The South African Flag Sign: An Electrocardiographic Flag for All Coronary Territories?

The South African flag sign (SAFS) is an acute, dynamic electrocardiographic (ECG) finding typically associated with first diagonal (D1) artery occlusion. We report the case of a 47-year-old woman who exhibited this pattern but subsequently revealed the dreaded "widow-maker" lesion (100% occluded proximal left anterior descending [LAD] artery) and severe multivessel disease (90% stenosis of the posterior left ventricular [PLV] artery and 80% stenosis of the left circumflex artery [LCx]).

Microtubule nucleation for spindle assembly: one molecule at a time.

The cell orchestrates the dance of chromosome segregation with remarkable speed and fidelity. The mitotic spindle is built from scratch after interphase through microtubule (MT) nucleation, which is dependent on the γ-tubulin ring complex (γ-TuRC), the universal MT template. Although several MT nucleation pathways build the spindle framework, the question of when and how γ-TuRC is targeted to these nucleation sites in the spindle and subsequently activated remains an active area of investigation. Recent advances facilitated the discovery of new MT nucleation effectors and their mechanisms of action. In this review, we illuminate each spindle assembly pathway and subsequently consider how the pathways are merged to build a spindle.

Unusual spin-orbit torque switching in perpendicular synthetic antiferromagnets with strong interlayer exchange coupling.

Synthetic antiferromagnet (SAF) is an outstanding system for controlling magnetic coupling via tuning the layer thickness and material composition. Here, we control the interlayer exchange coupling (IEC) in a perpendicularly magnetized SAF Pt/Co/Ir/CoFeB/MgO multilayer, which is tuned by varying the nonmagnetic layer Ir thickness and the magnetic layer Co thickness. And we study the spin-orbit torque (SOT) driven magnetization switching of the SAF. In the SAF with a weak IEC, the SOT-driven switching behavior is similar to that of a single ferromagnet system, which is dominated by the external magnetic field. In contrast, in the SAF with an ultra-strong IEC, the saturation magnetic field is large than 50 kOe, and the SOT-driven switching behavior is decided by the effective magnetic field. The effective field is correlated to the external magnetic field, the IEC field, magnetic moments of CoFeB and Co, and magnetic anisotropy. These results may advance the understanding of SOT switching of perpendicular SAFs and promote the applications of SAFs with low stray fields and lower power in spintronic devices.

Severe Fungal Asthma: A Role for Biologics and Inhaled Antifungals.

Allergic asthma has traditionally been treated with inhaled and systemic glucocorticosteroids. A continuum of allergic fungal airways disease associated with Aspergillus fumigatus colonization and/or atopic immune responses that encompasses fungal asthma, severe asthma with fungal sensitization and allergic bronchopulmonary aspergillosis is now recognized along a phenotypic severity spectrum of T2-high immune deviation lung disease. Oral triazoles have shown clinical, anti-inflammatory and microbiologic efficacy in this setting; in the future inhaled antifungals may improve the therapeutic index. Humanized monoclonal antibody biologic agents targeting T2-high disease also show efficacy and promise of improved control in difficult cases. Developments in these areas are highlighted in this overview.

The Clinical Implications of Aspergillus Fumigatus Sensitization in Difficult-To-Treat Asthma Patients.

