Estimating risk of consequences following hypoglycaemia exposure using the Hypo-RESOLVE cohort: a secondary analysis of pooled data from insulin clinical trials.

AIMS/HYPOTHESIS: Whether hypoglycaemia increases the risk of other adverse outcomes in diabetes remains controversial, especially for hypoglycaemia episodes not requiring assistance from another person. An objective of the Hypoglycaemia REdefining SOLutions for better liVEs (Hypo-RESOLVE) project was to create and use a dataset of pooled clinical trials in people with type 1 or type 2 diabetes to examine the association of exposure to all hypoglycaemia episodes across the range of severity with incident event outcomes: death, CVD, neuropathy, kidney disease, retinal disorders and depression. We also examined the change in continuous outcomes that occurred following a hypoglycaemia episode: change in eGFR, HbA1c, blood glucose, blood glucose variability and weight. METHODS: Data from 84 trials with 39,373 participants were pooled. For event outcomes, time-updated Cox regression models adjusted for age, sex, diabetes duration and HbA1c were fitted to assess association between: (1) outcome and cumulative exposure to hypoglycaemia episodes; and (2) outcomes where an acute effect might be expected (i.e. death, acute CVD, retinal disorders) and any hypoglycaemia exposure within the last 10 days. Exposures to any hypoglycaemia episode and to episodes of given severity (levels 1, 2 and 3) were examined. Further adjustment was then made for a wider set of potential confounders. The within-person change in continuous outcomes was also summarised (median of 40.4 weeks for type 1 diabetes and 26 weeks for type 2 diabetes). Analyses were conducted separately by type of diabetes. RESULTS: The maximally adjusted association analysis for type 1 diabetes found that cumulative exposure to hypoglycaemia episodes of any level was associated with higher risks of neuropathy, kidney disease, retinal disorders and depression, with risk ratios ranging from 1.55 (p=0.002) to 2.81 (p=0.002). Associations of a similar direction were found when level 1 episodes were examined separately but were significant for depression only. For type 2 diabetes cumulative exposure to hypoglycaemia episodes of any level was associated with higher risks of death, acute CVD, kidney disease, retinal disorders and depression, with risk ratios ranging from 2.35 (p<0.0001) to 3.00 (p<0.0001). These associations remained significant when level 1 episodes were examined separately. There was evidence of an association between hypoglycaemia episodes of any kind in the previous 10 days and death, acute CVD and retinal disorders in both type 1 and type 2 diabetes, with rate ratios ranging from 1.32 (p=0.017) to 2.68 (p<0.0001). These associations varied in magnitude and significance when examined separately by hypoglycaemia level. Within the range of hypoglycaemia defined by levels 1, 2 and 3, we could not find any evidence of a threshold at which risk of these consequences suddenly became pronounced. CONCLUSIONS/INTERPRETATION: These data are consistent with hypoglycaemia being associated with an increased risk of adverse events across several body systems in diabetes. These associations are not confined to severe hypoglycaemia requiring assistance.

Risk factors and prediction of hypoglycaemia using the Hypo-RESOLVE cohort: a secondary analysis of pooled data from insulin clinical trials.

