Bacterioruberin: Biosynthesis, Antioxidant Activity, and Therapeutic Applications in Cancer and Immune Pathologies.

Halophilic archaea, also termed haloarchaea, are a group of moderate and extreme halophilic microorganisms that constitute the major microbial populations in hypersaline environments. In these ecosystems, mainly aquatic, haloarchaea are constantly exposed to ionic and oxidative stress due to saturated salt concentrations and high incidences of UV radiation (mainly in summer). To survive under these harsh conditions, haloarchaea have developed molecular adaptations including hyperpigmentation. Regarding pigmentation, haloarchaeal species mainly synthesise the rare C50 carotenoid called bacterioruberin (BR) and its derivatives, monoanhydrobacterioruberin and bisanhydrobacterioruberin. Due to their colours and extraordinary antioxidant properties, BR and its derivatives have been the aim of research in several research groups all over the world during the last decade. This review aims to summarise the most relevant characteristics of BR and its derivatives as well as describe their reported antitumoral, immunomodulatory, and antioxidant biological activities. Based on their biological activities, these carotenoids can be considered promising natural biomolecules that could be used as tools to design new strategies and/or pharmaceutical formulas to fight against cancer, promote immunomodulation, or preserve skin health, among other potential uses.

Microbial bacterioruberin: The new C50 carotenoid player in food industries.

The demand for natural products has significantly increased, driving interest in carotenoids as bioactive compounds for both human and animal consumption. Carotenoids, natural pigments with several biological properties, like antioxidant and antimicrobial, are increasingly preferred over synthetic colorants by the consumers (chemophobia). The global carotenoid market is projected to reach US$ 2.45 billion by 2034, driven by consumer preferences for natural ingredients and regulatory restrictions on synthetic products. Among carotenoids, bacterioruberin (BR), a C50 carotenoid naturally found in microbial hyperhalophilic archaea and in moderate halophilic archaea, stands out for its exceptional antioxidant capabilities, surpassing even well-known carotenoids like astaxanthin. BR's and its derivatives unique structure, with 13 conjugated double bonds and four -OH groups, contributes to its potent antioxidant activity and potential applications in food, feed, supplements, pharmaceuticals, and cosmeceuticals. This review explores BR's chemical and biological properties, upstream and downstream technologies, analytical techniques, market applications, and prospects in the colorants industry. While BR is not intended to replace existing carotenoids, its inclusion enriches the range of natural products available to meet the rising demand for natural alternatives. Furthermore, BR's promising antioxidant capacity positions it as a key player in the future carotenoid market, offering diverse industries a natural and potent alternative for several applications.

Gluing constructions for Lorentzian length spaces.

We introduce an analogue to the amalgamation of metric spaces into the setting of Lorentzian pre-length spaces. This provides a very general process of constructing new spaces out of old ones. The main application in this work is an analogue of the gluing theorem of Reshetnyak for CAT(k) spaces, which roughly states that gluing is compatible with upper curvature bounds. Due to the absence of a notion of spacelike distance in Lorentzian pre-length spaces we can only formulate the theorem in terms of (strongly causal) spacetimes viewed as Lorentzian length spaces.

Spectral Bayesian network theory.

A Bayesian Network (BN) is a probabilistic model that represents a set of variables using a directed acyclic graph (DAG). Current algorithms for learning BN structures from data focus on estimating the edges of a specific DAG, and often lead to many 'likely' network structures. In this paper, we lay the groundwork for an approach that focuses on learning global properties of the DAG rather than exact edges. This is done by defining the structural hypergraph of a BN, which is shown to be related to the inverse-covariance matrix of the network. Spectral bounds are derived for the normalized inverse-covariance matrix, which are shown to be closely related to the maximum indegree of the associated BN.

A two-layer continuously distributed capillary O2 transport model applied to blood flow regulation in resting skeletal muscle.

