Asthma and landscape fire smoke: A Thoracic Society of Australia and New Zealand position statement.

Landscape fires are increasing in frequency and severity globally. In Australia, extreme bushfires cause a large and increasing health and socioeconomic burden for communities and governments. People with asthma are particularly vulnerable to the effects of landscape fire smoke (LFS) exposure. Here, we present a position statement from the Thoracic Society of Australia and New Zealand. Within this statement we provide a review of the impact of LFS on adults and children with asthma, highlighting the greater impact of LFS on vulnerable groups, particularly older people, pregnant women and Aboriginal and Torres Strait Islander peoples. We also highlight the development of asthma on the background of risk factors (smoking, occupation and atopy). Within this document we present advice for asthma management, smoke mitigation strategies and access to air quality information, that should be implemented during periods of LFS. We promote clinician awareness, and the implementation of public health messaging and preparation, especially for people with asthma.

Thunderstorm asthma in seasonal allergic rhinitis: The TAISAR study.

BACKGROUND: Asthma epidemics associated with thunderstorms have had catastrophic effects on individuals and emergency services. Seasonal allergic rhinitis (SAR) is present in the vast majority of people who develop thunderstorm asthma (TA), but there is little evidence regarding risk factors for TA among the SAR population. OBJECTIVE: We sought to identify risk factors for a history of TA and hospital presentation in a cohort of individuals with SAR. METHODS: This multicenter study recruited adults from Melbourne, Australia, with a past diagnosis of TA and/or self-reported SAR. Clinical information, spirometry results, white blood cell count, ryegrass pollen-specific (RGP-sp) IgE concentration, and fractional exhaled nitric oxide were measured to identify risk factors for a history of TA in individuals with SAR. RESULTS: From a total of 228 individuals with SAR, 35% (80 of 228) reported SAR only (the I-SAR group), 37% (84 of 228) reported TA symptoms but had not attended hospital for treatment (the O-TA group), and 28% (64 of 228) had presented to the hospital for TA (the H-TA group). All patients in the H-TA group reported a previous asthma diagnosis. Logistic regression analysis of factors associated with O-TA and H-TA indicated that lower FEV1 value and an Asthma Control Questionnaire score higher than 1.5 were associated with H-TA. Higher blood RGP-sp IgE concentration, eosinophil counts, and fractional exhaled nitric oxide level were significantly associated with both O-TA and H-TA. Receiver operating curve analysis showed an RGP-sp IgE concentration higher than 10.1 kU/L and a prebronchodilator FEV1 value of 90% or lower to be biomarkers of increased H-TA risk. CONCLUSION: Clinical tests can identify risk of a history of TA in individuals with SAR and thereby inform patient-specific treatment recommendations.

Sustained depletion of FXIII-A by inducing acquired FXIII-B deficiency.

The activated form of coagulation factor XIII (FXIII-A2B2), FXIII-A*, is a hemostatic enzyme essential for inhibiting fibrinolysis by irreversibly crosslinking fibrin and antifibrinolytic proteins. Despite its importance, there are no modulatory therapeutics. Guided by the observation that humans deficient in FXIII-B have reduced FXIII-A without severe bleeding, we hypothesized that a suitable small interfering RNA (siRNA) targeting hepatic FXIII-B could safely decrease FXIII-A. Here we show that knockdown of FXIII-B with siRNA in mice and rabbits using lipid nanoparticles resulted in a sustained and controlled decrease in FXIII-A. The concentration of FXIII-A in plasma was reduced by 90% for weeks after a single injection and for more than 5 months with repeated injections, whereas the concentration of FXIII-A in platelets was unchanged. Ex vivo, crosslinking of α2-antiplasmin and fibrin was impaired and fibrinolysis was enhanced. In vivo, reperfusion of carotid artery thrombotic occlusion was also enhanced. Re-bleeding events were increased after challenge, but blood loss was not significantly increased. This approach, which mimics congenital FXIII-B deficiency, provides a potential pharmacologic and experimental tool to modulate FXIII-A2B2 activity.