AIMS/HYPOTHESIS: The objective of the Hypoglycaemia REdefining SOLutions for better liVES (Hypo-RESOLVE) project is to use a dataset of pooled clinical trials across pharmaceutical and device companies in people with type 1 or type 2 diabetes to examine factors associated with incident hypoglycaemia events and to quantify the prediction of these events. METHODS: Data from 90 trials with 46,254 participants were pooled. Analyses were done for type 1 and type 2 diabetes separately. Poisson mixed models, adjusted for age, sex, diabetes duration and trial identifier were fitted to assess the association of clinical variables with hypoglycaemia event counts. Tree-based gradient-boosting algorithms (XGBoost) were fitted using training data and their predictive performance in terms of area under the receiver operating characteristic curve (AUC) evaluated on test data. Baseline models including age, sex and diabetes duration were compared with models that further included a score of hypoglycaemia in the first 6 weeks from study entry, and full models that included further clinical variables. The relative predictive importance of each covariate was assessed using XGBoost's importance procedure. Prediction across the entire trial duration for each trial (mean of 34.8 weeks for type 1 diabetes and 25.3 weeks for type 2 diabetes) was assessed. RESULTS: For both type 1 and type 2 diabetes, variables associated with more frequent hypoglycaemia included female sex, white ethnicity, longer diabetes duration, treatment with human as opposed to analogue-only insulin, higher glucose variability, higher score for hypoglycaemia across the 6 week baseline period, lower BP, lower lipid levels and treatment with psychoactive drugs. Prediction of any hypoglycaemia event of any severity was greater than prediction of hypoglycaemia requiring assistance (level 3 hypoglycaemia), for which events were sparser. For prediction of level 1 or worse hypoglycaemia during the whole follow-up period, the AUC was 0.835 (95% CI 0.826, 0.844) in type 1 diabetes and 0.840 (95% CI 0.831, 0.848) in type 2 diabetes. For level 3 hypoglycaemia, the AUC was lower at 0.689 (95% CI 0.667, 0.712) for type 1 diabetes and 0.705 (95% CI 0.662, 0.748) for type 2 diabetes. Compared with the baseline models, almost all the improvement in prediction could be captured by the individual's hypoglycaemia history, glucose variability and blood glucose over a 6 week baseline period. CONCLUSIONS/INTERPRETATION: Although hypoglycaemia rates show large variation according to sociodemographic and clinical characteristics and treatment history, looking at a 6 week period of hypoglycaemia events and glucose measurements predicts future hypoglycaemia risk.

Multi-omics subgroups associated with glycaemic deterioration in type 2 diabetes: an IMI-RHAPSODY Study.

Introduction: Type 2 diabetes (T2D) onset, progression and outcomes differ substantially between individuals. Multi-omics analyses may allow a deeper understanding of these differences and ultimately facilitate personalised treatments. Here, in an unsupervised "bottom-up" approach, we attempt to group T2D patients based solely on -omics data generated from plasma. Methods: Circulating plasma lipidomic and proteomic data from two independent clinical cohorts, Hoorn Diabetes Care System (DCS) and Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS), were analysed using Similarity Network Fusion. The resulting patient network was analysed with Logistic and Cox regression modelling to explore relationships between plasma -omic profiles and clinical characteristics. Results: From a total of 1,134 subjects in the two cohorts, levels of 180 circulating plasma lipids and 1195 proteins were used to separate patients into two subgroups. These differed in terms of glycaemic deterioration (Hazard Ratio=0.56;0.73), insulin sensitivity and secretion (C-peptide, p=3.7e-11;2.5e-06, DCS and GoDARTS, respectively; Homeostatic model assessment 2 (HOMA2)-B; -IR; -S, p=0.0008;4.2e-11;1.1e-09, only in DCS). The main molecular signatures separating the two groups included triacylglycerols, sphingomyelin, testican-1 and interleukin 18 receptor. Conclusions: Using an unsupervised network-based fusion method on plasma lipidomics and proteomics data from two independent cohorts, we were able to identify two subgroups of T2D patients differing in terms of disease severity. The molecular signatures identified within these subgroups provide insights into disease mechanisms and possibly new prognostic markers for T2D.

A Federated Database for Obesity Research: An IMI-SOPHIA Study.