The microcirculation is the site of direct oxygen (O2) transfer from blood to tissue, and also of O2 delivery control via regulation of local blood flow. In addition, a number of diseases including type II diabetes mellitus (DMII) and sepsis are known to produce microcirculatory dysfunction in their early phases. Given the complexity of microvascular structure and physiology, and the difficulty of measuring tissue oxygenation at the micro-scale, mathematical modelling has been necessary for understanding the physiology and pathophysiology of O2 transport in the microcirculation and for interpreting in vivo experiments. To advance this area, a model of blood-tissue O2 transport in skeletal muscle was recently developed which uses continuously distributed capillaries and includes O2 diffusion, convection, and consumption. The present work extends this model to two adjacent layers of skeletal muscle with different blood flow rates and applies it to study steady-state O2 transport when flow regulation is stimulated using an O2 exchange chamber. To generate a model which may be validated through in vivo experiments, an overlying O2 permeable membrane is included. The model is solved using traditional methods including separation of variables and Fourier decomposition, and to ensure smooth profiles at the muscle-muscle and muscle-membrane interfaces, matching conditions are developed. The study presents qualitative verification for the model, using visualizations of tissue O2 pressure (PO2) distributions for varying capillary density (CD), and presents capillary velocity response values in the near layer for varying chamber PO2 under the assumption that outlet capillary O2 saturation (SO2) is equalized between adjacent layers. These compensatory velocity profiles, along with effective 'no-flux' chamber PO2 values, are presented for varying CD and tissue O2 consumption values. Insights gained from the two-layer model provide guidance for interpreting and planning future in vivo experiments, and also provide motivation for further development of the model to improve understanding of the interaction between O2 transport and blood flow regulation.

Application of machine learning models based on decision trees in classifying the factors affecting mortality of COVID-19 patients in Hamadan, Iran.

BACKGROUND: Due to the high mortality of COVID-19 patients, the use of a high-precision classification model of patient's mortality that is also interpretable, could help reduce mortality and take appropriate action urgently. In this study, the random forest method was used to select the effective features in COVID-19 mortality and the classification was performed using logistic model tree (LMT), classification and regression tree (CART), C4.5, and C5.0 tree based on important features. METHODS: In this retrospective study, the data of 2470 COVID-19 patients admitted to hospitals in Hamadan, west Iran, were used, of which 75.02% recovered and 24.98% died. To classify, at first among the 25 demographic, clinical, and laboratory findings, features with a relative importance more than 6% were selected by random forest. Then LMT, C4.5, C5.0, and CART trees were developed and the accuracy of classification performance was evaluated with recall, accuracy, and F1-score criteria for training, test, and total datasets. At last, the best tree was developed and the receiver operating characteristic curve and area under the curve (AUC) value were reported. RESULTS: The results of this study showed that among demographic and clinical features gender and age, and among laboratory findings blood urea nitrogen, partial thromboplastin time, serum glutamic-oxaloacetic transaminase, and erythrocyte sedimentation rate had more than 6% relative importance. Developing the trees using the above features revealed that the CART with the values of F1-score, Accuracy, and Recall, 0.8681, 0.7824, and 0.955, respectively, for the test dataset and 0.8667, 0.7834, and 0.9385, respectively, for the total dataset had the best performance. The AUC value obtained for the CART was 79.5%. CONCLUSIONS: Finding a highly accurate and qualified model for interpreting the classification of a response that is considered clinically consequential is critical at all stages, including treatment and immediate decision making. In this study, the CART with its high accuracy for diagnosing and classifying mortality of COVID-19 patients as well as prioritizing important demographic, clinical, and laboratory findings in an interpretable format, risk factors for prognosis of COVID-19 patients mortality identify and enable immediate and appropriate decisions for health professionals and physicians.

Proteome-Based Serotyping of the Food-Borne Pathogens Salmonella Enterica by Label-Free Mass Spectrometry.

Food-borne diseases caused by Salmonella enterica of 2500 serovars represent a serious public health problem worldwide. A quick identification for the pathogen serovars is critical for controlling food pollution and disease spreading. Here, we applied a mass spectrum-based proteomic profiling for identifying five epidemiologically important Salmonella enterica subsp. enterica serovars (Enteritidis, Typhimurium, London, Rissen and Derby) in China. By label-free analysis, the 53 most variable serovar-related peptides, which were almost all enzymes related to nucleoside phosphate and energy metabolism, were screened as potential peptide biomarkers, and based on which a C5.0 predicted model for Salmonella enterica serotyping with four predictor peptides was generated with the accuracy of 94.12%. In comparison to the classic gene patterns by PFGE analysis, the high-throughput proteomic fingerprints were also effective to determine the genotypic similarity among Salmonella enteric isolates according to each strain of proteome profiling, which is indicative of the potential breakout of food contamination. Generally, the proteomic dissection on Salmonella enteric serovars provides a novel insight and real-time monitoring of food-borne pathogens.

