Prevalence of Symptoms of Severe Asthma and Allergies in Irish School Children: An ISAAC Protocol Study, 1995–2007

Childhood asthma is a recurring health burden and symptoms of severe asthma in children are also emerging as a health and economic issue. This study examined changing patterns in symptoms of severe asthma and allergies (ever eczema and hay fever), using the Irish International Study of Asthma and Allergies in Childhood (ISAAC) protocol. ISAAC is a cross-sectional self-administered questionnaire survey of randomly selected representative post-primary schools. Children aged 13–14 years were studied: 2,670 (in 1995), 2,273 (in 1998), 2,892 (in 2002–2003), and 2,805 (in 2007). Generalized linear modelling using Poisson distribution was employed to compute adjusted prevalence ratios (PR). A 39% significant increase in symptoms of severe asthma was estimated in 2007 relative to the baseline year 1995 (adjusted PR: 1.39 [95% CI: 1.14–1.69]) increasing from 12% in 1995 to 15.3% in 2007. Opposite trends were observed for allergies, showing a decline in 2007, with an initial rise. The potential explanations for such a complex disease pattern whose aetiological hypothesis is still evolving are speculative. Changing environmental factors may be a factor, for instance, an improvement in both outdoor and indoor air quality further reinforcing the hygiene hypothesis but obesity as a disease modifier must also be considered

Enhancing Self-Consistency and Performance of Pre-Trained Language Models through Natural Language Inference

While large pre-trained language models are powerful, their predictions often lack logical consistency across test inputs. For example, a state-of-the-art Macaw question-answering (QA) model answers 'Yes' to 'Is a sparrow a bird?' and 'Does a bird have feet?' but answers 'No' to 'Does a sparrow have feet?'. To address this failure mode, we propose a framework, Consistency Correction through Relation Detection, or ConCoRD, for boosting the consistency and accuracy of pre-trained NLP models using pre-trained natural language inference (NLI) models without fine-tuning or re-training. Given a batch of test inputs, ConCoRD samples several candidate outputs for each input and instantiates a factor graph that accounts for both the model's belief about the likelihood of each answer choice in isolation and the NLI model's beliefs about pair-wise answer choice compatibility. We show that a weighted MaxSAT solver can efficiently compute high-quality answer choices under this factor graph, improving over the raw model's predictions. Our experiments demonstrate that ConCoRD consistently boosts accuracy and consistency of off-the-shelf closed-book QA and VQA models using off-the-shelf NLI models, notably increasing accuracy of LXMERT on ConVQA by 5% absolute. See https://ericmitchell.ai/emnlp-2022-concord/ for code and data.Comment: 16 pages. EMNLP 2022 Camera Ready. See https://ericmitchell.ai/emnlp-2022-concord/ for code and dat

Genetic Loci Associated With Atrial Fibrillation: Relation to Left Atrial Structure in the Framingham Heart Study

Background: Atrial fibrillation (AF) results in significant morbidity and mortality. Genome‐wide association studies (GWAS) have identified genetic variants associated with AF. Whether genetic variants associated with AF are also associated with atrial structure, an intermediate phenotype for AF, has had limited investigation. We sought to investigate associations between single nucleotide polymorphisms (SNPs) and atrial structure obtained by cardiovascular imaging in the Framingham Heart Study. Methods and Results: We selected 11 SNPs that have been associated with AF in GWAS. We examined the SNPs' relations to cross‐sectional left atrial (LA) dimensions (determined by transthoracic echocardiography) and LA volume (determined by cardiovascular magnetic resonance [CMR]) employing linear regression. The total sample included 1555 participants with CMR LA volume (age 60±9 years, 53% women) and 6861 participants with echocardiographic LA diameter (age 48±13 years, 52% women) measured. We employed a significance threshold of P<0.0023 to account for multiple testing of the 11 SNPs and 2 LA measures. In a primary analysis, no SNPs were significantly related to the LA measures. Likewise, in secondary analyses excluding individuals with prevalent AF (n=77, CMR sample; n=105, echocardiography sample) no SNPs were related to LA volume or diameter. Conclusion: In a community‐based cohort, we did not identify a statistically significant association between selected SNPs associated with AF and measures of LA anatomy. Further investigations with larger longitudinally assessed samples and a broader array of SNPs may be necessary to determine the relation between genetic loci associated with AF and atrial structure