Fermi Surface and Mass Renormalization in the Iron-Based Superconductor YFe_{2}Ge_{2}.

Interaction-enhanced carrier masses are central to the phenomenology of iron-based superconductors. Quantum oscillation measurements in the new unconventional superconductor YFe_{2}Ge_{2} resolve all four Fermi surface pockets expected from band structure calculations, which predict an electron pocket in the Brillouin zone corner and three hole pockets enveloping the centers of the top and bottom of the Brillouin zone. Carrier masses reach up to 20 times the bare electron mass and are among the highest ever observed in any iron-based material, accounting for the enhanced heat capacity Sommerfeld coefficient ≃100 mJ/mol K^{2}. Mass renormalization is uniform across reciprocal space, suggesting predominantly local correlations, as in the Hund's metal scenario.

Mid-Cenozoic climate change, extinction, and faunal turnover in Madagascar, and their bearing on the evolution of lemurs.

BACKGROUND: Was there a mid-Cenozoic vertebrate extinction and recovery event in Madagascar and, if so, what are its implications for the evolution of lemurs? The near lack of an early and mid-Cenozoic fossil record on Madagascar has inhibited direct testing of any such hypotheses. We compare the terrestrial vertebrate fauna of Madagascar in the Holocene to that of early Cenozoic continental Africa to shed light on the probability of a major mid-Cenozoic lemur extinction event, followed by an "adaptive radiation" or recovery. We also use multiple analytic approaches to test competing models of lemur diversification and the null hypothesis that no unusual mid-Cenozoic extinction of lemurs occurred. RESULTS: Comparisons of the terrestrial vertebrate faunas of the early Cenozoic on continental Africa and Holocene on Madagascar support the inference that Madagascar suffered a major mid-Cenozoic extinction event. Evolutionary modeling offers some corroboration, although the level of support varies by phylogeny and model used. Using the lemur phylogeny and divergence dates generated by Kistler and colleagues, RPANDA and TESS offer moderate support for the occurrence of unusual extinction at or near the Eocene-Oligocene (E-O) boundary (34 Ma). TreePar, operating under the condition of obligate mass extinction, found peak diversification at 31 Ma, and low probability of survival of prior lineages. Extinction at the E-O boundary received greater support than other candidate extinctions or the null hypothesis of no major extinction. Using the lemur phylogeny and divergence dates generated by Herrera & Dàvalos, evidence for large-scale extinction diminishes and its most likely timing shifts to before 40 Ma, which fails to conform to global expectations. CONCLUSIONS: While support for large-scale mid-Cenozoic lemur extinction on Madagascar based on phylogenetic modeling is inconclusive, the African fossil record does provide indirect support. Furthermore, a major extinction and recovery of lemuriforms during the Eocene-Oligocene transition (EOT) would coincide with other major vertebrate extinctions in North America, Europe, and Africa. It would suggest that Madagascar's lemurs were impacted by the climate shift from "greenhouse" to "ice-house" conditions that occurred at that time. This could, in turn, help to explain some of the peculiar characteristics of the lemuriform clade.

The 2016 Melbourne thunderstorm asthma epidemic: Risk factors for severe attacks requiring hospital admission.