Null Distance and Convergence of Lorentzian Length Spaces.

The null distance of Sormani and Vega encodes the manifold topology as well as the causality structure of a (smooth) spacetime. We extend this concept to Lorentzian length spaces, the analog of (metric) length spaces, which generalize Lorentzian causality theory beyond the manifold level. We then study Gromov-Hausdorff convergence based on the null distance in warped product Lorentzian length spaces and prove first results on its compatibility with synthetic curvature bounds.

Characterization and biological activities of carotenoids produced by three haloarchaeal strains isolated from Algerian salt lakes.

Halophilic archaea represent a promising natural source of carotenoids. However, little information is available about these archaeal metabolites and their biological effects. In the present work, carotenoids of strains Haloferax sp. ME16, Halogeometricum sp. ME3 and Haloarcula sp. BT9, isolated from Algerian salt lakes, were produced, extracted and identified by high-performance liquid chromatography-diode array detector and liquid chromatography-mass spectrometry. Analytical results revealed a variation in the composition depending on the strain with a predominance of bacterioruberin. The evaluation of antioxidant capacity using ABTS [(2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)] and DPPH (2,2-diphenyl-1-picrylhydrazyl) assays showed that these extracts have a strong antioxidant potential, in particular those of Haloferax sp. ME16 which displayed antioxidant power significantly higher than that of ascorbic acid used as standard. Antibacterial activity of carotenoid extracts against four human-pathogenic strains and four fish-pathogenic strains was evaluated by agar disk diffusion method. The results showed a good antibacterial activity. These findings suggest that the C50 carotenoids from the studied strains offer promising prospects for biotechnological applications.

Diagnostic performance of classification trees and hematological functions in hematologic disorders: an application of multidimensional scaling and cluster analysis.

BACKGROUND: Several hematological indices have been already proposed to discriminate between iron deficiency anemia (IDA) and ß-thalassemia trait (ßTT). This study compared the diagnostic performance of different hematological discrimination indices with decision trees and support vector machines, so as to discriminate IDA from ßTT using multidimensional scaling and cluster analysis. In addition, decision trees were used to determine the diagnostic classification scheme of patients. METHODS: Consisting of 1178 patients with hypochromic microcytic anemia (708 patients with ßTT and 470 patients with IDA), this cross-sectional study compared the diagnostic performance of 43 hematological discrimination indices with classification tree algorithms and support vector machines in order to discriminate IDA from ßTT. Moreover, multidimensional scaling and cluster analysis were used to identify the homogeneous subgroups of discrimination methods with similar performance. RESULTS: All the classification tree algorithms except the LOTUS tree algorithm showed acceptable accuracy measures for discrimination between IDA and ßTT in comparison with other hematological discrimination indices. The results indicated that the CRUISE and C5.0 tree algorithms had better diagnostic performance and efficiency among other discrimination methods. Moreover, the AUC of CRUISE and C5.0 tree algorithms indicated more precise classification with values of 0.940 and 0.999, indicating excellent diagnostic accuracy of such models. Moreover, the CRUISE and C5.0 tree algorithms showed that mean corpuscular volume can be considered as the main variable in discrimination between IDA and ßTT. CONCLUSIONS: CRUISE and C5.0 tree algorithms as powerful methods in data mining techniques can be used to develop accurate differential methods along with other laboratory parameters for the discrimination of IDA and ßTT. In addition, the multidimensional scaling method and cluster analysis can be considered as the most appropriate techniques to determine the discrimination indices with similar performance for future hematological studies.

The effect of room sound absorption on a teleconference system and the differences in subjective assessments between elderly and young people.

