Multi-locus sequence typing and phylogenetics of Cryptococcus neoformans AD hybrids.

Hybrid AD strains of the human pathogenic Cryptococcus neoformans species complex have been reported from many parts of the world. However, their origin, diversity, and evolution are incompletely understood. In this study, we analyzed 102 AD hybrid strains representing 21 countries on five continents. For each strain, we obtained its mating type and its allelic sequences at each of the seven loci that have been used for genotyping haploid serotypes A and D strains of the species complex by the Cryptococcus research community. Our results showed that most AD hybrids exhibited loss of heterozygosity at one or more of the seven analyzed loci. Phylogenetic and population genetic analyses of the allelic sequences revealed multiple origins of the hybrids within each continent, dating back to one million years ago in Africa and up to the present in other continents. We found evidence for clonal reproduction and long-distance dispersal of these hybrids in nature. Comparisons with the global haploid serotypes A and D strains identified new alleles and new haploid multi-locus genotypes in AD hybrids, consistent with the presence of yet-to-be discovered genetic diversity in haploid populations of this species complex in nature. Together, our results indicate that AD hybrids can be effectively genotyped using the same multi-locus sequencing type approach as that established for serotypes A and D strains. Our comparisons of the AD hybrids among each other as well as with the global haploid serotypes A and D strains revealed novel genetic diversity as well as evidence for multiple origins and dynamic evolution of these hybrids in nature.

Metabolic pathways in immune senescence and inflammaging: Novel therapeutic strategy for chronic inflammatory lung diseases. An EAACI position paper from the Task Force for Immunopharmacology.

The accumulation of senescent cells drives inflammaging and increases morbidity of chronic inflammatory lung diseases. Immune responses are built upon dynamic changes in cell metabolism that supply energy and substrates for cell proliferation, differentiation, and activation. Metabolic changes imposed by environmental stress and inflammation on immune cells and tissue microenvironment are thus chiefly involved in the pathophysiology of allergic and other immune-driven diseases. Altered cell metabolism is also a hallmark of cell senescence, a condition characterized by loss of proliferative activity in cells that remain metabolically active. Accelerated senescence can be triggered by acute or chronic stress and inflammatory responses. In contrast, replicative senescence occurs as part of the physiological aging process and has protective roles in cancer surveillance and wound healing. Importantly, cell senescence can also change or hamper response to diverse therapeutic treatments. Understanding the metabolic pathways of senescence in immune and structural cells is therefore critical to detect, prevent, or revert detrimental aspects of senescence-related immunopathology, by developing specific diagnostics and targeted therapies. In this paper, we review the main changes and metabolic alterations occurring in senescent immune cells (macrophages, B cells, T cells). Subsequently, we present the metabolic footprints described in translational studies in patients with chronic asthma and chronic obstructive pulmonary disease (COPD), and review the ongoing preclinical studies and clinical trials of therapeutic approaches aiming at targeting metabolic pathways to antagonize pathological senescence. Because this is a recently emerging field in allergy and clinical immunology, a better understanding of the metabolic profile of the complex landscape of cell senescence is needed. The progress achieved so far is already providing opportunities for new therapies, as well as for strategies aimed at disease prevention and supporting healthy aging.

Enantioselective Synthesis of ß-l-5-[(E)-2-Bromovinyl)-1-((2S,4S)-2-(hydroxymethyl)-1,3-(dioxolane-4-yl) Uracil)] (l-BHDU) via Chiral Pure l-Dioxolane.