Obesity is considered by many as a lifestyle choice rather than a chronic progressive disease. The Innovative Medicines Initiative (IMI) SOPHIA (Stratification of Obesity Phenotypes to Optimize Future Obesity Therapy) project is part of a momentum shift aiming to provide better tools for the stratification of people with obesity according to disease risk and treatment response. One of the challenges to achieving these goals is that many clinical cohorts are siloed, limiting the potential of combined data for biomarker discovery. In SOPHIA, we have addressed this challenge by setting up a federated database building on open-source DataSHIELD technology. The database currently federates 16 cohorts that are accessible via a central gateway. The database is multi-modal, including research studies, clinical trials, and routine health data, and is accessed using the R statistical programming environment where statistical and machine learning analyses can be performed at a distance without any disclosure of patient-level data. We demonstrate the use of the database by providing a proof-of-concept analysis, performing a federated linear model of BMI and systolic blood pressure, pooling all data from 16 studies virtually without any analyst seeing individual patient-level data. This analysis provided similar point estimates compared to a meta-analysis of the 16 individual studies. Our approach provides a benchmark for reproducible, safe federated analyses across multiple study types provided by multiple stakeholders.

Longitudinal support for the correlative triad among aging, dopamine D2-like receptor loss, and memory decline.

Dopamine decline is suggested to underlie aging-related cognitive decline, but longitudinal examinations of this link are currently missing. We analyzed 5-year longitudinal data for a sample of healthy, older adults (baseline: n = 181, age: 64-68 years; 5-year follow-up: n = 129) who underwent positron emission tomography with 11C-raclopride to assess dopamine D2-like receptor (DRD2) availability, magnetic resonance imaging to evaluate structural brain measures, and cognitive tests. Health, lifestyle, and genetic data were also collected. A data-driven approach (k-means cluster analysis) identified groups that differed maximally in DRD2 decline rates in age-sensitive brain regions. One group (n = 47) had DRD2 decline exclusively in the caudate and no cognitive decline. A second group (n = 72) had more wide-ranged DRD2 decline in putamen and nucleus accumbens and also in extrastriatal regions. The latter group showed significant 5-year working memory decline that correlated with putamen DRD2 decline, along with higher dementia and cardiovascular risk and a faster biological pace of aging. Taken together, for individuals with more extensive DRD2 decline, dopamine decline is associated with memory decline in aging.

An omics-based machine learning approach to predict diabetes progression: a RHAPSODY study.

AIMS/HYPOTHESIS: People with type 2 diabetes are heterogeneous in their disease trajectory, with some progressing more quickly to insulin initiation than others. Although classical biomarkers such as age, HbA1c and diabetes duration are associated with glycaemic progression, it is unclear how well such variables predict insulin initiation or requirement and whether newly identified markers have added predictive value. METHODS: In two prospective cohort studies as part of IMI-RHAPSODY, we investigated whether clinical variables and three types of molecular markers (metabolites, lipids, proteins) can predict time to insulin requirement using different machine learning approaches (lasso, ridge, GRridge, random forest). Clinical variables included age, sex, HbA1c, HDL-cholesterol and C-peptide. Models were run with unpenalised clinical variables (i.e. always included in the model without weights) or penalised clinical variables, or without clinical variables. Model development was performed in one cohort and the model was applied in a second cohort. Model performance was evaluated using Harrel's C statistic. RESULTS: Of the 585 individuals from the Hoorn Diabetes Care System (DCS) cohort, 69 required insulin during follow-up (1.0-11.4 years); of the 571 individuals in the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) cohort, 175 required insulin during follow-up (0.3-11.8 years). Overall, the clinical variables and proteins were selected in the different models most often, followed by the metabolites. The most frequently selected clinical variables were HbA1c (18 of the 36 models, 50%), age (15 models, 41.2%) and C-peptide (15 models, 41.2%). Base models (age, sex, BMI, HbA1c) including only clinical variables performed moderately in both the DCS discovery cohort (C statistic 0.71 [95% CI 0.64, 0.79]) and the GoDARTS replication cohort (C 0.71 [95% CI 0.69, 0.75]). A more extensive model including HDL-cholesterol and C-peptide performed better in both cohorts (DCS, C 0.74 [95% CI 0.67, 0.81]; GoDARTS, C 0.73 [95% CI 0.69, 0.77]). Two proteins, lactadherin and proto-oncogene tyrosine-protein kinase receptor, were most consistently selected and slightly improved model performance. CONCLUSIONS/INTERPRETATION: Using machine learning approaches, we show that insulin requirement risk can be modestly well predicted by predominantly clinical variables. Inclusion of molecular markers improves the prognostic performance beyond that of clinical variables by up to 5%. Such prognostic models could be useful for identifying people with diabetes at high risk of progressing quickly to treatment intensification. DATA AVAILABILITY: Summary statistics of lipidomic, proteomic and metabolomic data are available from a Shiny dashboard at https://rhapdata-app.vital-it.ch .