In recent years, the rapid development of information and communication technology (ICT) and the influence of the novel coronavirus (COVID-19) have affected our lives and work in various fields such as medical and welfare, construction and manufacturing and education, etc. With this global background, teleconference systems have received attention and become a new trend. However, the acoustics of rooms using teleconference system often overlap the acoustic characteristics from multiple rooms on both the speaker and listener sides. Therefore, it can sometimes be difficult to listen to each other. A prior study suggested that the installation of sound-absorbing panels improves intelligibility and reduces the listening difficulty for young people. However, elderly people must be included in the target owing to the effects of aging. This study aimed to clarify improvements in the subjective assessments of elderly people in a room where a teleconference system is used. In addition, the differences in subjective assessments between young people and elderly people were also investigated. The results of an experiment indicate that, first, a room using a teleconference system demonstrated a greater improvement in subjective assessments after the acoustic improvements compared to the same room where face-to-face meetings. Second, the subjective assessments and improvements of them for elderly people differed greatly since older user had listening habits and experiences that varied from those of young people.

Stability analysis of the hiv model through incommensurate fractional-order nonlinear system.

In this study, it is employed a new model of HIV infection in the form of incommensurate fractional differential equations systems involving the Caputo fractional derivative. Existence of the model's equilibrium points has been investigated. According to some special cases of the derivative-orders in the proposed model, the asymptotic stability of the infection-free equilibrium and endemic equilibrium has been proved under certain conditions. These stability conditions related to the derivative-orders depend on not only the basic reproduction rate frequently emphasized in the literature but also the newly obtained conditions in this study. Qualitative analysis results were complemented by numerical simulations in Matlab, illustrating the obtained stability result.

WHERE DID THE TUMOR START? AN INVERSE SOLVER WITH SPARSE LOCALIZATION FOR TUMOR GROWTH MODELS.

We present a numerical scheme for solving an inverse problem for parameter estimation in tumor growth models for glioblastomas, a form of aggressive primary brain tumor. The growth model is a reaction-diffusion partial differential equation (PDE) for the tumor concentration. We use a PDE-constrained optimization formulation for the inverse problem. The unknown parameters are the reaction coefficient (proliferation), the diffusion coefficient (infiltration), and the initial condition field for the tumor PDE. Segmentation of Magnetic Resonance Imaging (MRI) scans drive the inverse problem where segmented tumor regions serve as partial observations of the tumor concentration. Like most cases in clinical practice, we use data from a single time snapshot. Moreover, the precise time relative to the initiation of the tumor is unknown, which poses an additional difficulty for inversion. We perform a frozen-coefficient spectral analysis and show that the inverse problem is severely ill-posed. We introduce a biophysically motivated regularization on the structure and magnitude of the tumor initial condition. In particular, we assume that the tumor starts at a few locations (enforced with a sparsity constraint on the initial condition of the tumor) and that the initial condition magnitude in the maximum norm is equal to one. We solve the resulting optimization problem using an inexact quasi-Newton method combined with a compressive sampling algorithm for the sparsity constraint. Our implementation uses PETSc and AccFFT libraries. We conduct numerical experiments on synthetic and clinical images to highlight the improved performance of our solver over a previously existing solver that uses standard two-norm regularization for the calibration parameters. The existing solver is unable to localize the initial condition. Our new solver can localize the initial condition and recover infiltration and proliferation. In clinical datasets (for which the ground truth is unknown), our solver results in qualitatively different solutions compared to the two-norm regularized solver.

Species Widely Distributed in Halophilic Archaea Exhibit Opsin-Mediated Inhibition of Bacterioruberin Biosynthesis.