BACKGROUND: Fungal sensitivity has been associated with severe asthma outcomes. However, the clinical implication of Aspergillus fumigatus sensitization in difficult-to-treat (or difficult) asthma is unclear. OBJECTIVES: To characterize the clinical implications of A fumigatus sensitization in a large difficult asthma cohort. METHODS: Participants who underwent both skin prick and specific IgE testing to A fumigatus (n = 318) from the longitudinal real-life Wessex AsThma CoHort of difficult asthma, United Kingdom, were characterized by A fumigatus sensitization (either positive skin prick test result or specific IgE) and allergic bronchopulmonary aspergillosis status using clinical/pathophysiological disease measures. RESULTS: A fumigatus sensitization was found in 23.9% (76 of 318) of patients with difficult asthma. Compared with A fumigatus nonsensitized subjects, those with sensitization were significantly more often male (50% vs 31%), older (58 years) with longer asthma duration (33 years), higher maintenance oral corticosteroid (39.7%) and asthma biologic use (27.6%), raised current/maximum log10 total IgE+1 (2.43/2.72 IU/L), worse prebronchodilator airflow obstruction (FEV1 62.2% predicted, FEV1/forced vital capacity 61.2%, forced expiratory flow between 25% and 75% exhalation 30.9% predicted), and frequent radiological bronchiectasis (40%), but had less psychophysiologic comorbidities. Allergic bronchopulmonary aspergillosis diagnosis was associated with higher treatment needs and stronger eosinophilic signals. Factors independently associated with A fumigatus sensitization in difficult asthma included maintenance oral corticosteroid use (odds ratio [OR], 3.34) and maximum log10 total IgE+1 (OR, 4.30), whereas for allergic bronchopulmonary aspergillosis included maintenance oral corticosteroid use (OR, 6.98), maximum log10 total IgE+1 (OR, 4.65), and radiological bronchiectasis (OR, 4.08). CONCLUSIONS: A fumigatus sensitization in difficult asthma identifies a more severe form of airways disease associated with greater morbidity, treatment need, and airways dysfunction/damage, but fewer psychophysiologic comorbidities. Screening of A fumigatus status should be an early element in the comprehensive assessment of patients with difficult asthma.

New Perspectives in the Diagnosis and Management of Allergic Fungal Airway Disease.

Allergy to airway-colonising, thermotolerant, filamentous fungi represents a distinct eosinophilic endotype of often severe lung disease. This endotype, which particularly affects adult asthma, but also complicates other airway diseases and sometimes occurs de novo, has a heterogeneous presentation ranging from severe eosinophilic asthma to lobar collapse. Its hallmark is lung damage, characterised by fixed airflow obstruction (FAO), bronchiectasis and lung fibrosis. It has a number of monikers including severe asthma with fungal sensitisation (SAFS) and allergic bronchopulmonary aspergillosis/mycosis (ABPA/M), but these exclusive terms constitute only sub-sets of the condition. In order to capture the full extent of the syndrome we prefer the inclusive term allergic fungal airway disease (AFAD), the criteria for which are IgE sensitisation to relevant fungi in association with airway disease. The primary fungus involved is Aspergillus fumigatus, but a number of other thermotolerant species from several genera have been implicated. The unifying mechanism involves germination of inhaled fungal spores in the lung in the context of IgE sensitisation, leading to a persistent and vigorous eosinophilic inflammatory response in association with release of fungal proteases. Most allergenic fungi, including Alternaria and Cladosporium species, are not thermotolerant and cannot germinate in the airways so only act as aeroallergens and do not cause AFAD. Studies of the airway mycobiome have shown that A. fumigatus colonises the normal as much as the asthmatic airway, suggesting it is the tendency to become IgE-sensitised that is the critical triggering factor for AFAD rather than colonisation per se. Treatment is aimed at preventing exacerbations with glucocorticoids and increasingly by the use of anti-T2 biological therapies. Anti-fungal therapy has a limited place in management, but is an effective treatment for fungal bronchitis which complicates AFAD in about 10% of cases.

Allergic fungal airways disease (AFAD): an under-recognised asthma endotype.