Emergence of winner-takes-all connectivity paths in random nanowire networks

Nanowire networks are promising memristive architectures for neuromorphic applications due to their connectivity and neurosynaptic-like behaviours. Here, we demonstrate a self-similar scaling of the conductance of networks and the junctions that comprise them. We show this behavior is an emergent property of any junction-dominated network. A particular class of junctions naturally leads to the emergence of conductance plateaus and a “winner-takes-all” conducting path that spans the entire network, and which we show corresponds to the lowest-energy connectivity path. The memory stored in the conductance state is distributed across the network but encoded in specific connectivity pathways, similar to that found in biological systems. These results are expected to have important implications for development of neuromorphic devices based on reservoir computing

Opposite associations between alanine aminotransferase and γ-glutamyl transferase levels and all-cause mortality in type 2 diabetes: analysis of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study

Aims Reported associations between liver enzymes and mortality may not hold true in type 2 diabetes, owing to a high prevalence of non-alcoholic fatty liver disease, which has been linked to cardiovascular disease and mortality in its own right. Our study aimed to determine whether alanine aminotransferase (ALT) or γ-glutamyl transferase (GGT) levels predict mortality in type 2 diabetes, and to examine possible mechanisms. Methods Data from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study were analysed to examine the relationship between liver enzymes and all-cause and cause-specific mortality over 5 years. Results Over 5 years, 679 (6.9%) individuals died. After adjustment, for every standard deviation increase in ALT (13.2U/L), the HR for death on study was 0.85 (95% CI 0.78-0.93), p70 U/L, compared with GGT ≤70 U/L, had HR 1.82 (1.48−2.24), p70 U/L was associated with higher risks of death due to cardiovascular disease, cancer and non-cancer/non-cardiovascular causes. The relationship for ALT persisted after adjustment for indirect measures of frailty but was attenuated by elevated hsCRP. Conclusions As in the general population, ALT has a negative, and GGT a positive, correlation with mortality in type 2 diabetes when ALT is less than two times the upper limit of normal. The relationship 4 for ALT appears specific for death due to cardiovascular disease. Links of low ALT with frailty, as a potential mechanism for relationships seen, were neither supported nor conclusively refuted by our analysis and other factors are also likely to be important in those with type 2 diabetes

Dalhousie dyspnea scales: construct and content validity of pictorial scales for measuring dyspnea

BACKGROUND: Because there are no child-friendly, validated, self-report measures of dyspnea or breathlessness, we developed, and provided initial validation, of three, 7-item, pictorial scales depicting three sub-constructs of dyspnea: throat closing, chest tightness, and effort. METHODS: We developed the three scales (Throat closing, Chest tightness, and Effort) using focus groups with 25 children. Subsequently, seventy-nine children (29 children with asthma, 30 children with cystic fibrosis. and 20 children who were healthy) aged 6 to 18 years rated each picture in each series, using a 0–10 scale. In addition, each child placed each picture in each series on a 100-cm long Visual Analogue Scale, with the anchors "not at all" and "a lot". RESULTS: Children aged eight years or older rated the scales in the correct order 75% to 98% correctly, but children less than 8 years of age performed unreliably. The mean distance between each consecutive item in each pictorial scale was equal. CONCLUSION: Preliminary results revealed that children aged 8 to 18 years understood and used these three scales measuring throat closing, chest tightness, and effort appropriately. The scales appear to accurately measure the construct of breathlessness, at least at an interval level. Additional research applying these scales to clinical situations is warranted

A robust methodology to subclassify pseudokinases based on their nucleotide-binding properties