Halophilic Archaea are a distinctive pink color due to a carotenoid pigment called bacterioruberin. To sense or utilize light, many halophilic Archaea also produce rhodopsins, complexes of opsin proteins with a retinal prosthetic group. Both bacterioruberin and retinal are synthesized from isoprenoid precursors, with lycopene as the last shared intermediate. We previously described a regulatory mechanism by which Halobacterium salinarum bacterioopsin and Haloarcula vallismortis cruxopsin inhibit bacterioruberin synthesis catalyzed by lycopene elongase. In this work, we found that opsins in all three major Halobacteria clades inhibit bacterioruberin synthesis, suggesting that this regulatory mechanism existed in the common Halobacteria ancestor. Halophilic Archaea, which are generally heterotrophic and aerobic, likely evolved from an autotrophic, anaerobic methanogenic ancestor by acquiring many genes from Bacteria via lateral gene transfer. These bacterial "imports" include genes encoding opsins and lycopene elongases. To determine if opsins from Bacteria inhibit bacterioruberin synthesis, we tested bacterial opsins and found that an opsin from Curtobacterium, in the Actinobacteria phylum, inhibits bacterioruberin synthesis catalyzed by its own lycopene elongase, as well as that catalyzed by several archaeal enzymes. We also determined that the lycopene elongase from Halococcus salifodinae, a species from a family of Halobacteria lacking opsin homologs, retained the capacity to be inhibited by opsins. Together, our results indicate that opsin-mediated inhibition of bacterioruberin biosynthesis is a widely distributed mechanism found in both Archaea and Bacteria, possibly predating the divergence of the two domains. Further analysis may provide insight into the acquisition and evolution of the genes and their host species.IMPORTANCE All organisms use a variety of mechanisms to allocate limited resources to match their needs in their current environment. Here, we explore how halophilic microbes use a novel mechanism to allow efficient production of rhodopsin, a complex of an opsin protein and a retinal prosthetic group. We previously demonstrated that Halobacterium salinarum bacterioopsin directs available resources toward retinal by inhibiting synthesis of bacterioruberin, a molecule that shares precursors with retinal. In this work, we show that this mechanism can be carried out by proteins from halophilic Archaea that are not closely related to H. salinarum and those in at least one species of Bacteria Therefore, opsin-mediated inhibition of bacterioruberin synthesis may be a highly conserved, ancient regulatory mechanism.

Application of data mining methods to improve screening for the risk of early gastric cancer.

BACKGROUND: Although gastric cancer is a malignancy with high morbidity and mortality in China, the survival rate of patients with early gastric cancer (EGC) is high after surgical resection. To strengthen diagnosing and screening is the key to improve the survival and life quality of patients with EGC. This study applied data mining methods to improve screening for the risk of EGC on the basis of noninvasive factors, and displayed important influence factors for the risk of EGC. METHODS: The dataset was derived from a project of the First Hospital Affiliated Guangdong Pharmaceutical University. A series of questionnaire surveys, serological examinations and endoscopy plus pathology biopsy were conducted in 618 patients with gastric diseases. Their risk of EGC was categorized into low and high risk of EGC by the results of endoscopy plus pathology biopsy. The synthetic minority oversampling technique (SMOTE) was used to solve imbalance categories of the risk of EGC. Four classification models of the risk of EGC was established, including logistic regression (LR) and three data mining algorithms. RESULTS: The three data mining models had higher accuracy than the LR model. Gain curves of the three data mining models were convexes more closer to ideal curves by contrast with that of the LR model. AUC of the three data mining models were larger than that of the LR model as well. The three data mining models predicted the risk of EGC more effectively in comparison with the LR model. Moreover, this study found 16 important influence factors for the risk of EGC, such as occupations, helicobacter pylori infection, drinking hot water and so on. CONCLUSIONS: The three data mining models have optimal predictive behaviors over the LR model, therefore can effectively evaluate the risk of EGC and assist clinicians in improving the diagnosis and screening of EGC. Sixteen important influence factors for the risk of EGC were illustrated, which may helpfully assess gastric carcinogenesis, and remind to early prevention and early detection of gastric cancer. This study may also be conducive to clinical researchers in selecting and conducting the optimal predictive models.

Opsin-Mediated Inhibition of Bacterioruberin Synthesis in Halophilic Archaea.