ß-l-5-((E)-2-Bromovinyl)-1-((2S,4S)-2-(hydroxymethyl)-1,3-(dioxolane-4-yl) uracil (l-BHDU, 17) is a potent and selective inhibitor of the varicella-zoster virus (VZV). l-BHDU (17) has demonstrated excellent anti-VZV activity and is a preclinical candidate to treat chickenpox, shingles (herpes zoster), and herpes simplex virus 1 (HSV-1) infections. Its monophosphate prodrug (POM-l-BHDU-MP, 24) demonstrated an enhanced pharmacokinetic and antiviral profile. POM-l-BHDU-MP (24), in vivo, effectively reduced the VZV viral load and was effective for the topical treatment of VZV and HSV-1 infections. Therefore, a viable synthetic procedure for developing POM-l-BHDU-MP (24) is needed. In this article, an efficient approach for the synthesis of l-BHDU (17) from a readily available starting material is described in 7 steps. An efficient and practical methodology for both chiral pure l- & d-dioxolane 11 and 13 were developed via diastereomeric chiral amine salt formation. Neutralization of the amine carboxylate salt of l-dioxolane 10 provides enantiomerically pure l-dioxane 11 (ee ≥ 99%). Optically pure 11 was utilized to construct the final nucleoside l-BHDU (17) and its monophosphate ester prodrug (POM-l-BHDU-MP, 24). Notably, the reported process eliminates expensive chiral chromatography for the synthesis of chiral pure l- & d-dioxolane, which offers avenues for the development and structure-activity relationship studies of l- & d-dioxolane-derived nucleosides.

Real Gas Effects in High-Pressure Ignition of n-Dodecane/Air Mixtures.

This work studies the real gas effects on the autoignition of hydrocarbon fuels under high pressures, using normal dodecane (n-dodecane) as the representative fuel and the Redlich-Kwong equation of state (EoS) as the real gas description. It is demonstrated that the real gas description yields a shorter ignition delay time (IDT) compared with the ideal gas description, especially in low-temperature regimes which could encompass the negative temperature coefficient (NTC) phenomena and has a stronger dependence on the molecular volume than the attractive potential. The study further shows that high pressure facilitates low-temperature reaction pathways, where the compressibility factors of key reactants contribute to real gas effects. Moreover, the results suggest that accounting for real gas behavior leads to an increase in the formation of polycyclic aromatic hydrocarbons (PAHs), which, in turn, promotes soot generation.

On explosive boiling of a multicomponent Leidenfrost drop.

The gasification of multicomponent fuel drops is relevant in various energy-related technologies. An interesting phenomenon associated with this process is the self-induced explosion of the drop, producing a multitude of smaller secondary droplets, which promotes overall fuel atomization and, consequently, improves the combustion efficiency and reduces emissions of liquid-fueled engines. Here, we study a unique explosive gasification process of a tricomponent droplet consisting of water, ethanol, and oil ("ouzo"), by high-speed monitoring of the entire gasification event taking place in the well-controlled, levitated Leidenfrost state over a superheated plate. It is observed that the preferential evaporation of the most volatile component, ethanol, triggers nucleation of the oil microdroplets/nanodroplets in the remaining drop, which, consequently, becomes an opaque oil-in-water microemulsion. The tiny oil droplets subsequently coalesce into a large one, which, in turn, wraps around the remnant water. Because of the encapsulating oil layer, the droplet can no longer produce enough vapor for its levitation, and, thus, falls and contacts the superheated surface. The direct thermal contact leads to vapor bubble formation inside the drop and consequently drop explosion in the final stage.

Healthy Eating Report Card for Pre-school Children in Hong Kong.

INTRODUCTION: This study aimed to develop the Healthy Eating Report Card for Pre-school Children in Hong Kong for evaluating the prevalence of healthy eating behaviours and favourable family home food environments (FHFEs) among pre-school children in Hong Kong. METHODS: In this cross-sectional study, 538 parent-child dyads from eight kindergartens in Hong Kong were recruited. Parents or guardians completed a questionnaire comprising Report Card items. The Report Card included two indicators of Children's Eating Behaviours (ie, Children's Dietary Patterns and Children's Mealtime Behaviours) and three indicators of FHFEs (ie, Parental Food Choices and Preparation, Avoidance of Unhealthy Foods, and Family Mealtime Environments). Each indicator and its specific items were assigned a letter grade representing the percentage of participants achieving the predefined benchmarks. The grades were defined as A (≥80%, Excellent); B (60%-79%, Good); C (40%-59%, Fair); D (20%-39%, Poor); and F (<20%, Very poor). Plus (+) and minus (-) signs were used to indicate the upper or lower 5% of each grade. RESULTS: Overall, Children's Eating Behaviours were classified as Fair (average grade of 'C'), whereas FHFEs were classified as Good (average grade of 'B'). The sub-grades ranged from 'C' to 'A-', as follows: Children's Dietary Patterns, 'C+'; Children's Mealtime Behaviours, 'C'; Parental Food Choices and Preparation, 'C+'; Avoidance of Unhealthy Foods, 'B'; and Family Mealtime Environments, 'A-'. CONCLUSION: The findings highlight areas for improvement in healthy eating among children. The Healthy Eating Report Card could offer novel insights into intervention tools that promote healthy eating.

