Predictive Modelling in Clinical Bioinformatics: Key Concepts for Startups.

Clinical bioinformatics is a newly emerging field that applies bioinformatics techniques for facilitating the identification of diseases, discovery of biomarkers, and therapy decision. Mathematical modelling is part of bioinformatics analysis pipelines and a fundamental step to extract clinical insights from genomes, transcriptomes and proteomes of patients. Often, the chosen modelling techniques relies on either statistical, machine learning or deterministic approaches. Research that combines bioinformatics with modelling techniques have been generating innovative biomedical technology, algorithms and models with biotech applications, attracting private investment to develop new business; however, startups that emerge from these technologies have been facing difficulties to implement clinical bioinformatics pipelines, protect their technology and generate profit. In this commentary, we discuss the main concepts that startups should know for enabling a successful application of predictive modelling in clinical bioinformatics. Here we will focus on key modelling concepts, provide some successful examples and briefly discuss the modelling framework choice. We also highlight some aspects to be taken into account for a successful implementation of cost-effective bioinformatics from a business perspective.

Social Support and Cognitive Impairment: Results from a Portuguese 4-Year Prospective Study.

(1) Background: In an ageing society, social relationships may benefit cognitive performance with an impact on the health of older people. This study aims to estimate the effect of different social support sources on the risk of cognitive impairment in a sample of older Portuguese people. (2) Methods: From the Portuguese EpiPorto cohort study, we followed a sample of participants with 60 to 85 years (N = 656) between 2009 and 2015 (4.63 mean years of follow-up). The participants' perception of social support from family, friends and significant others was evaluated. Cox's regression models were used to investigate the association between this and sociodemographic variables. (3) Results: It was found that social support from friends reduces the risk of cognitive impairment. Men, participants aged 60 to 64 and those not married have a lower risk of cognitive impairment after adjusting for other variables. Participants between 80 and 85 years old (p = 0.021), those with less than four years of education (p < 0.001), and those with cognitive impairment (p = 0.007) have perception of less social support from friends. (4) Conclusions: A social support network from friends reduces the risk of cognitive impairment for older people.

MALDI-ToF Mass Spectra Phenomic Analysis for Human Disease Diagnosis Enabled by Cutting-Edge Data Processing Pipelines and Bioinformatics Tools.

Current methods for diagnosing human disease are still incapable of rapidly and accurately screening for multiple diseases simultaneously on a large scale, and at an affordable price. MALDI-ToF mass spectrometry is an ultra-sensitive, ultra-fast, lowcost, high-throughput technology that has the potential to achieve this goal, allowing human phenotype characterization and thus phenomic screening for multiple disease states. In this review, we will discuss the main advances achieved so far, putting forward targeted applications of MALDI-ToF mass spectrometry in the service of human disease detection. This review focuses on the methodological workflow as MALDI-ToF data processing for phenomic analysis, using state-of-the-art bioinformatic pipelines and software tools. The role of mathematical modelling, machine learning, and artificial intelligence algorithms for disease screening are considered. Moreover, we present some previously developed tools for disease diagnostics and screening based on MALDI-ToF analysis. We discuss the remaining challenges that are ahead when implementing MALDI-ToF into clinical laboratories. Differentiating a standard profile from a single disease phenotype is challenging, but the potential to simultaneously run multiple algorithm screens for different disease phenotypes may only be limited by computing power once this initial hurdle is overcome. The ability to explore the full potential of human clinical phenomics may be closer than imagined; this review gives an insight into the benefits this technology may reap for the future of clinical diagnostics.

Prevalence and incidence of cognitive impairment in an elder Portuguese population (65-85 years old).