The term allergic fungal airways disease has a liberal definition based on IgE sensitisation to thermotolerant fungi and evidence of fungal-related lung damage. It arose from a body of work looking into the role of fungi in asthma. Historically fungi were considered a rare complication of asthma, exemplified by allergic bronchopulmonary aspergillosis; however, there is a significant proportion of individuals with Aspergillus fumigatus sensitisation who do not meet these criteria, who are at high risk for the development of lung damage. The fungi that play a role in asthma can be divided into two groups; those that can grow at body temperature referred to as thermotolerant, which are capable of both infection and allergy, and those that cannot but can still act as allergens in IgE sensitised individuals. Sensitisation to thermotolerant filamentous fungi (Aspergillus and Penicillium), and not non-thermotolerant fungi (Alternaria and Cladosporium) is associated with lower lung function and radiological abnormalities (bronchiectasis, tree-in-bud, fleeting shadows, collapse/consolidation and fibrosis). For antifungals to play a role in treatment, the focus should be on fungi capable of growing in the airways thereby causing a persistent chronic allergenic stimulus and releasing tissue damaging proteases and other enzymes which may disrupt the airway epithelial barrier and cause mucosal damage and airway remodelling. All patients with IgE sensitisation to thermotolerant fungi in the context of asthma and other airway disease are at risk of progressive lung damage, and as such should be monitored closely.

Real-World Effectiveness of Anti-IL-5/5R Therapy in Severe Atopic Eosinophilic Asthma with Fungal Sensitization.

BACKGROUND: Severe asthma with fungal sensitization (SAFS) is a complex clinical phenotype associated with poorly controlled type 2 inflammation and significant morbidity from both the disease itself and a high steroid burden. OBJECTIVE: To assess the effectiveness of biologic therapies targeting eosinophilic inflammation in SAFS. METHODS: We assessed the effectiveness of treatment with mepolizumab or benralizumab in patients with SAFS, and compared outcomes with patients with severe atopic asthma without fungal sensitization and patients with severe nonatopic asthma. Baseline clinical characteristics and clinical outcomes at 48 weeks were evaluated. A subgroup analysis was performed of patients who met the criteria for allergic bronchopulmonary aspergillosis (ABPA) rather than SAFS. RESULTS: A total of 193 patients treated with mepolizumab (n = 63) or benralizumab (n = 130) were included. Patients with SAFS had higher baseline IgE level compared with patients with severe atopic asthma without fungal sensitization and severe nonatopic asthma (733 ± 837 IU/mL vs 338 ± 494 and 142 ± 171, respectively; both P < .001). There were no other significant baseline differences in clinical characteristics between groups. At 48 weeks, there were significant improvements in 6-item asthma control questionnaire score and exacerbation frequency, and reduction in maintenance oral corticosteroid dose across all groups (all P < .05). No significant between-group differences in outcomes were observed at 48 weeks. Patients with ABPA (n = 9) had a significant reduction in exacerbation frequency (P = .013) with treatment. CONCLUSIONS: Treatment with eosinophil-targeting biologics led to improvements in exacerbation frequency, oral corticosteroid requirements, and patient-reported outcomes in patients with SAFS, with a reduction in exacerbations in the subgroup of patients with ABPA. These data highlight the potential clinical utility of targeting eosinophilic inflammation in SAFS and ABPA.

An appraisal of allergic disorders in India and an urgent call for action.

India is the second most populous country in the world with a population of nearly 1.3 billion, comprising 20% of the global population. There are an estimated 37.5 million cases of asthma in India, and recent studies have reported a rise in prevalence of allergic rhinitis and asthma. Overall, 40-50% of paediatric asthma cases in India are uncontrolled or severe. Treatment of allergic rhinitis and asthma is sub-optimal in a significant proportion of cases due to multiple factors relating to unaffordability to buy medications, low national gross domestic product, religious beliefs, myths and stigma regarding chronic ailment, illiteracy, lack of allergy specialists, and lack of access to allergen-specific immunotherapy for allergic rhinitis and biologics for severe asthma. High quality allergen extracts for skin tests and adrenaline auto-injectors are currently not available in India. Higher postgraduate specialist training programmes in Allergy and Immunology are also not available. Another major challenge for the vast majority of the Indian population is an unacceptably high level of exposure to particulate matter (PM)2.5 generated from traffic pollution and use of fossil fuel and biomass fuel and burning of incense sticks and mosquito coils. This review provides an overview of the burden of allergic disorders in India. It appraises current evidence and justifies an urgent need for a strategic multipronged approach to enhance quality of care for allergic disorders. This may include creating an infrastructure for education and training of healthcare professionals and patients and involving regulatory authorities for making essential treatments accessible at subsidised prices. It calls for research into better phenotypic characterisation of allergic disorders, as evidence generated from high income western countries are not directly applicable to India, due to important confounders such as ethnicity, air pollution, high rates of parasitic infestation, and other infections.