Synthesis of Fluorinated Nucleosides/Nucleotides and Their Antiviral Properties.

The FDA has approved several drugs based on the fluorinated nucleoside pharmacophore, and numerous drugs are currently in clinical trials. Fluorine-containing nucleos(t)ides offer significant antiviral and anticancer activity. The insertion of a fluorine atom, either in the base or sugar of nucleos(t)ides, alters its electronic and steric parameters and transforms the lipophilicity, pharmacodynamic, and pharmacokinetic properties of these moieties. The fluorine atom restricts the oxidative metabolism of drugs and provides enzymatic metabolic stability towards the glycosidic bond of the nucleos(t)ide. The incorporation of fluorine also demonstrates additional hydrogen bonding interactions in receptors with enhanced biological profiles. The present article discusses the synthetic methodology and antiviral activities of FDA-approved drugs and ongoing fluoro-containing nucleos(t)ide drug candidates in clinical trials.

Adverse roles of mast cell chymase-1 in COPD.

BACKGROUND: COPD is the third leading cause of death worldwide. Cigarette smoke (CS)-induced chronic inflammation inducing airway remodelling, emphysema and impaired lung function is the primary cause. Effective therapies are urgently needed. Human chymase (hCMA)1 and its orthologue mCMA1/mouse mast cell protease (mMCP)5 are exocytosed from activated mast cells and have adverse roles in numerous disorders, but their role in COPD is unknown. METHODS: We evaluated hCMA1 levels in lung tissues of COPD patients. We used mmcp5-deficient (-/-) mice to evaluate this protease's role and potential for therapeutic targeting in CS-induced experimental COPD. In addition, we used ex vivo/in vitro studies to define mechanisms. RESULTS: The levels of hCMA1 mRNA and CMA1+ mast cells were increased in lung tissues from severe compared to early/mild COPD patients, non-COPD smokers and healthy controls. Degranulated mast cell numbers and mMCP5 protein were increased in lung tissues of wild-type mice with experimental COPD. mmcp5 -/- mice were protected against CS-induced inflammation and macrophage accumulation, airway remodelling, emphysema and impaired lung function in experimental COPD. CS extract challenge of co-cultures of mast cells from wild-type, but not mmcp5 -/- mice with wild-type lung macrophages increased in tumour necrosis factor (TNF)-α release. It also caused the release of CMA1 from human mast cells, and recombinant hCMA-1 induced TNF-α release from human macrophages. Treatment with CMA1 inhibitor potently suppressed these hallmark features of experimental COPD. CONCLUSION: CMA1/mMCP5 promotes the pathogenesis of COPD, in part, by inducing TNF-α expression and release from lung macrophages. Inhibiting hCMA1 may be a novel treatment for COPD.

Probing Flat Band Physics in Spin Ice Systems via Polarized Neutron Scattering.

In this Letter, we illustrate how polarized neutron scattering can be used to isolate the spin-spin correlations of modes forming flat bands in a frustrated magnetic system hosting a classical spin liquid phase. In particular, we explain why the nearest-neighbor spin ice model, whose interaction matrix has two flat bands, produces a dispersionless (i.e., "flat") response in the non-spin-flip (NSF) polarized neutron scattering channel and demonstrate that NSF scattering is a highly sensitive probe of correlations induced by weak perturbations that lift the flat band degeneracy. We use this to explain the experimentally measured dispersive (i.e., nonflat) NSF channel of the dipolar spin ice compound Ho_{2}Ti_{2}O_{7}.