BACKGROUND: The world's most catastrophic and deadly thunderstorm asthma epidemic struck Melbourne, Australia, on November 21, 2016. OBJECTIVE: Among thunderstorm-affected patients presenting to emergency rooms (ERs), we investigated risk factors predicting severe attacks requiring admission to hospital. METHODS: Thunderstorm-affected patients were identified from ER records at the eight major Melbourne health services and interviewed by telephone. Risk factors for hospital admission were analyzed. RESULTS: We interviewed 1435/2248 (64%) of thunderstorm-affected patients, of whom 164 (11.4%) required hospital admission. Overall, rhinitis was present in 87%, and current asthma was present in 28%. Odds for hospital admission were higher with increasing age (odds ratio 1.010, 95% CI 1.002, 1.019) and among individuals with current asthma (adjusted odds ratio [aOR] 1.87, 95% CI 1.26, 2.78). Prior hospitalization for asthma in the previous 12 months further increased the odds for hospital admission (aOR 3.16, 95% CI 1.63, 6.12). Among patients of Asian ethnicity, the odds for hospital admission were lower than for non-Asian patients (aOR 0.59, 95% CI 0.38, 0.94), but higher if born in Australia (OR = 5.42, 95% CI 1.56, 18.83). CONCLUSIONS: In epidemic thunderstorm asthma patients who presented to the ER, higher odds for hospital admission among patients with known asthma were further amplified by recent asthma admission, highlighting the vulnerability conferred by suboptimal disease control. Odds for hospital admission were lower in Asian patients born overseas, but higher in Asian patients born locally, than in non-Asian patients; these observations suggest susceptibility to severe thunderstorm asthma may be enhanced by gene-environment interactions.

A new interpretation of Madagascar's megafaunal decline: The "Subsistence Shift Hypothesis".

Fundamental disagreements remain regarding the relative importance of climate change and human activities as triggers for Madagascar's Holocene megafaunal extinction. We use stable isotope data from stalagmites from northwest Madagascar coupled with radiocarbon and butchery records from subfossil bones across the island to investigate relationships between megafaunal decline, climate change, and habitat modification. Archaeological and genetic evidence support human presence by 2000 years Before Common Era (BCE). Megafaunal decline was at first slow; it hastened at ∼700 Common Era (CE) and peaked between 750 and 850 CE, just before a dramatic vegetation transformation in the northwest that resulted in the replacement of C3 woodland habitat with C4 grasslands, during a period of heightened monsoonal activity. Cut and chop marks on subfossil lemur bones reveal a shift in primary hunting targets from larger, now-extinct species prior to ∼900 CE, to smaller, still-extant species afterwards. By 1050 CE, megafaunal populations had essentially collapsed. Neither the rapid megafaunal decline beginning ∼700 CE, nor the dramatic vegetation transformation in the northwest beginning ∼890 CE, was influenced by aridification. However, both roughly coincide with a major transition in human subsistence on the island from hunting/foraging to herding/farming. We offer a new hypothesis, which we call the "Subsistence Shift Hypothesis," to explain megafaunal decline and extinction in Madagascar. This hypothesis acknowledges the importance of wild-animal hunting by early hunter/foragers, but more critically highlights negative impacts of the shift from hunting/foraging to herding/farming, settlement by new immigrant groups, and the concomitant expansion of the island's human population. The interval between 700 and 900 CE, when the pace of megafaunal decline quickened and peaked, coincided with this economic transition. While early megafaunal decline through hunting may have helped to trigger the transition, there is strong evidence that the economic shift itself hastened the crash of megafaunal populations.

Treatable traits can be identified in a severe asthma registry and predict future exacerbations.

BACKGROUND AND OBJECTIVE: A new taxonomic and management approach, termed treatable traits, has been proposed for airway diseases including severe asthma. This study examined whether treatable traits could be identified using registry data and whether particular treatable traits were associated with future exacerbation risk. METHODS: The Australasian Severe Asthma Web-Based Database (SAWD) enrolled 434 participants with severe asthma and a comparison group of 102 participants with non-severe asthma. Published treatable traits were mapped to registry data fields and their prevalence was described. Participants were characterized at baseline and every 6 months for 24 months. RESULTS: In SAWD, 24 treatable traits were identified in three domains: pulmonary, extrapulmonary and behavioural/risk factors. Patients with severe asthma expressed more pulmonary and extrapulmonary treatable traits than non-severe asthma. Allergic sensitization, upper-airway disease, airflow limitation, eosinophilic inflammation and frequent exacerbations were common in severe asthma. Ten traits predicted exacerbation risk; among the strongest were being prone to exacerbations, depression, inhaler device polypharmacy, vocal cord dysfunction and obstructive sleep apnoea. CONCLUSION: Treatable traits can be assessed using a severe asthma registry. In severe asthma, patients express more treatable traits than non-severe asthma. Traits may be associated with future asthma exacerbation risk demonstrating the clinical utility of assessing treatable traits.