Coupling self-sustaining air flotation screening with conventional CSTR enhances anaerobic biodegradability of corn stover.

The anaerobic biodegradability of lignocellulosic crop waste could be improved by proper pretreatments, but little information is available on enhancing straw digestibility through the reactor configuration. In a lab-based batch experiment, a novel reactor was established to testify the possibility to enhance anaerobic biodegradability of corn stover (CS) by coupling a self-sustaining air flotation screening (SAFS) unit with conventional continuous stirred tank reactor (CSTR). The SAFS-CSTR improved the maximum methane production by 14.27% with the duration of 16 d compared with the conventional CSTR for 20 d. The temporal and spatial distribution of basic indexes significantly differed from conventional CSTR. Elevated bacterial diversity and marked shifts in bacterial community composition were observed in different locations of reactor, with Bacteroidetes and Proteobacteria being the dominant phyla. SAFS unit would serve to separate inhibitors effectively and meanwhile enhance the mass-transfer efficiency, thus providing reference to upgrade or retrofit the conventional CSTR.

An Estimate of the Burden of Fungal Disease in Norway.

The aim of this study was to examine the burden of fungal disease in Norway, contributing to a worldwide effort to improve awareness of the needs for better diagnosis and treatment of such infections. We used national registers and actual data from the Departments of Microbiology from 2015 and estimated the incidence and/or prevalence of superficial, allergic and invasive fungal disease using published reports on specific populations at risk. One in 6 Norwegians suffered from fungal disease: Superficial skin infections (14.3%: 745,600) and recurrent vulvovaginal candidiasis in fertile women (6%: 43,123) were estimated to be the most frequent infections. Allergic fungal lung disease was estimated in 17,755 patients (341/100,000). Pneumocystis jirovecii was diagnosed in 262 patients (5/100,000), invasive candidiasis in 400 patients (7.7/100,000), invasive aspergillosis in 278 patients (5.3/100,000) and mucormycosis in 7 patients (0.1/100,000). Particular fungal infections from certain geographic areas were not observed. Overall, 1.79% of the population was estimated to be affected by serious fungal infections in Norway in 2015. Even though estimates for invasive infections are small, the gravity of such infections combined with expected demographic changes in the future emphasizes the need for better epidemiological data.

Can Controlling Endoplasmic Reticulum Dysfunction Treat Allergic Inflammation in Severe Asthma With Fungal Sensitization?

Severe asthma is a heterogeneous disease entity to which diverse cellular components and pathogenetic mechanisms contribute. Current asthma therapies, including new biologic agents, are mainly targeting T helper type 2 cell-dominant inflammation, so that they are often unsatisfactory in the treatment of severe asthma. Respiratory fungal exposure has long been regarded as a precipitating factor for severe asthma phenotype. Moreover, as seen in clinical definitions of allergic bronchopulmonary aspergillosis (ABPA) and severe asthma with fungal sensitization (SAFS), fungal allergy-associated severe asthma phenotype is increasingly thought to have distinct pathobiologic mechanisms requiring different therapeutic approaches other than conventional treatment. However, there are still many unanswered questions on the direct causality of fungal sensitization in inducing severe allergic inflammation in SAFS. Recently, growing evidence suggests that stress response from the largest organelle, endoplasmic reticulum (ER), is closely interconnected to diverse cellular immune/inflammatory platforms, thereby being implicated in severe allergic lung inflammation. Interestingly, a recent study on this issue has suggested that ER stress responses and several associated molecular platforms, including phosphoinositide 3-kinase-δ and mitochondria, may be crucial players in the development of severe allergic inflammation in the SAFS. Defining emerging roles of ER and associated cellular platforms in SAFS may offer promising therapeutic options in the near future.