Sensitivity analysis and parameters estimation for the transmission of lymphatic filariasis.

Lymphatic filariasis is a neglected tropical disease which poses public health concern and socio-economic challenges in developing and low-income countries. In this paper, we formulate a deterministic mathematical model for transmission dynamics of lymphatic filariasis to generate data by white noise and use least square method to estimate parameter values. The validity of estimated parameter values is tested by Gaussian distribution method. The residuals of model outputs are normally distributed and hence can be used to study the dynamics of Lymphatic filariasis. After deriving the basic reproduction number, R0 by the next generation matrix approach, the Partial Rank Correlation Coefficient is employed to explore which parameters significantly affect and most influential to the model outputs. The analysis for equilibrium states shows that the Lymphatic free equilibrium is globally asymptotically stable when the basic reproduction number is less a unity and endemic equilibrium is globally asymptotically stable when R0≥1. The findings reveal that rate of human infection, recruitment rate of mosquitoes increase the average new infections for Lymphatic filariasis. Moreover, asymptomatic individuals contribute significantly in the transmission of Lymphatic filariasis.

Towards a Systemic Concept of the Brain Ishemia Stroke: Monte Carlo Driven in Silico Model.

BACKGROUND: The work proposes a new mathematical model of dynamic processes of a typical spatially heterogeneous biological system, and sets and solves a mathematical problem of modeling the dynamics of the system of neurovascular units of the brain in conditions of ischemic stroke. There is a description of only a small number of mathematical models of stroke in the literature. This model is being studied and a numerical and software implementation of the corresponding mathematical problem is proposed. METHODS: This work is the first attempt ever aiming to employ a Monte Carlo computational approach for In Silico simulation of the most critical parameters in molecular and cellular pathogenesis of the brain ischemic stroke. In this work, a new mathematical model of the development of ischemic stroke is proposed in the form of a discrete model based on neurovascular units (NVU) as elements. RESULTS: As a result of testing the program with the assignment of empirically selected coefficients, data were obtained on the evolution of the states of the lattice of the cellular automaton of the model for the spread of stroke in a region of the brain tissue. A resulting new theoretical model of the particular pathologically altered biosystem might be taken as a promising tool for further studies in neurology; general pathology and cell biology. CONCLUSION: For the first time, a mathematical model has been constructed that allows us to represent the spatial dynamics of the development of the affected area in ischemic stroke of the brain, taking into account neurovascular units as single morphofunctional structures.

Triggering gel-sol transition by weak magnetic field.

The self-assembly of small and always chiral molecules into fiber-like structures is a mysterious process, as the physics underlying such self-assembly is unclear. The energy necessary for this process exceeds the one provided by common dispersion interactions and hydrogen bonding. The recent results obtained by the scientific group of Prof. Naaman from the Weizmann Institute of Science fed light on the nature of forces providing for the self-assembly of chiral molecules and attributed these forces to spin-exchange interactions. Therefore, the self-assembly of chiral molecules should be magneto-sensitive. We found such sensitivity in solutions of trifluoroacetylated α -amino alcohols, and the process was inhibited by the magnetic field when fibers grew on the surface of the substrate. On the contrary, in bulk, the self-assembly was enhanced by the magnetic field and led to the formation of a dense gel, while no gelation was observed in the absence of the external magnetic field. The latter observations are the theme of this short report, aimed to declare the effect itself but not pretend to describe it in full.

Maximizing the value of twin studies in health and behaviour.