Halophilic archaea often inhabit environments with limited oxygen, and many produce ion-pumping rhodopsin complexes that allow them to maintain electrochemical gradients when aerobic respiration is inhibited. Rhodopsins require a protein, an opsin, and an organic cofactor, retinal. We previously demonstrated that in Halobacterium salinarum, bacterioopsin (BO), when not bound by retinal, inhibits the production of bacterioruberin, a biochemical pathway that shares intermediates with retinal biosynthesis. In this work, we used heterologous expression in a related halophilic archaeon, Haloferax volcanii, to demonstrate that BO is sufficient to inhibit bacterioruberin synthesis catalyzed by the H. salinarum lycopene elongase (Lye) enzyme. This inhibition was observed both in liquid culture and in a novel colorimetric assay to quantify bacterioruberin abundance based on the colony color. Addition of retinal to convert BO to the bacteriorhodopsin complex resulted in a partial rescue of bacterioruberin production. To explore if this regulatory mechanism occurs in other organisms, we expressed a Lye homolog and an opsin from Haloarcula vallismortis in H. volcaniiH. vallismortis cruxopsin-3 expression inhibited bacterioruberin synthesis catalyzed by H. vallismortis Lye but had no effect when bacterioruberin synthesis was catalyzed by H. salinarum or H. volcanii Lye. Conversely, H. salinarum BO did not inhibit H. vallismortis Lye activity. Together, our data suggest that opsin-mediated inhibition of Lye is potentially widespread and represents an elegant regulatory mechanism that allows organisms to efficiently utilize ion-pumping rhodopsins obtained through lateral gene transfer.IMPORTANCE Many enzymes are complexes of proteins and nonprotein organic molecules called cofactors. To ensure efficient formation of functional complexes, organisms must regulate the production of proteins and cofactors. To study this regulation, we used bacteriorhodopsin from the archaeon Halobacterium salinarum Bacteriorhodopsin consists of the bacterioopsin protein and a retinal cofactor. In this article, we further characterize a novel regulatory mechanism in which bacterioopsin promotes retinal production by inhibiting a reaction that consumes lycopene, a retinal precursor. By expressing H. salinarum genes in a different organism, Haloferax volcanii, we demonstrated that bacterioopsin alone is sufficient for this inhibition. We also found that an opsin from Haloarcula vallismortis has inhibitory activity, suggesting that this regulatory mechanism might be found in other organisms.

The re-polarisation of M2 and M1 macrophages and its role on cancer outcomes.

The anti-tumour and pro-tumour roles of Th1/Th2 immune cells and M1/M2 macrophages have been documented by numerous experimental studies. However, it is still unknown how these immune cells interact with each other to control tumour dynamics. Here, we use a mathematical model for the interactions between mouse melanoma cells, Th2/Th1 cells and M2/M1 macrophages, to investigate the unknown role of the re-polarisation between M1 and M2 macrophages on tumour growth. The results show that tumour growth is associated with a type-II immune response described by large numbers of Th2 and M2 cells. Moreover, we show that (i) the ratio k of the transition rates k12 (for the re-polarisation M1→M2) and k21 (for the re-polarisation M2→M1) is important in reducing tumour population, and (ii) the particular values of these transition rates control the delay in tumour growth and the final tumour size. We also perform a sensitivity analysis to investigate the effect of various model parameters on changes in the tumour cell population, and confirm that the ratio k alone and the ratio of M2 and M1 macrophage populations at earlier times (e.g., day 7) cannot always predict the final tumour size.

Probability distributions for multimeric systems.

We propose a fast and accurate method of obtaining the equilibrium mono-modal joint probability distributions for multimeric systems. The method necessitates only two assumptions: the copy number of all species of molecule may be treated as continuous; and, the probability density functions (pdf) are well-approximated by multivariate skew normal distributions (MSND). Starting from the master equation, we convert the problem into a set of equations for the statistical moments which are then expressed in terms of the parameters intrinsic to the MSND. Using an optimization package on Mathematica, we minimize a Euclidian distance function comprising of a sum of the squared difference between the left and the right hand sides of these equations. Comparison of results obtained via our method with those rendered by the Gillespie algorithm demonstrates our method to be highly accurate as well as efficient.

Value of next generation sequencing (NGS) testing in advanced cancer patients.

