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.

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.

Coagulation factor VIIa binds to herpes simplex virus 1-encoded glycoprotein C forming a factor X-enhanced tenase complex oriented on membranes.

BACKGROUND: The cell membrane-derived initiators of coagulation, tissue factor (TF) and anionic phospholipid (aPL), are constitutive on the herpes simplex virus type 1 (HSV1) surface, bypassing physiological regulation. TF and aPL accelerate proteolytic activation of factor (F) X to FXa by FVIIa to induce clot formation and cell signaling. Thus, infection in vivo is enhanced by virus surface TF. HSV1-encoded glycoprotein C (gC) is implicated in this tenase activity by providing viral FX binding sites and increasing FVIIa function in solution. OBJECTIVE: To examine the biochemical influences of gC on FVIIa-dependent FX activation. METHODS: Immunogold electron microscopy (IEM), kinetic chromogenic assays and microscale thermophoresis were used to dissect tenase biochemistry. Recombinant TF and gC were solubilized (s) by substituting the transmembrane domain with poly-histidine, which could be orientated on synthetic unilamellar vesicles containing Ni-chelating lipid (Ni-aPL). These constructs were compared to purified HSV1 TF±/gC ± variants. RESULTS: IEM confirmed that gC, TF, and aPL are simultaneously expressed on a single HSV1 particle where the contribution of gC to tenase activity required the availability of viral TF. Unlike viral tenase activity, the cofactor effects of sTF and sgC on FVIIa was additive when bound to Ni-aPL. FVIIa was found to bind to sgC and this was enhanced by FX. Orientation of sgC on a lipid membrane was critical for FVIIa-dependent FX activation. CONCLUSIONS: The assembly of gC with FVIIa/FX parallels that of TF and may involve other constituents on the HSV1 envelope with implications in virus infection and pathology.

Beta-blocker use is an independent risk factor for thunderstorm asthma.

OBJECTIVE: To identify risk factors for thunderstorm asthma (TA) in subjects ≥15 years of age from information available in routine clinical records. METHODS: Retrospective and hospital-based case-control study of various clinical factors in all TA cases (n = 53) who presented to a single-site ED in November 2016 (TA16) and in a control group of patients (n = 156) who presented to the same ED with asthma during the pollen season over eight non-TA years. Bivariate analysis and multivariable logistic regression modelling was performed to calculate the odds of TA asthma in the presence of potential risk factors. RESULTS: A logistic regression model revealed that the odds of TA were lower for age (odds ratio [OR] 0.97, 95% confidence interval [CI] 0.95-0.99), higher for Asian country of birth (OR 4.09, 95% CI 1.40-11.95) and higher for oral beta-blocker use (OR 6.43, 95% CI 1.58-26.33) compared to controls. No difference was found between TA16 cases and controls for allergies (to medication, grass pollen, animal), hayfever, smoking, oral non-steroidal anti-inflammatory drugs, or aspirin. Newly diagnosed asthma was higher in TA16 cases versus controls (32.1% vs 12.2%, P = 0.001). CONCLUSIONS: Oral beta-blocker medications, younger age and Asian-born heritage are risk factors for TA. Further study is required to explore the potential association between beta-blockers and TA.

Virus envelope tissue factor promotes infection in mice.

Essentials The coagulation initiator, tissue factor (TF), is on the herpes simplex virus 1 (HSV1) surface. HSV1 surface TF was examined in mice as an antiviral target since it enhances infection in vitro. HSV1 surface TF facilitated infection of all organs evaluated and anticoagulants were antiviral. Protease activated receptor 2 inhibited infection in vivo and its pre-activation was antiviral. SUMMARY: Background Tissue factor (TF) is the essential cell surface initiator of coagulation, and mediates cell signaling through protease-activated receptor (PAR) 2. Having a diverse cellular distribution, TF is involved in many biological pathways and pathologies. Our earlier work identified host cell-derived TF on the envelope covering several viruses, and showed its involvement in enhanced cell infection in vitro. Objective In the current study, we evaluated the in vivo effects of virus surface TF on infection and on the related modulator of infection PAR2. Methods With the use of herpes simplex virus type 1 (HSV1) as a model enveloped virus, purified HSV1 was generated with or without envelope TF through propagation in a TF-inducible cell line. Infection was studied after intravenous inoculation of BALB/c, C57BL/6J or C57BL/6J PAR2 knockout mice with 5 × 105 plaque-forming units of HSV1, mimicking viremia. Three days after inoculation, organs were processed, and virus was quantified with plaque-forming assays and quantitative real-time PCR. Results Infection of brain, lung, heart, spinal cord and liver by HSV1 required viral TF. Demonstrating promise as a therapeutic target, virus-specific anti-TF mAbs or small-molecule inhibitors of coagulation inhibited infection. PAR2 modulates HSV1 in vivo as demonstrated with PAR2 knockout mice and PAR2 agonist peptide. Conclusion TF is a constituent of many permissive host cell types. Therefore, the results presented here may explain why many viruses are correlated with hemostatic abnormalities, and indicate that TF is a novel pan-specific envelope antiviral target.

