups that correspond with morphology-based classification systems. Molecular data indicated that the genus contains two distinct lineages based on pigmentation of median cells and four distinct groupings based on morphology of apical appendages. The analyses did not support reliability of other phenotypic characters of this genus, such as spore dimensions. Characters with particular phylogenetic significance are discussed in relation to the taxonomy of Pestalotiopsis.