In Vivo Efficacy of Olorofim against Systemic Scedosporiosis and Lomentosporiosis.

Clinically relevant members of the Scedosporium/Pseudallescheria species complex and Lomentospora prolificans are generally resistant against currently available systemic antifungal agents in vitro, and infection due to these species is difficult to treat. We studied the in vivo efficacy of a new fungicidal agent, olorofim (formerly F901318), against scedosporiosis and lomentosporiosis in neutropenic animals. Cyclophosphamide-immunosuppressed CD-1 mice infected by Scedosporium apiospermum, Pseudallescheria boydii (Scedosporium boydii), and Lomentospora prolificans were treated by intraperitoneal administration of olorofim (15 mg/kg of body weight every 8 h for 9 days). The efficacy of olorofim treatment was assessed by the survival rate at 10 days postinfection, levels of serum (1-3)-ß-d-glucan (BG), histopathology, and fungal burdens of kidneys 3 days postinfection. Olorofim therapy significantly improved survival compared to that of the untreated controls; 80%, 100%, and 100% of treated mice survived infection by Scedosporium apiospermum, Pseudallescheria boydii, and Lomentospora prolificans, respectively, while less than 20% of the control mice (phosphate-buffered saline [PBS] treated) survived at 10 days postinfection. In the olorofim-treated neutropenic CD-1 mice infected with any of the three species, serum BG levels were significantly suppressed and fungal DNA detected in the target organs was significantly lower than in controls. Furthermore, histopathology of kidneys revealed no or only a few lesions with hyphal elements in the olorofim-treated mice, while numerous fungal hyphae were present in control mice. These results indicate olorofim to be a promising therapeutic agent for systemic scedosporiosis/lomentosporiosis, devastating emerging fungal infections that are difficult to treat with currently available antifungals.

Kinetic Study of Two-Stage Low-Temperature Heat Release in iso-Octane Autoignition.

Recognizing that low-temperature ignition of alkanes is usually associated with one heat release peak, we report herein that, for iso-octane under certain ranges of initial temperatures and pressures, two separate heat release peaks were observed through computational simulations using several kinetic mechanisms. The inherent chemical reason for this phenomenon is discussed using reaction channel analysis and is identified to result from the competition between R + O2 → RO2 and the ß scission reactions. By further utilizing sensitivity and path flux analyses, an isomeric effect is identified in that the different isomeric structures produced through the H-abstraction reactions can lead to differences in the subsequent low-temperature reaction pathways.

Statistical Analysis on Rate Parameters of the H2-O2 Reaction System.

Quantitative rate determination of elementary reactions is a major task in the study of chemical kinetics. To ensure the fidelity of their determination, progressively tightened constraints need to be placed on their measurement, especially with the development of various notable experimental techniques. However, the evaluation of reaction rates and their uncertainties is frequently conducted with substantial subjectivity due to data source, thermodynamic conditions, sampling range, and sparsity. To reduce the extent of biased rate evaluation, we propose herein an approach of uncertainty-weighted statistical analysis, utilizing weighted average, and weighted least-square regression in statistical inference. Based on the backbone H2/O2 chemistry, rate data for each elementary reaction are collected from the time-history profile in shock tube experiments and high-level theoretical calculations, with their assigned weight inversely depending on uncertainty, which would overall avoid subjective assessments and provide more accurate rate evaluation. Aided by sensitivity analysis, the rates of a few key reactions are further constrained in the less investigated low- to intermediate-temperature conditions using high-fidelity flow reactor data. Good performance of the constructed mechanism is confirmed with validation against the target of the high-fidelity flow reactor data. This study demonstrates a systematic approach for reaction rate evaluation and uncertainty quantification.

Findings from the first public COVID-19 temporary test centre in Hong Kong.