Impact of an Integrated Antibiotic Allergy Testing Program on Antimicrobial Stewardship: A Multicenter Evaluation.

Background: Despite the high prevalence of patient-reported antibiotic allergy (so-called antibiotic allergy labels [AALs]) and their impact on antibiotic prescribing, incorporation of antibiotic allergy testing (AAT) into antimicrobial stewardship (AMS) programs (AAT-AMS) is not widespread. We aimed to evaluate the impact of an AAT-AMS program on AAL prevalence, antibiotic usage, and appropriateness of prescribing. Methods: AAT-AMS was implemented at two large Australian hospitals during a 14-month period beginning May 2015. Baseline demographics, AAL history, age-adjusted Charlson comorbidity index, infection history, and antibiotic usage for 12 months prior to testing (pre-AAT-AMS) and 3 months following testing (post-AAT-AMS) were recorded for each participant. Study outcomes included the proportion of patients who were "de-labeled" of their AAL, spectrum of antibiotic courses pre- and post-AAT-AMS, and antibiotic appropriateness (using standard definitions). Results: From the 118 antibiotic allergy-tested patients, 226 AALs were reported (mean, 1.91/patient), with 53.6% involving 1 or more penicillin class drug. AAT-AMS allowed AAL de-labeling in 98 (83%) patients-56% (55/98) with all AALs removed. Post-AAT, prescribing of narrow-spectrum penicillins was more likely (adjusted odds ratio [aOR], 2.81, 95% confidence interval [CI], 1.45-5.42), as was narrow-spectrum ß-lactams (aOR, 3.54; 95% CI, 1.98-6.33), and appropriate antibiotics (aOR, 12.27; 95% CI, 5.00-30.09); and less likely for restricted antibiotics (aOR, 0.16; 95% CI, .09-.29), after adjusting for indication, Charlson comorbidity index, and care setting. Conclusions: An integrated AAT-AMS program was effective in both de-labeling of AALs and promotion of improved antibiotic usage and appropriateness, supporting the routine incorporation of AAT into AMS programs.

Dengue virus binding and replication by platelets.

Dengue virus (DENV) infection causes ∼200 million cases of severe flulike illness annually, escalating to life-threatening hemorrhagic fever or shock syndrome in ∼500,000. Although thrombocytopenia is typical of both mild and severe diseases, the mechanism triggering platelet reduction is incompletely understood. As a probable initiating event, direct purified DENV-platelet binding was followed in the current study by quantitative reverse transcription-polymerase chain reaction and confirmed antigenically. Approximately 800 viruses specifically bound per platelet at 37°C. Fewer sites were observed at 25°C, the blood bank storage temperature (∼350 sites), or 4°C, known to attenuate virus cell entry (∼200 sites). Dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) and heparan sulfate proteoglycan were implicated as coreceptors because only the combination of anti-DC-SIGN and low-molecular-weight heparin prevented binding. Interestingly, at 37°C and 25°C, platelets replicated the positive sense single-stranded RNA genome of DENV by up to ∼4-fold over 7 days. Further time course experiments demonstrated production of viral NS1 protein, which is known to be highly antigenic in patient serum. The infectivity of DENV intrinsically decayed in vitro, which was moderated by platelet-mediated generation of viable progeny. This was shown using a transcription inhibitor and confirmed by freeze-denatured platelets being incapable of replicating the DENV genome. For the first time, these data demonstrate that platelets directly bind DENV saturably and produce infectious virus. Thus, expression of antigen encoded by DENV is a novel consideration in the pathogen-induced thrombocytopenia mechanism. These results furthermore draw attention to the possibility that platelets may produce permissive RNA viruses in addition to DENV.

Dengue virus persists and replicates during storage of platelet and red blood cell units.