In the classical twin design, researchers compare trait resemblance in cohorts of identical and non-identical twins to understand how genetic and environmental factors correlate with resemblance in behaviour and other phenotypes. The twin design is also a valuable tool for studying causality, intergenerational transmission, and gene-environment correlation and interaction. Here we review recent developments in twin studies, recent results from twin studies of new phenotypes and recent insights into twinning. We ask whether the results of existing twin studies are representative of the general population and of global diversity, and we conclude that stronger efforts to increase representativeness are needed. We provide an updated overview of twin concordance and discordance for major diseases and mental disorders, which conveys a crucial message: genetic influences are not as deterministic as many believe. This has important implications for public understanding of genetic risk prediction tools, as the accuracy of genetic predictions can never exceed identical twin concordance rates.

Identification of biomarkers for glycaemic deterioration in type 2 diabetes.

We identify biomarkers for disease progression in three type 2 diabetes cohorts encompassing 2,973 individuals across three molecular classes, metabolites, lipids and proteins. Homocitrulline, isoleucine and 2-aminoadipic acid, eight triacylglycerol species, and lowered sphingomyelin 42:2;2 levels are predictive of faster progression towards insulin requirement. Of ~1,300 proteins examined in two cohorts, levels of GDF15/MIC-1, IL-18Ra, CRELD1, NogoR, FAS, and ENPP7 are associated with faster progression, whilst SMAC/DIABLO, SPOCK1 and HEMK2 predict lower progression rates. In an external replication, proteins and lipids are associated with diabetes incidence and prevalence. NogoR/RTN4R injection improved glucose tolerance in high fat-fed male mice but impaired it in male db/db mice. High NogoR levels led to islet cell apoptosis, and IL-18R antagonised inflammatory IL-18 signalling towards nuclear factor kappa-B in vitro. This comprehensive, multi-disciplinary approach thus identifies biomarkers with potential prognostic utility, provides evidence for possible disease mechanisms, and identifies potential therapeutic avenues to slow diabetes progression.

Modeling cryptosporidiosis in humans and cattle: Deterministic and stochastic approaches.

Cryptosporidiosis is a zoonotic disease caused by Cryptosporidium. The disease poses a public and veterinary health problem worldwide. A deterministic model and its corresponding continuous time Markov chain (CTMC) stochastic model are developed and analyzed to investigate cryptosporidiosis transmission dynamics in humans and cattle. The basic reproduction number R 0 for the deterministic model and stochastic threshold for the CTMC stochastic model are computed by the next generation matrix method and multitype branching process, respectively. The normalized forward sensitivity index method is used to determine the sensitivity index for each parameter in R 0 . Per capita birth rate of cattle, the rate of cattle to acquire cryptosporidiosis infection from the environment and the rate at which infected cattle shed Cryptosporidium oocysts in the environment play an important role in the persistence of the disease whereas Cryptosporidium oocysts natural death rate, cattle recovery rate and cattle natural death rate are most negative sensitive parameters in the dynamics of cryptosporidiosis. Numerical results for CTMC stochastic model show that the likelihood of cryptosporidiosis extinction is high when it arises from an infected human. However, there is a major outbreak if cryptosporidiosis emerges either from infected cattle or from Cryptosporidium oocysts in the environment or when it emerges from all three infectious compartments. Therefore to control the disease, control measures should focus on maintaining personal and cattle farm hygiene and decontaminating the environment to destroy Cryptosporidium oocysts.

Anti-cancer activity of ultra-short single-stranded polydeoxyribonucleotides.

One of the features that differentiate cancer cells is their increased proliferation rate, which creates an opportunity for general anti-tumor therapy directed against the elevated activity of replicative apparatus in tumor cells. Besides DNA synthesis, successful genome replication requires the reparation of the newly synthesized DNA. Malfunctions in reparation can cause fatal injuries in the genome and cell death. Recently we have found that the ultra-short single-stranded deoxyribose polynucleotides of random sequence (ssDNA) effectively inhibit the catalytic activity of DNA polymerase [Formula: see text]. This effect allowed considering these substances as potential anti-tumor drugs, which was confirmed experimentally both in vitro (using cancer cell cultures) and in vivo (using cancer models in mice). According to the obtained results, ssDNA significantly suppresses cancer development and tumor growth, allowing consideration of them as novel candidates for anti-cancer drugs.