BACKGROUND: The increase in average life expectancy increases the risk of illness and frailty in the elderly, especially in the cognitive arena. This study has the objective to estimate the prevalence and incidence of cognitive impairment, in a representative sample of 65 to 85 years old followed for a mean period of 6-years. METHODS: Subjects aged 65-85 years (n = 586) were screened at baseline (1999-2004) to estimate the prevalence of cognitive impairment using the Mini-Mental State Examination. A total of 287 individuals with a normal MMSE at baseline were reassessed after 6.2 mean years (± 4.30 years) to evaluate the incidence of cognitive impairment, defined as scoring below the age and education-adjusted MMSE cut-off points adapted for the Portuguese population. We did not exclude Dementia. RESULTS: The baseline prevalence of cognitive impairment was 15.5% (95% CI: 12.7-18.7). Higher in women (18.9%; 95% CI: 14.9-23.3), that in men (10.4%; 95% CI: 6.7-15.1). Increased with age and was highest for participants without any schooling. The overall incidence rate was 26.97 per 1000 person-years; higher in women (33.8 per 1000 person-years) than in men (18.0 per 1000 person-years). Higher for the oldest participants and those with no schooling. Taking the standard European population, we estimated a prevalence of 16.5% and an incidence of 34.4 per 1000 person-years. CONCLUSION: The prevalence of cognitive impairment in Portugal is within the estimated interval for the European population, and the incidence is lower than for the majority of the European countries. Women, senior and elders without education have a higher risk of cognitive impairment. In our sample, neither employment nor marital status has a significant effect on cognitive impairment.

Simulation of multiple microenvironments shows a pivot role of RPTPs on the control of Epithelial-to-Mesenchymal Transition.

Epithelial-to-Mesenchymal Transition (EMT) is a natural and reversible process involved in embryogenesis, wound healing and thought to participate in the process of metastasis. Multiple signals from the microenvironment have been reported to drive EMT. However, the tight control of this process on physiological scenarios and how it is disrupted during cancer progression is not fully understood. Here, we analysed a regulatory network of EMT accounting for 10 key microenvironment signals focusing on the impact of two cell contact signals on the reversibility of EMT and the stability of resulting phenotypes. The analysis showed that the microenvironment is not enough for stabilizing Hybrid and Amoeboid-like phenotypes, requiring intracellular de-regulations as reported during cancer progression. Our simulations demonstrated that RPTP activation by cell contacts have the potential to inhibit the process of EMT and trigger its reversibility under tissue growth and chronic inflammation scenarios. Simulations also showed that hypoxia inhibits the capacity of RPTPs to control EMT. Our analysis further provided a theoretical explanation for the observed correlation between hypoxia and metastasis under chronic inflammation, and predicted that de-regulations in FAT4 signalling may promote Hybrid stabilization. Taken together, we propose a natural control mechanism of EMT that supports the idea that EMT is tightly regulated by the microenvironment.

Global Cognitive Impairment Prevalence and Incidence in Community Dwelling Older Adults-A Systematic Review.

(1) Background: We proposed to review worldwide estimates of cognitive impairment prevalence and incidence in adults older than 50 years of age living in the community. (2) Methods: Systematic searches were performed in January 2019 using MEDLINE/PubMed. Articles were selected if they referred to cognitive impairment, prevalence, incidence, elders, and population or community-based studies. Analysis, aggregated by different methodologic features, was performed. (3) Results: Prevalence (80 studies) ranged between 5.1% and 41% with a median of 19.0% (25th percentile = 12.0%; 75th percentile = 24.90%). Incidence (11 studies) ranged from 22 to 76.8 per 1000 person-years with a median of 53.97 per 1000 person-years (25th percentile = 39.0; 75th percentile = 68.19). No statistically significant effects were found except for inclusion age. (4) Conclusion: We propose that the homogenization and clarification of the definition of what constitutes cognitive impairment are essential to refine the epidemiological understanding of this entity. The results of this review reinforce the importance of adherence to standardized cut-off scores for cognitive tests to promote study comparability.

Predicting the evolution and control of the COVID-19 pandemic in Portugal.

Coronavirus disease 2019 (COVID-19) is a worldwide pandemic that has been affecting Portugal since 2 March 2020. The Portuguese government has been making efforts to contradict the exponential growth through lockdown, social distancing and the usage of masks. However, these measures have been implemented without controlling the compliance degree and how much is necessary to achieve an effective control. To address this issue, we developed a mathematical model to estimate the strength of Government-Imposed Measures (GIM) and predict the impact of the degree of compliance on the number of infected cases and peak of infection. We estimate the peak to be around 650 thousand infected cases with 53 thousand requiring hospital care by the beginning of May if no measures were taken. The model shows that the population compliance of the GIM was gradual between   30% to 75%, contributing to a significant reduction on the infection peak and mortality. Importantly, our simulations show that the infection burden could have been further reduced if the population followed the GIM immediately after their release on 18 March.