Can Controlling Endoplasmic Reticulum Dysfunction Treat Allergic Inflammation in Severe Asthma With Fungal Sensitization?

Severe asthma is a heterogeneous disease entity to which diverse cellular components and pathogenetic mechanisms contribute. Current asthma therapies, including new biologic agents, are mainly targeting T helper type 2 cell-dominant inflammation, so that they are often unsatisfactory in the treatment of severe asthma. Respiratory fungal exposure has long been regarded as a precipitating factor for severe asthma phenotype. Moreover, as seen in clinical definitions of allergic bronchopulmonary aspergillosis (ABPA) and severe asthma with fungal sensitization (SAFS), fungal allergy-associated severe asthma phenotype is increasingly thought to have distinct pathobiologic mechanisms requiring different therapeutic approaches other than conventional treatment. However, there are still many unanswered questions on the direct causality of fungal sensitization in inducing severe allergic inflammation in SAFS. Recently, growing evidence suggests that stress response from the largest organelle, endoplasmic reticulum (ER), is closely interconnected to diverse cellular immune/inflammatory platforms, thereby being implicated in severe allergic lung inflammation. Interestingly, a recent study on this issue has suggested that ER stress responses and several associated molecular platforms, including phosphoinositide 3-kinase-δ and mitochondria, may be crucial players in the development of severe allergic inflammation in the SAFS. Defining emerging roles of ER and associated cellular platforms in SAFS may offer promising therapeutic options in the near future.

Allergic Fungal Airway Disease.

Fungi are ubiquitous and form their own kingdom. Up to 80 genera of fungi have been linked to type I allergic disease, and yet, commercial reagents to test for sensitization are available for relatively few species. In terms of asthma, it is important to distinguish between species unable to grow at body temperature and those that can (thermotolerant) and thereby have the potential to colonize the respiratory tract. The former, which include the commonly studied Alternaria and Cladosporium genera, can act as aeroallergens whose clinical effects are predictably related to exposure levels. In contrast, thermotolerant species, which include fungi from the Candida, Aspergillus, and Penicillium genera, can cause a persistent allergenic stimulus independent of their airborne concentrations. Moreover, their ability to germinate in the airways provides a more diverse allergenic stimulus, and may result in noninvasive infection, which enhances inflammation. The close association between IgE sensitization to thermotolerant filamentous fungi and fixed airflow obstruction, bronchiectasis, and lung fibrosis suggests a much more tissue-damaging process than that seen with aeroallergens. This review provides an overview of fungal allergens and the patterns of clinical disease associated with exposure. It clarifies the various terminologies associated with fungal allergy in asthma and makes the case for a new term (allergic fungal airway disease) to include all people with asthma at risk of developing lung damage as a result of their fungal allergy. Lastly, it discusses the management of fungirelated asthma.

Burden of serious fungal infections in Nepal.

There are few reports of serious fungal infections in Nepal though the pathogenic and allergenic fungi including Aspergillus species are common in the atmosphere. Herein, we estimate the burden of serious fungal infections in Nepal. All published papers reporting fungal infection rates from Nepal were identified. When few data existed, we used specific populations at risk and fungal infection frequencies in those populations to estimate national incidence or prevalence. Of the 27.3 M population, about 1.87% was estimated to suffer from serious fungal infections annually. We estimated the incidence of fungal keratitis at 73 per 100,000 annually. Chronic obstructive pulmonary disease is common with 215,765 cases, contributing to 1119 cases of invasive aspergillosis annually. Of 381,822 adult asthma cases, we estimated 9546 patients (range 2673-13,364) develop allergic bronchopulmonary aspergillosis and 12,600 have severe asthma with fungal sensitisation. Based on 26,219 cases of pulmonary tuberculosis, the annual incidence of new chronic pulmonary aspergillosis (CPA) cases was estimated at 1678 with a 5 year period prevalence of 5289, 80% of CPA cases. Of 22,994 HIV patients with CD4 counts <350 not on antiretrovirals, Pneumocystis pneumonia was estimated at 990 cases annually. Cases of oral and oesophageal candidiasis in HIV/AIDS patients were estimated at 10,347 and 2950, respectively. There is a significant burden of serious fungal infections in Nepal. Epidemiological studies are necessary to validate these estimates.