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.

Delayed Diagnosis and Complications of Predominantly Antibody Deficiencies in a Cohort of Australian Adults.

Background: Predominantly antibody deficiencies (PADs) are the most common type of primary immunodeficiency in adults. PADs frequently pass undetected leading to delayed diagnosis, delayed treatment, and the potential for end-organ damage including bronchiectasis. In addition, PADs are frequently accompanied by comorbid autoimmune disease, and an increased risk of malignancy. Objectives: To characterize the diagnostic and clinical features of adult PAD patients in Victoria, Australia. Methods: We identified adult patients receiving, or having previously received immunoglobulin replacement therapy for a PAD at four hospitals in metropolitan Melbourne, and retrospectively characterized their clinical and diagnostic features. Results: 179 patients from The Royal Melbourne, Alfred and Austin Hospitals, and Monash Medical Centre were included in the study with a median age of 49.7 years (range: 16-87 years), of whom 98 (54.7%) were female. The majority of patients (116; 64.8%) met diagnostic criteria for common variable immunodeficiency (CVID), and 21 (11.7%) were diagnosed with X-linked agammaglobulinemia (XLA). Unclassified hypogammaglobulinemia (HGG) was described in 22 patients (12.3%), IgG subclass deficiency (IGSCD) in 12 (6.7%), and specific antibody deficiency (SpAD) in 4 individuals (2.2%). The remaining four patients had a diagnosis of Good syndrome (thymoma with immunodeficiency). There was no significant difference between the age at diagnosis of the disorders, with the exception of XLA, with a median age at diagnosis of less than 1 year. The median age of reported symptom onset was 20 years for those with a diagnosis of CVID, with a median age at diagnosis of 35 years. CVID patients experienced significantly more non-infectious complications, such as autoimmune cytopenias and lymphoproliferative disease, than the other antibody deficiency disorders. The presence of non-infectious complications was associated with significantly reduced survival in the cohort. Conclusion: Our data are largely consistent with the experience of other centers internationally, with clear areas for improvement, including reducing diagnostic delay for patients with PADs. It is likely that these challenges will be in part overcome by continued advances in implementation of genomic sequencing for diagnosis of PADs, and with that opportunities for targeted treatment of non-infectious complications.

A biochemical network can control formation of a synthetic material by sensing numerous specific stimuli.

Developing bio-compatible smart materials that assemble in response to environmental cues requires strategies that can discriminate multiple specific stimuli in a complex milieu. Synthetic materials have yet to achieve this level of sensitivity, which would emulate the highly evolved and tailored reaction networks of complex biological systems. Here we show that the output of a naturally occurring network can be replaced with a synthetic material. Exploiting the blood coagulation system as an exquisite biological sensor, the fibrin clot end-product was replaced with a synthetic material under the biological control of a precisely regulated cross-linking enzyme. The functions of the coagulation network remained intact when the material was incorporated. Clot-like polymerization was induced in indirect response to distinct small molecules, phospholipids, enzymes, cells, viruses, an inorganic solid, a polyphenol, a polysaccharide, and a membrane protein. This strategy demonstrates for the first time that an existing stimulus-responsive biological network can be used to control the formation of a synthetic material by diverse classes of physiological triggers.

The procoagulant envelope virus surface: contribution to enhanced infection.