INTRODUCTION: The Hospital Authority of Hong Kong Special Administrative Region established a coronavirus disease 2019 (COVID-19) temporary test centre at the AsiaWorld-Expo from March 2020 to April 2020, which allowed high-risk individuals to undergo early assessment of potential severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This study reviewed the characteristics and outcomes of individuals who attended the centre for COVID-19 testing. METHODS: This retrospective cross-sectional study collected epidemiological and clinical data. The primary outcome was a positive or negative SARS-CoV-2 test result, according to reverse transcription polymerase chain reaction analyses of pooled nasopharyngeal and throat swabs collected at the centre. The relationships of clinical characteristics with SARS-CoV-2 positive test results were assessed by multivariable binary logistic regression. RESULTS: Of 1258 attendees included in the analysis, 86 individuals tested positive for SARS-CoV-2 infection (positivity rate=6.84%; 95% confidence interval [CI]=5.57%-8.37%). Of these 86 individuals, 40 (46.5%) were aged 15 to 24 years and 81 (94.2%) had a history of recent travel. Symptoms were reported by 86.0% and 96.3% of individuals with positive and negative test results, respectively. The clinical characteristics most strongly associated with a positive test result were anosmia (adjusted odds ratio [ORadj]=8.30; 95% CI=1.12-127.09) and fever ORadj=1.32; 95% CI=1.02-3.28). CONCLUSION: The temporary test centre successfully helped identify individuals with COVID-19 who exhibited mild disease symptoms. Healthcare providers should carefully consider the epidemiological and clinical characteristics of COVID-19 to arrange early testing to reduce community spread.

Connectivity patterns between multiple allergen specific IgE antibodies and their association with severe asthma.

BACKGROUND: Allergic sensitization is associated with severe asthma, but assessment of sensitization is not recommended by most guidelines. OBJECTIVE: We hypothesized that patterns of IgE responses to multiple allergenic proteins differ between sensitized participants with mild/moderate and severe asthma. METHODS: IgE to 112 allergenic molecules (components, c-sIgE) was measured using multiplex array among 509 adults and 140 school-age and 131 preschool children with asthma/wheeze from the Unbiased BIOmarkers for the PREDiction of respiratory diseases outcomes cohort, of whom 595 had severe disease. We applied clustering methods to identify co-occurrence patterns of components (component clusters) and patterns of sensitization among participants (sensitization clusters). Network analysis techniques explored the connectivity structure of c-sIgE, and differential network analysis looked for differences in c-sIgE interactions between severe and mild/moderate asthma. RESULTS: Four sensitization clusters were identified, but with no difference between disease severity groups. Similarly, component clusters were not associated with asthma severity. None of the c-sIgE were identified as associates of severe asthma. The key difference between school children and adults with mild/moderate compared with those with severe asthma was in the network of connections between c-sIgE. Participants with severe asthma had higher connectivity among components, but these connections were weaker. The mild/moderate network had fewer connections, but the connections were stronger. Connectivity between components with no structural homology tended to co-occur among participants with severe asthma. Results were independent from the different sample sizes of mild/moderate and severe groups. CONCLUSIONS: The patterns of interactions between IgE to multiple allergenic proteins are predictors of asthma severity among school children and adults with allergic asthma.

Rapid Nanopore Whole-Genome Sequencing for Anthrax Emergency Preparedness.

Human anthrax cases necessitate rapid response. We completed Bacillus anthracis nanopore whole-genome sequencing in our high-containment laboratory from a human anthrax isolate hours after receipt. The de novo assembled genome showed no evidence of known antimicrobial resistance genes or introduced plasmid(s). Same-day genomic characterization enhances public health emergency response.

Effect of couple-based cognitive behavioural intervention on prevention of postnatal depression: multisite randomised controlled trial.