Magnetic field and nuclear spin influence on the DNA synthesis rate.

The rate of a chemical reaction can be sensitive to the isotope composition of the reactants, which provides also for the sensitivity of such "spin-sensitive" reactions to the external magnetic field. Here we demonstrate the effect of the external magnetic field on the enzymatic DNA synthesis together with the effect of the spin-bearing magnesium ions ([Formula: see text]Mg). The rate of DNA synthesis monotonously decreased with the external magnetic field induction increasing in presence of zero-spin magnesium ions ([Formula: see text]Mg). On the contrary, in the presence of the spin-bearing magnesium ions, the dependence of the reaction rate on the magnetic field induction was non-monotonous and possess a distinct minimum at 80-100 mT. To describe the observed effect, we suggested a chemical scheme and biophysical mechanism considering a competition between Zeeman and Fermi interactions in the external magnetic field.

OrthoDB v11: annotation of orthologs in the widest sampling of organismal diversity.

OrthoDB provides evolutionary and functional annotations of genes in a diverse sampling of eukaryotes, prokaryotes, and viruses. Genomics continues to accelerate our exploration of gene diversity and orthology is the most precise way of bridging gene functional knowledge with the rapidly expanding universe of genomic sequences. OrthoDB samples the most diverse organisms with the best quality genomics data to provide the leading coverage of species diversity. This update of the underlying data to over 18 000 prokaryotes and almost 2000 eukaryotes with over 100 million genes propels the coverage to another level. This achievement also demonstrates the scalability of the underlying OrthoLoger software for delineation of orthologs, freely available from https://orthologer.ezlab.org. In addition to the ab-initio computations of gene orthology used for the OrthoDB release, the OrthoLoger software allows mapping of novel gene sets to precomputed orthologs and thereby links to their annotations. The LEMMI-style benchmarking of OrthoLoger ensures its state-of-the-art performance and is available from https://lemortho.ezlab.org. The OrthoDB web interface has been further developed to include a pairwise orthology view from any gene to any other sampled species. OrthoDB-computed evolutionary annotations as well as extensively collated functional annotations can be accessed via REST API or SPARQL/RDF, downloaded or browsed online from https://www.orthodb.org.

Optimal control analysis of Taenia saginata bovine cysticercosis and human taeniasis.

Bovine cysticercosis and human taeniasis are neglected food-borne diseases that pose challenge to food safety, human health and livelihood of rural livestock farmers. In this paper, we have formulated and analyzed a deterministic model for transmission dynamics and control of taeniasis and cysticercosis in humans and cattle respectively. The analysis shows that both the disease free equilibrium (DFE) and endemic equilibrium (EE) exist. To study the dynamics of the diseases, we derived the basic reproduction number R 0 by next generation matrix method which shows whether the diseases die or persist in humans and cattle. The diseases clear if R 0 < 1 and persist when R 0 > 1. The normalized forward sensitivity index is used to derive sensitive indices of model parameters. Sensitivity analysis results indicate that human's and cattle's recruitment rates, infection rate of cattle from contaminated environment, probability of humans to acquire taeniasis due to consumption of infected meat, defecation rate of humans with taeniasis and the consumption rate of raw or undercooked infected meat are the most positive sensitive parameters whereas the natural death rates for humans, cattle, Taenia saginata eggs and the proportion of unconsumed infected meat are the most negative sensitive parameters in diseases' transmission. These results suggest that control measures such as improving meat cooking, meat inspection and treatment of infected humans will be effective for controlling taeniasis and cysticercosis in humans and cattle respectively. The optimal control theory is applied by considering three time dependent controls which are improved meat cooking, vaccination of cattle, and treatment of humans with taeniasis when they are implemented in combination. The Pontryagin's maximum principle is adopted to find the necessary conditions for existence of the optimal controls. The Runge Kutta order four forward-backward sweep method is implemented in Matlab to solve the optimal control problem. The results indicate that a strategy which focuses on improving meat cooking and treatment of humans with taeniasis is the optimal strategy for diseases' control.