Many virus types are covered by a lipid bilayer. This structure called an envelope, is derived from the host cell and includes host- and virus-encoded proteins. Because envelope components first interact with the host, it is the trigger for infection, immunity and pathology. The roles of especially host-derived constituents are poorly understood. Focusing on herpes simplex type 1 (HSV1) as a model, we have shown that the envelope acquires the physiological initiators of coagulation from the host cell; tissue factor (TF) and procoagulant phospholipid (proPL). Unlike resting cells, where TF and proPL accessibility is carefully restricted, their expression is constitutive on the purified virus enabling factor VIIa (FVIIa)-dependant factor Xa (FXa) and thrombin generation. Interestingly, HSV1-encoded glycoprotein C (gC) on the virus enhances FXa production. In addition to coagulation proteases, HSV1 also facilitates fibrinolytic plasmin generation. HSV1 TF and gC combine to optimally enhance cultured cell infection when both FVIIa and FXa are available through protease activated receptor (PAR) 2. Plasmin also increases infection through PAR2, whereas thrombin provides an additive effect via PAR1. Thus, depending on the host cell, TF and proPL may be a general feature of enveloped viruses, enabling coagulation protease activation and PAR-mediated effects on infection.

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 young surgeon's perspective on alternate surgical training pathways.

Most residents in training today are in focused on their training, and the thoughts of changing the structure of residencies and fellowships is something that they are ambivalent about or have never heard anything about. The small minority who are vocal on these issues represent an activist group supporting change. This group is very vocal and raises many of the excellent questions we have examined. In discussion with residents, some feel that shortened training will help with the financial issues facing residents. However, many people today add additional years to their training with research years or "super" fellowships. The residents demonstrate that they want to get the skill sets that they desire despite the added length of training. This is unlikely to change even if the minimum number of years of training changes with the evolution of tracked training programs. Medical students, in the Resident and Associate Society of the American College of Surgeons survey, did not indicate that shortened training would have an affect on decision to pursue or not pursue a surgical career. If the focus of these changes is to encourage medical students to pursue a residency in surgical specialties, we may need to look at other options to increase medical student interest. Medical students indicated that lifestyle issues, types of clinical problems, stress-related concerns, and interactions with the surgical faculty were far more important in their decision to enter a surgical specialty than work hours or duration of training. If we are to make a difference in the quality and quantity of applicants for surgical residencies, then changes in the structure of residencies do not seem to be the most effective way to accomplish this. We should possibly focus more on faculty and medical student interaction and the development of positive role models for medical students to see surgeons with attractive practices that minimize some of the traditionally perceived negative stereotypes. Residents in general surgery training programs often do not make decisions on the type of fellowship that they will pursue until late in their residency. Many residents are apprehensive about these types of tracked training programs because it will accelerate the timeline for choosing a track. Changes in the structure of residency and fellowships would result in residents having to decide and "match" in their second or third postgraduate years of training instead of the fourth or fifth postgraduate year time frame. Many residents will not have been exposed to all of the types of tracks by their third postgraduate year and many voice concerns over being ready to make this decision that early in their training. Acceptance and enthusiasm about this concept among all residents will likely depend on the final version of any planned changes. A wholesale rewrite of surgical training in the United States would likely not be well received. However, the addition of alternate pathways, on a limited scale and under close scrutiny and supervision, could evaluate interest and ease into this type of program. Before embarking on massive changes in surgical training, scientific, statistically valid research determining the interest of residents in these types of programs will target changes to make these programs successful.

Upper extremity vascular injury: a current in-theater wartime report from Operation Iraqi Freedom.

Past wartime experience and recent civilian reports indicate upper extremity (UE) vascular injury occurs less often and with less limb loss than lower extremity (LE) injury. Given advances in critical care, damage control techniques, and military armor technology, the objective of this evaluation was to define contemporary patterns of UE injury and effectiveness of vascular surgical management in UE vascular injury during Operation Iraqi Freedom (OIF). From 1 September 2004 through 31 August 2005, 2,473 combat-related injuries were treated at the central echelon III surgical facility in Iraq. Patients with UE vascular injuries upon arrival were reviewed. Vessels injured were delineated. Therapeutic interventions, early limb viability, and complication rates following vascular repair were recorded. Of casualties treated during the study period, 43 (1.7%) UE and 83 (3.3%) LE vascular injuries were identified. Of the UE injuries, 11 (26%) had been operated on at forward locations and six (14%) had temporary shunts in place upon arrival at our facility. Injury levels included 10 (23%) subclavian-axillary, 25 (58%) brachial, and 10 (23%) distal to the brachial bifurcation. Two patients had multilevel injury. Twenty-eight grafts were placed, and 10 vessel repairs and eight ligations were performed. Two (4.7%) brachial interposition grafts required removal due to infection. Four (9.3%) subacute brachial graft thromboses occurred. Four (9.3%) patients underwent early UE amputation. In this most recent U.S. military evaluation of wartime UE vascular injury, UE injury appears rare, with LE injury twice as frequent. Yet, UE limb loss appears more substantial than noted previously. These findings are likely related to significant tissue destruction occurring with the combined mechanisms of injury sustained in OIF.