BACKGROUND: Dengue virus (DENV) is a transfusion-transmissible arbovirus that threatens blood donor systems with approximately 200 million high-titer asymptomatic infections occurring annually. Here we investigated the viability of DENV during storage of donor-derived platelet (PLT) and red blood cell (RBC) units. While purified PLTs have been shown to generate viable DENV, RBCs are replication incompetent. Combined with different storage criteria, distinct virus persistence profiles were anticipated in PLT and RBC units. STUDY DESIGN AND METHODS: Mimicking the virus titer of asymptomatic donors, purified DENV was spiked (10(5) -10(6) infectious units/mL) into PLT or RBC units produced and stored according to blood bank operating procedures. DENV was measured by infectious plaque-forming assays and by quantitative reverse transcription-polymerase chain reaction. RESULTS: In both PLT (7 days, 20-24°C) and RBC (42 days, 1-6°C) units, infectious DENV persisted throughout storage despite logarithmic decay. In buffer alone, DENV infectivity was insignificant by Day 1 at 20 to 24°C or 14 days at 1 to 6°C. Infectious virus production was identified in stored PLT units using a translation inhibitor and supported by virus genome replication. Surprisingly, DENV was also produced in RBC units, implying the involvement of cells other than RBCs. CONCLUSION: Both virus propagation and effects independent of cell function mitigate the intrinsic lability of DENV. Nevertheless, the overall rapid storage decay suggests that aged PLT and RBC units may be safer. These data raise awareness to the possible persistence of other conceivably more robust RNA viruses during the storage of cellular blood products.

Spatial and temporal arrival patterns of Madagascar's vertebrate fauna explained by distance, ocean currents, and ancestor type.

How, when, and from where Madagascar's vertebrates arrived on the island is poorly known, and a comprehensive explanation for the distribution of its organisms has yet to emerge. We begin to break that impasse by analyzing vertebrate arrival patterns implied by currently existing taxa. For each of 81 clades, we compiled arrival date, source, and ancestor type (obligate freshwater, terrestrial, facultative swimmer, or volant). We analyzed changes in arrival rates, with and without adjusting for clade extinction. Probability of successful transoceanic dispersal is negatively correlated with distance traveled and influenced by ocean currents and ancestor type. Obligate rafters show a decrease in probability of successful transoceanic dispersal from the Paleocene onward, reaching the lowest levels after the mid-Miocene. This finding is consistent with a paleoceanographic model [Ali JR, Huber M (2010) Nature 463:653-656] that predicts Early Cenozoic surface currents periodically conducive to rafting or swimming from Africa, followed by a reconfiguration to present-day flow 15-20 million years ago that significantly diminished the ability for transoceanic dispersal to Madagascar from the adjacent mainland.

Tissue factor and glycoprotein C on herpes simplex virus type 1 are protease-activated receptor 2 cofactors that enhance infection.

The coagulation system provides physiologic host defense, but it can also be exploited by pathogens for infection. On the HSV1 surface, host-cell-derived tissue factor (TF) and virus-encoded glycoprotein C (gC) can stimulate protease activated receptor 1 (PAR1)-enhanced infection by triggering thrombin production. Using novel engineered HSV1 variants deficient in either TF and/or gC, in the present study, we show that activated coagulation factors X (FXa) or VII (FVIIa) directly affect HSV1 infection of human umbilical vein endothelial cells in a manner that is dependent on viral TF and gC. The combination of FXa and FVIIa maximally enhanced infection for TF(+)/gC(+) HSV1 and receptor desensitization and Ab inhibition demonstrated that both proteases act on PAR2. Inhibitory TF Abs showed that the required TF source was viral. Individually, TF or gC partly enhanced the effect of FXa, but not FVIIa, revealing gC as a novel PAR2 cofactor for FVIIa. In sharp contrast, thrombin enhanced infection via PAR1 independently of viral TF and gC. Thrombin combined with FXa/FVIIa enhanced infection, suggesting that PAR1 and PAR2 are independently involved in virus propagation. These results show that HSV1 surface cofactors promote cellular PAR2-mediated infection, indicating a novel mode by which pathogens exploit the initiation phase of the host hemostatic system.