The First Detection of Abomasal Nematode Ashworthius sidemi in Fallow Deer (Dama dama) in Russia.

PURPOSE: The aim of the study was to supplement the data concerning the spreading of nematode Ashworthius sidemi among wild ruminants in Russia. METHODS: The samples of A. sidemi were collected from two fallow deer, which were born and raised in the game farm in Smolensk region (55° 16' N-34° 29' E). The affiliation of the detected nematodes as A. sidemi was made using morphological features (shape of the spicules and the dorsal ray of bursa for males, as well as the presence and shape of the neodont in the buccal cavity for males and females). RESULTS: The intensity of infection in 2 studied fallow deer was 7 and 19 individuals of A. sidemi. All of the specimens of A. sidemi had the features of juvenile forms. The registration of fallow deer as another one host of A. sidemi in Russia indicates a further spreading of this nematode and confirms the necessity of strengthening the control of this parasite. CONCLUSION: The finding of this nematode in non-native captive animals shows the imperfection of control in this sphere. A. sidemi could have been introduced to the game farm both with imported or with native animals due to insufficient quarantine and isolation. More wide further research would be useful in the light of control this potentially dangerous parasite.

Dynamics for a non-autonomous fall armyworm-maize interaction model with a saturation functional response.

In this study, we present a non-autonomous model with a Holling type II functional response, to study the complex dynamics for fall armyworm-maize biomass interacting in a periodic environment. Understanding how seasonal variations affect fall armyworm-maize dynamics is critical since maize is one of the most important cereals globally. Firstly, we study the dynamical behaviours of the basic model; that is, we investigate positive invariance, boundedness, permanence, global stability and non-persistence. We then extended the model to incorporate time dependent controls. We investigate the impact of reducing fall armyworm egg and larvae population, at minimal cost, through traditional methods and use of chemical insecticides. We noted that seasonal variations play a significant role on the patterns for all fall armyworm populations (egg, larvae, pupae and moth). We also noted that in all scenarios, the optimal control can greatly reduce the sizes of fall armyworm populations and in some scenarios, total elimination may be attained. The modeling approach presented here provides a framework for designing effective control strategies to manage the fall armyworm during outbreaks.

Distinct Molecular Signatures of Clinical Clusters in People With Type 2 Diabetes: An IMI-RHAPSODY Study.

Type 2 diabetes is a multifactorial disease with multiple underlying aetiologies. To address this heterogeneity, investigators of a previous study clustered people with diabetes according to five diabetes subtypes. The aim of the current study is to investigate the etiology of these clusters by comparing their molecular signatures. In three independent cohorts, in total 15,940 individuals were clustered based on five clinical characteristics. In a subset, genetic (N = 12,828), metabolomic (N = 2,945), lipidomic (N = 2,593), and proteomic (N = 1,170) data were obtained in plasma. For each data type, each cluster was compared with the other four clusters as the reference. The insulin-resistant cluster showed the most distinct molecular signature, with higher branched-chain amino acid, diacylglycerol, and triacylglycerol levels and aberrant protein levels in plasma were enriched for proteins in the intracellular PI3K/Akt pathway. The obese cluster showed higher levels of cytokines. The mild diabetes cluster with high HDL showed the most beneficial molecular profile with effects opposite of those seen in the insulin-resistant cluster. This study shows that clustering people with type 2 diabetes can identify underlying molecular mechanisms related to pancreatic islets, liver, and adipose tissue metabolism. This provides novel biological insights into the diverse aetiological processes that would not be evident when type 2 diabetes is viewed as a homogeneous disease.