Herpes simplex virus type 1-encoded glycoprotein C contributes to direct coagulation factor X-virus binding.

The HSV1 (herpes simplex virus type 1) surface has been shown recently to initiate blood coagulation by FVIIa (activated Factor VII)-dependent proteolytic activation of FX (Factor X). At least two types of direct FX-HSV1 interactions were suggested by observing that host cell-encoded tissue factor and virus-encoded gC (glycoprotein C) independently enhance FVIIa function on the virus. Using differential sedimentation to separate bound from free 125I-ligand, we report in the present study that, in the presence of Ca2+, FX binds directly to purified wild-type HSV1 with an apparent dissociation constant (K(d)) of 1.5+/-0.4 muM and 206+/-24 sites per virus at saturation. The number of FX-binding sites on gC-deficient virus was reduced to 43+/-5, and the remaining binding had a lower K(d) (0.7+/-0.2 microM), demonstrating an involvement of gC. Engineering gC back into the deficient strain or addition of a truncated soluble recombinant form of gC (sgC), increased the K(d) and the number of binding sites. Consistent with a gC/FX stoichiometry of approximately 1:1, 121+/-6 125I-sgC molecules were found to bind per wild-type HSV1. In the absence of Ca2+, the number of FX-binding sites on the wild-type virus was similar to the gC-deficient strain in the presence of Ca2+. Furthermore, in the absence of Ca2+, direct sgC binding to HSV1 was insignificant, although sgC was observed to inhibit the FX-virus association, suggesting a Ca2+-independent solution-phase FX-sgC interaction. Cumulatively, these data demonstrate that gC constitutes one type of direct FX-HSV1 interaction, possibly providing a molecular basis for clinical correlations between recurrent infection and vascular pathology.

Herpes simplex virus type 1-encoded glycoprotein C enhances coagulation factor VIIa activity on the virus.

Tissue factor (TF) is the blood coagulation initiator, whose cofactor function is required for physiological factor VIIa (FVIIa)-mediated activation of factor X (FX) to FXa. A previous study reported TF on herpes simplex virus type 1 (HSV1), but this explained only part of FVIIa-dependent FXa generation observed on the virus surface (Sutherland et al. (1997) Proc. Natl. Acad. Sci. USA. 94:13510-14). In the current study, we investigated the role of HSV1-encoded glycoprotein C (gC) in this process. Purified gC-deficient HSV1 facilitated several fold less FX activation by FVIIa than either wild type or gC-rescued strains. To confirm the implication of gC in FVIIa-dependent FX activation, purified soluble gC (sgC) enhanced FXa production in the absence of TF. sgC required FVIIa, calcium and anionic phospholipid to participate in FX activation, suggesting similarity to TF. When purified virus was combined with sgC, the sgC-dependent FXa generation was enhanced three orders of magnitude, suggesting synergy with an additional HSV1 component and explaining the relatively low activity of purified sgC compared to the viral counterpart. FX activation on gC-competent HSV1 was inhibited 20% by a gC-specific antibody, inhibited 40% by a TF-specific antibody, inhibited 65% by combining the gC- and TF-specific antibodies, and nearly completely inhibited by the TF antibody alone on gC-deficient HSV-1. Cumulatively, these observations show that two pathways initiating FX activation function in parallel on the virus surface. In addition to the previously described TF-dependent pathway, HSV-1-encoded gC also enhances FXa generation, and like TF, requires FVIIa.

Heparin-induced thrombocytopenia and thrombosis syndrome after cardiac surgery.

A case report of multisystem organ failure and limb loss associated with coronary artery bypass is reported. Heparin-induced thrombocytopenia and thrombosis syndrome (HITTS) occurs in 1% to 2% of patients suffering from thrombocytopenia associated with heparin or heparinoid use, which amounts to less than 1.4% of the cardiac surgical population. It carries a risk of significant comorbidity and mortality. Providers involved in the care of such patients should be well versed in the etiology and potential complications of HITTS, the treatment options, and alternative modalities of anticoagulation available for use.