A conceptional model integrating geographic information systems (GIS) and social media data for disease exposure assessment.

Although previous studies have acknowledged the potential of geographic information systems (GIS) and social media data (SMD) in assessment of exposure to various environmental risks, none has presented a simple, effective and user-friendly tool. This study introduces a conceptual model that integrates individual mobility patterns extracted from social media, with the geographic footprints of infectious diseases and other environmental agents utilizing GIS. The efficacy of the model was independently evaluated for selected case studies involving lead in the ground; particulate matter in the air; and an infectious, viral disease (COVID- 19). A graphical user interface (GUI) was developed as the final output of this study. Overall, the evaluation of the model demonstrated feasibility in successfully extracting individual mobility patterns, identifying potential exposure sites and quantifying the frequency and magnitude of exposure. Importantly, the novelty of the developed model lies not merely in its efficiency in integrating GIS and SMD for exposure assessment, but also in considering the practical requirements of health practitioners. Although the conceptual model, developed together with its associated GUI, presents a promising and practical approach to assessment of the exposure to environmental risks discussed here, its applicability, versatility and efficacy extends beyond the case studies presented in this study.

Progressive Reduction in Preventable Mortality in a State Trauma System Using Continuous Preventable Mortality Review to Drive Provider Education: Results of Analyzing 1,979 Trauma Deaths from 2015 to 2022.

BACKGROUND: The state legislature codified and funded the Arkansas Trauma System (ATS) in 2009. Quarterly preventable mortality reviews (PMRs) by the ATS began in 2015 and were used to guide state-wide targeted education to reduce preventable or potentially preventable (P/PP) deaths. We present the results of this PMR-education initiative from 2015 to 2022. STUDY DESIGN: The ATS uses a statistical sampling model of the Arkansas Trauma Registry to select ~40% of the deaths for quarterly review, reflecting the overall the Arkansas Trauma Registry mortality population. A multispecialty PMR committee reviews the medical records from prehospital care to death, and hospital and regional advisory council reviews for each death. The PMR committee assigns opportunities for improvement (OFIs), cause(s) of death, and the likelihood of preventability for each case. Education to improve trauma care includes annual state-wide trauma meetings, novel classes targeted at level III/IV trauma center hospital providers, trauma evidence-based guidelines, and PMR "pearls." RESULTS: We reviewed 1,979 deaths with 211 (10.6%) deaths judged to be P/PP deaths. There was a progressive decrease in P/PP deaths and OFIs for P/PP deaths. Five OFI types targeted by education accounted for 72% of the 24 possible OFI types in the P/PP cases, and 94% of the "contributory OFIs." Reductions in "delay in treatment" resulted in the most rapid decrease in P/PP deaths. CONCLUSIONS: Using ongoing PMR studies to target provider education led to a reduction in P/PP deaths and OFIs for P/PP deaths. Focusing on education designed to improve preventable mortality can result in a substantial decrease in P/PP deaths by 43% (14% to 8%) for trauma systems.

Nearshore wave buoy data from southeastern Australia for coastal research and management.

Wind wave observations in shallow coastal waters are essential for calibrating, validating, and improving numerical wave models to predict sediment transport, shoreline change, and coastal hazards such as beach erosion and oceanic inundation. Although ocean buoys and satellites provide near-global coverage of deep-water wave conditions, shallow-water wave observations remain sparse and often inaccessible. Nearshore wave conditions may vary considerably alongshore due to coastline orientation and shape, bathymetry and islands. We present a growing dataset of in-situ wave buoy observations from shallow waters (<35 m) in southeast Australia that comprises over 7,000 days of measurements at 20 locations. The moored buoys measured wave conditions continuously for several months to multiple years, capturing ambient and storm conditions in diverse settings, including coastal hazard risk sites. The dataset includes tabulated time series of spectral and time-domain parameters describing wave height, period and direction at half-hourly temporal resolution. Buoy displacement and wave spectra data are also available for advanced applications. Summary plots and tables describing wave conditions measured at each location are provided.