Burden of serious fungal infections in Spain.

Estimates of the incidence and prevalence of serious fungal infections, based on epidemiological data, are essential in order to inform public health priorities given the lack of resources dedicated to the diagnosis and treatment of these serious fungal diseases. However, epidemiology of these infections is largely unknown, except for candidaemia and cryptococcosis. The aim of this work is to calculate the burden of serious fungal infections in Spain. All published epidemiology papers reporting fungal infection rates from Spain were identified. Where no data existed, we used specific populations at risk and fungal infection frequencies in those populations to estimate national incidence or prevalence, depending on the condition. Around 8.1 million people suffer a fungal infection every year. Most of them are skin or mucosal infections causing no deaths. Candidaemia is more common than in other European countries and has risen by 1.88-fold in frequency in the last decade (8.1 cases × 100,000). Good estimates of invasive aspergillosis (2.75 cases × 100,000) and mucormycosis (0.04 × 100,000) are available. Fungal infections with a high mortality such as invasive aspergillosis, candidaemia, Pneumocystis pneumonia and mucormycosis are not numerous in Spain, but they affect those with severe underlying diseases and are therefore linked to poor outcomes. Additional studies are required, especially for high burden diseases such as recurrent thrush in women (∼9000 cases × 100,000 women), allergic bronchopulmonary aspergillosis (126 cases × 100,000) and severe asthma with fungal sensitisation (198 cases × 100,000).

Fungal allergy in asthma-state of the art and research needs.

Sensitization to fungi and long term or uncontrolled fungal infection are associated with poor control of asthma, the likelihood of more severe disease and complications such as bronchiectasis and chronic pulmonary aspergillosis. Modelling suggests that >6.5 million people have severe asthma with fungal sensitizations (SAFS), up to 50% of adult asthmatics attending secondary care have fungal sensitization, and an estimated 4.8 million adults have allergic bronchopulmonary aspergillosis (ABPA). There is much uncertainty about which fungi and fungal allergens are relevant to asthma, the natural history of sensitisation to fungi, if there is an exposure response relationship for fungal allergy, and the pathogenesis and frequency of exacerbations and complications. Genetic associations have been described but only weakly linked to phenotypes. The evidence base for most management strategies in ABPA, SAFS and related conditions is weak. Yet straightforward clinical practice guidelines for management are required. The role of environmental monitoring and optimal means of controlling disease to prevent disability and complications are not yet clear. In this paper we set out the key evidence supporting the role of fungal exposure, sensitisation and infection in asthmatics, what is understood about pathogenesis and natural history and identify the numerous areas for research studies.

Resting metabolic rate and heat increment of feeding in juvenile South American fur seals (Arctocephalus australis).

Bio-energetic models used to characterize an animal's energy budget require the accurate estimate of different variables such as the resting metabolic rate (RMR) and the heat increment of feeding (HIF). In this study, we estimated the in air RMR of wild juvenile South American fur seals (SAFS; Arctocephalus australis) temporarily held in captivity by measuring oxygen consumption while at rest in a postabsorptive condition. HIF, which is an increase in metabolic rate associated with digestion, assimilation and nutrient interconversion, was estimated as the difference in resting metabolic rate between the postabsorptive condition and the first 3.5h postprandial. As data were hierarchically structured, linear mixed effect models were used to compare RMR measures under both physiological conditions. Results indicated a significant increase (61%) for the postprandial RMR compared to the postabsorptive condition, estimated at 17.93±1.84 and 11.15±1.91mL O2 min(-1)kg(-1), respectively. These values constitute the first estimation of RMR and HIF in this species, and should be considered in the energy budgets for juvenile SAFS foraging at-sea.