OBJECTIVE: To compare a couple-based cognitive behavioural intervention (CBI) for postnatal depression with CBI delivered to women alone and control (standard perinatal care). DESIGN: Multisite randomised controlled trial. SETTING: Antenatal clinics at three regional public hospitals in Hong Kong. SAMPLE: 388 low-risk childbearing couples. METHODS: Childbearing couples were randomly allocated to couple-based CBI (n = 134), women-alone CBI (n = 124) or control (n = 130). The CBI consists of a 3-hour antenatal group session and two 30-minute postnatal telephone follow-up sessions. MAIN OUTCOME MEASURES: The primary outcome was depressive symptoms, measured on the Edinburgh Postnatal Depression Scale (EPDS). Assessments were collected at baseline (during pregnancy), 6 weeks, 6 months, and 12 months postpartum. RESULTS: Depressive symptoms were significantly more improved at 6 weeks postpartum for mothers in couple-based CBI than in women-alone CBI (difference 1.46, 95% CI 0.11-2.81) or control groups (difference 1.71, 95% CI 0.29-3.13). The proportion of mothers with postnatal depression (EPDS score ≥ 10) was significantly lower at 6 weeks postpartum in couple-based CBI than in control (difference 17.8%, 95% CI 3.6-32.0). However, the treatment effect was not maintained at 6 and 12 months. There was no significant intervention effect among fathers. CONCLUSIONS: Couple-based CBI is more effective than CBI delivered to mothers alone and standard perinatal care in reducing the incidence of postnatal depression among Chinese mothers in the early postpartum period. TWEETABLE ABSTRACT: Couple-based cognitive behavioural intervention is effective in reducing postnatal depression among Chinese mothers in the early postpartum period.

Ab Initio Kinetics of Methylamine Radical Thermal Decomposition and H-Abstraction from Monomethylhydrazine by H-Atom.

Methylamine radicals (CH3NH) and amino radicals (NH2) are major products in the early pyrolysis/ignition of monomethylhydrazine (CH3NHNH2). Ab initio kinetics of thermal decomposition of CH3NH radicals was analyzed by RRKM master equation simulations. It was found that ß-scission of the methyl H-atom from CH3NH radicals is predominant and fast enough to induce subsequent H-abstraction reactions in CH3NHNH2 to trigger ignition. Consequently, the kinetics of H-abstraction reactions from CH3NHNH2 by H-atoms was further investigated. It was found that the energy barriers for abstraction of the central amine H-atom, two terminal amine H-atoms, and methyl H-atoms are 4.16, 2.95, 5.98, and 8.50 kcal mol-1, respectively. In units of cm3 molecule-1 s-1, the corresponding rate coefficients were found to be k8 = 9.63 × 10-20T2.596 exp(-154.2/T), k9 = 2.04 × 10-18T2.154 exp(104.1/T), k10 = 1.13 × 10-20T2.866 exp(-416.3/T), and k11 = 2.41 × 10-23T3.650 exp(-870.5/T), respectively, in the 290-2500 K temperature range. The results reveal that abstraction of the terminal amine H-atom to form trans-CH3NHNH radicals is the dominant channel among the different abstraction channels. At 298 K, the total theoretical H-abstraction rate coefficient, calculated with no adjustable parameters, is 8.16 × 10-13 cm3 molecule-1 s-1, which is in excellent agreement with Vaghjiani's experimental observation of (7.60 ± 1.14) × 10-13 cm3 molecule-1 s-1 ( J. Phys. Chem. A 1997, 101, 4167-4171, DOI: 10.1021/jp964044z).

Augmented decision-making for acral lentiginous melanoma detection using deep convolutional neural networks.

BACKGROUND: Several studies have achieved high-level performance of melanoma detection using convolutional neural networks (CNNs). However, few have described the extent to which the implementation of CNNs improves the diagnostic performance of the physicians. OBJECTIVE: This study is aimed at developing a CNN for detecting acral lentiginous melanoma (ALM) and investigating whether its implementation can improve the initial decision for ALM detection made by the physicians. METHODS: A CNN was trained using 1072 dermoscopic images of acral benign nevi, ALM and intermediate tumours. To investigate whether the implementation of CNN can improve the initial decision for ALM detection, 60 physicians completed a three-stage survey. In Stage I, they were asked for their decisions solely on the basis of dermoscopic images provided to them. In Stage II, they were also provided with clinical information. In Stage III, they were provided with the additional diagnosis and probability predicted by the CNN. RESULTS: The accuracy of ALM detection in the participants was 74.7% (95% confidence interval [CI], 72.6-76.8%) in Stage I and 79.0% (95% CI, 76.7-81.2%) in Stage II. In Stage III, it was 86.9% (95% CI, 85.3-88.4%), which exceeds the accuracy delivered in Stage I by 12.2%p (95% CI, 10.1-14.3%p) and Stage II by 7.9%p (95% CI, 6.0-9.9%p). Moreover, the concordance between the participants considerably increased (Fleiss-κ of 0.436 [95% CI, 0.437-0.573] in Stage I, 0.506 [95% CI, 0.621-0.749] in Stage II and 0.684 [95% CI, 0.621-0.749] in Stage III). CONCLUSIONS: Augmented decision-making improved the performance of and concordance between the clinical decisions of a diverse group of experts. This study demonstrates the potential use of CNNs as an adjoining, decision-supporting system for physicians' decisions.