Protein kinase-like domains that lack conserved residues known to catalyse phosphoryl transfer, termed pseudokinases, have emerged as important signalling domains across all kingdoms of life. Although predicted to function principally as catalysis-independent protein-interaction modules, several pseudokinase domains have been attributed unexpected catalytic functions, often amid controversy. We established a thermal-shift assay as a benchmark technique to define the nucleotide-binding properties of kinase-like domains. Unlike in vitro kinase assays, this assay is insensitive to the presence of minor quantities of contaminating kinases that may otherwise lead to incorrect attribution of catalytic functions to pseudokinases. We demonstrated the utility of this method by classifying 31 diverse pseudokinase domains into four groups: devoid of detectable nucleotide or cation binding; cation-independent nucleotide binding; cation binding; and nucleotide binding enhanced by cations. Whereas nine pseudokinases bound ATP in a divalent cation-dependent manner, over half of those examined did not detectably bind nucleotides, illustrating that pseudokinase domains predominantly function as non-catalytic protein-interaction modules within signalling networks and that only a small subset is potentially catalytically active. We propose that henceforth the thermal-shift assay be adopted as the standard technique for establishing the nucleotide-binding and catalytic potential of kinase-like domains

Internalization of Modified Lipids by CD36 and SR-A Leads to Hepatic Inflammation and Lysosomal Cholesterol Storage in Kupffer Cells

Non-alcoholic steatohepatitis (NASH) is characterized by steatosis and inflammation, which can further progress into fibrosis and cirrhosis. Recently, we demonstrated that combined deletion of the two main scavenger receptors, CD36 and macrophage scavenger receptor 1 (MSR1), which are important for modified cholesterol-rich lipoprotein uptake, reduced NASH. The individual contributions of these receptors to NASH and the intracellular mechanisms by which they contribute to inflammation have not been established. We hypothesize that CD36 and MSR1 contribute independently to the onset of inflammation in NASH, by affecting intracellular cholesterol distribution inside Kupffer cells (KCs).Ldlr(-/-) mice were transplanted with wild-type (Wt), Cd36(-/-) or Msr1(-/-) bone marrow and fed a Western diet for 3 months. Cd36(-/-)- and Msr1(-/-)- transplanted (tp) mice showed a similar reduction in hepatic inflammation compared to Wt-tp mice. While the total amount of cholesterol inside KCs was similar in all groups, KCs of Cd36(-/-)- and Msr1(-/-)-tp mice showed increased cytoplasmic cholesterol accumulation, while Wt-tp mice showed increased lysosomal cholesterol accumulation.CD36 and MSR1 contribute similarly and independently to the progression of inflammation in NASH. One possible explanation for the inflammatory response related to expression of these receptors could be abnormal cholesterol trafficking in KCs. These data provide a new basis for prevention and treatment of NASH

An animal-specific FSI model of the abdominal aorta in anesthetized mice

Recent research has revealed that angiotensin II-induced abdominal aortic aneurysm in mice can be related to medial ruptures occurring in the vicinity of abdominal side branches. Nevertheless a thorough understanding of the biomechanics near abdominal side branches in mice is lacking. In the current work we present a mouse-specific fluid-structure interaction (FSI) model of the abdominal aorta in ApoE(-/-) mice that incorporates in vivo stresses. The aortic geometry was based on contrast-enhanced in vivo micro-CT images, while aortic flow boundary conditions and material model parameters were based on in vivo high-frequency ultrasound. Flow waveforms predicted by FSI simulations corresponded better to in vivo measurements than those from CFD simulations. Peak-systolic principal stresses at the inner and outer aortic wall were locally increased caudal to the celiac and left lateral to the celiac and mesenteric arteries. Interestingly, these were also the locations at which a tear in the tunica media had been observed in previous work on angiotensin II-infused mice. Our preliminary results therefore suggest that local biomechanics play an important role in the pathophysiology of branch-related ruptures in angiotensin-II infused mice. More elaborate follow-up research is needed to demonstrate the role of biomechanics and mechanobiology in a longitudinal setting