OBJECTIVE: The availability of targeted therapies for oncology patients is increasing. Available genomic tests to identify treatment-eligible patients include single gene tests and gene panel tests, including the whole-exome, whole-transcriptome OncoExTra test. We assessed the costs and clinical benefits of test choice. METHODS: A Microsoft Excel-based model was developed to evaluate test choice in patients with advanced/metastatic non-small cell lung cancer (NSCLC), breast, prostate, and colorectal cancer. Treatment pathways were based on NCCN guidelines and medical expert opinion. Inputs were derived from published literature. Annual economic results and lifetime clinical results with OncoExTra testing were projected per-tested-patient and compared with single gene testing and no testing. Separately, results were estimated for a US health plan without the OncoExTra test and with its use in 5% of patients. RESULTS: Compared with no genomic testing, OncoExTra test use increased costs by $4,915 per patient; however, 82%-92% of individuals across tumour types were identified as eligible for targeted therapy or a clinical trial. Compared with single gene testing, OncoExTra test use decreased costs by $9,966 per-patient-tested while increasing use of approved or investigational targeted therapies by 20%. When considering a hypothetical health plan with 1 million members, 858 patients were eligible for genomic testing. Using the OncoExTra test in 5% of those eligible, per-member per-month costs decreased by $0.003, ranging from cost-savings of $0.026 in NSCLC patients to a $0.009 increase in prostate cancer patients. Cost-savings were driven by reduced treatment costs with increased clinical trial enrolment and reduced direct and indirect medical costs associated with targeted treatments. LIMITATIONS: Limitations include the required simplifications in modelling complex conditions that may not fully reflect evolving real-world testing and treatment patterns. CONCLUSIONS: Compared to single-gene testing, results indicate that using next generation sequencing test such as OncoExTra identified more actionable alterations, leading to improved outcomes and reduced costs.

The prognostic value of peak oxygen uptake in obstructive hypertrophic cardiomyopathy: a literature review to inform economic model development.

AIMS: Patients with obstructive hypertrophic cardiomyopathy (oHCM) experience significant clinical burden which is associated with a high economic burden. Peak oxygen uptake (pVO2), measured by cardiopulmonary exercise testing, is used to quantify functional capacity, and has been studied as a primary endpoint in recent clinical trials. This study aimed to gather evidence to consolidate the prognostic value of pVO2 in oHCM and to assess whether it is feasible to predict health outcomes in an economic model based on changes in pVO2. METHODS: A targeted literature review was conducted in MEDLINE (via PubMed) and Embase databases to identify evidence on the prognostic value of pVO2 as a surrogate health outcome to support future oHCM economic model development. Following screening, study characteristics, population characteristics, and pVO2 prognostic association data were extracted. RESULTS: A total of 4,687 studies were identified. In total, 3,531 and 538 studies underwent title/abstract and full-text screening, respectively, of which 151 were included and nine of these were in hypertrophic cardiomyopathy (HCM); only three studies focused on oHCM. The nine HCM studies consisted of one systematic literature review and eight primary studies reporting on 27 potentially predictive relationships from a pVO2-based metric with clinical outcomes including all-cause mortality, cardiovascular mortality, sudden cardiac death, transplant, paroxysmal, and permanent atrial fibrillation. pVO2 was described as a predictor of single and composite endpoints, in three and six studies, respectively, with one study reporting on both. LIMITATIONS: This study primarily uses systemic literature review methods but does not qualify as one due to not entailing parallel reviewers during title-abstract and full-text stages of review. CONCLUSION: The findings of this study suggest pVO2 is predictive of multiple health outcomes, providing a rationale to use pVO2 in the development of an economic model.

Obstructive hypertrophy cardiomyopathy (oHCM) is a condition where the heart muscle thickens, obstructing blood flow and potentially impacting health. Peak oxygen uptake (pVO2) measures the highest amount of oxygen consumption during peak exercise and serves as an indicator of fitness. pVO2 can be used to assess heart health and predict severe conditions and death, acting as a surrogate endpoint. Surrogate endpoints are valuable in drug investigations since they allow earlier decisions on drug approval and funding before longer-term patient follow-up is available.This study reviewed evidence on the relationship between pVO2 values in patients with heart disease and the risk of becoming sicker or dying. Our goal was to assess if these relationships had been established and whether it is feasible to use them to predict future treatment benefits and support economic evaluations of new treatments. Our review found that most studies reported on patients with heart failure, with only nine focusing on HCM. Evidence indicates that low pVO2 values in patients with heart disease are linked to an increased risk of developing other heart conditions, needing a heart transplant, or dying.