Non-melanoma skin cancer as a clinical marker for internal malignancies: a nationwide population-based cohort study.

INTRODUCTION: Non-melanoma skin cancers (NMSCs) are the most common cancers in the world, but the risk of internal malignancy in patients with NMSC has not been well investigated. OBJECTIVES: We aimed to assess the risk of internal malignancy in patients with NMSC compared with controls without NMSC in Korean population. METHODS: This nationwide cohort study, compared 27 259 NMSC patients with 54 518 matched controls without NMSC, 40 years or older using the data from Korea Health Insurance Review and Assessment Service from 2007 to 2016. The first 2 years were washout period, and we followed the patients for 8 years to observe the development of any internal malignancies after a diagnosis of NMSC. The Cox proportional hazard model was used to determine the hazard ratios (HRs) for developing internal malignancies. RESULTS: The overall risk of internal malignancies at all sites was 2727.7 and 1392.4 per 100 000 person-years for the patients with NMSC and controls, respectively. The risk was significantly higher in the patients with NMSC (HR 1.866, 95% confidence interval [CI] 1.768-1.970). Bone cancer showed the highest risk (HR 12.745, 95% CI 6.288-25.834), followed by nasal cavity and larynx (HR 10.279, 95% CI 6.178-7.103), oral cavity and pharynx (HR 10.211, 95% CI 7.375-14.137), anus and anal canal (HR 8.147, 95% CI 3.893-17.051) and cervical (HR 5.900, 95% CI 3.694-9.423) cancers with risks greater than fivefold higher in NMSC patients compared with the controls. The risks of cancers of the thorax, oesophagus, breast, lung, stomach, thyroid gland and non-Hodgkin's lymphoma were also statistically higher in the patients with NMSC. In contrast, the risks of cancers of the colon and rectum were found to be significantly decreased in the patients with NMSC (HR 0.765, 95% CI 0.657-0.890). CONCLUSION: Patients with NMSC require careful screening and follow-up for internal malignancy.

A cellular automata model for expanding turbulent flames.

Cellular automata models based on population dynamics, introduced by Von Neumann in the 1950s, has been successfully used to describe pattern development and front propagation in many applications, such as crystal growth, forest fires, fractal growth in biological media, etc. We, herein, explore the possibility of using a cellular automaton, based on the population dynamics of flamelets, as a low-order model to describe the dynamics of an expanding flame propagating in a turbulent environment. A turbulent flame is constituted by numerous flamelets, each of which interacts with their neighborhood composed of other flamelets, as well as unburned and burnt fluid particles. This local interaction leads to global flame dynamics. The effect of turbulence is simulated by introducing stochasticity in the local interaction and hence in the temporal evolution of the flamefront. Our results show that the model preserves various multifractal characteristics of the expanding turbulent flame and captures several characteristics of expanding turbulent flames observed in experiments. For example, at low turbulence levels, an increase in global burning rate leads to an increase in the turbulence level, while beyond a critical turbulence level, the expanding flame becomes increasingly fragmented, and consequently, the total burning rate decreases with increasing turbulence. Furthermore, at an extremely high turbulence level, the ignition kernel quenches at its nascent state and consequently loses its ability to propagate as an expanding flame.