Bioinformatic identification of euploid and aneuploid embryo secretome signatures in IVF culture media based on MALDI-ToF mass spectrometry.

PURPOSE: Embryo genotyping in IVF clinics aims to identify aneuploid embryos, and current methodologies rely on costly, invasive and time-consuming approaches such as PGT-A screening. MALDI-ToF-based mass spectral analysis of embryo culture has been demonstrated to be a non-invasive, affordable and accurate technique that is able to capture secretome profiles from embryo culture media extremely quick. Thus, aneuploid embryo genotypes can be distinguished from euploids from these profiles towards the development of novel embryo selection tools. METHODS: A retrospective cohort study, including 292 spent media samples from embryo cultures collected from a single IVF clinic in USA. There were 149 euploid and 165 aneuploid embryos previously analysed by PGT-A next-generation sequencing techniques. Secretome mass spectra of embryos were generated using MALDI-ToF mass spectrometry in the UK. Data was systematically analysed using a fully automated and ultra-fast bioinformatic pipeline developed for the identification of mass spectral signatures. RESULTS: Distinct spectral patterns were found for euploid and aneuploid genotypes in embryo culture media. We identified 12 characteristic peak signatures for euploid and 17 for aneuploid embryos. Data analysis also revealed a high degree of complementarity among regions showing that 22 regions are required to differentiate between genotypes with a sensitivity of 84% and a false positive rate of 18%. CONCLUSION: Ultra-fast and fully automated screening of an embryo genotype is possible based on multiple combinations of specific mass spectral peak signatures. This constitutes a breakthrough towards the implementation of non-invasive and ultra-fast tools for embryo selection immediately prior to transfer.

Prevalence and Causes of Cognitive Impairment and Dementia in a Population-Based Cohort From Northern Portugal.

BACKGROUND: Vascular disease may play an important role in the epidemiology of dementia in countries with high stroke incidence, such as Portugal. OBJECTIVE: To assess the prevalence and etiology of cognitive impairment in a population-based cohort from Portugal. METHODS: Individuals ≥55 years (n = 730) from the EPIPorto cohort were assessed using the Mini-Mental State Examination and the Montreal Cognitive Assessment. Those scoring below the age-/education-adjusted cutoff points were further evaluated to identify dementia or mild cognitive impairment (MCI) and to define its most common causes. RESULTS: Thirty-six cases of MCI/dementia were identified, corresponding to adjusted prevalences of 4.1% for MCI and 1.3% for dementia. The most common cause of MCI/dementia was vascular (52.8%), followed by Alzheimer's disease (36.1%). CONCLUSION: These findings highlight the importance of vascular cognitive impairment in the epidemiology of dementia in Portugal and carry an important public health message regarding its prevention and management, possibly extending to other countries with a high-stroke burden.

A circular toxicity approach to isoprostanes: From markers of oxidative stress, to epidemiological warning systems and agents of aquatic toxicity.

Isoprostanes (IsoPs) are a class of oxidation products naturally formed in vivo that are indicative of endogenous oxidative stress. In individuals with chronic and oxidative stress related diseases, IsoPs are increased to pathological levels. Since they are excreted through urine into sewage systems, IsoPs can be detected in wastewater treatment plants' (WWTPs) effluents and thus can be used to evaluate the health status of a given population. The underlying principle is that higher isoprostanes WWTPs' levels correspond to populations undergoing higher levels of oxidative stress, and thus disease. However, IsoPs are not eliminated by WWTPs and will end up being released into the aquatic environment, where they will be available for uptake by aquatic species. Being bioactive molecules, it has been suggested that IsoPs in the environment may elicit oxidative stress in aquatic organisms. In this context, we have critically reviewed the available data on IsoPs as products and effectors of toxicity, and propose the new concept of "circular toxicity". In general, IsoPs excreted by humans as a consequence of oxidative stress are released into the aquatic environment where they may interact with aquatic organisms and induce the production of more IsoPs. These stress markers, in turn, will also be excreted, increasing the already high levels of stressors in the aquatic environment and thus create an escalating cycle of oxidative stress.

Copper-substituted forms of the wild type and C42A variant of rubredoxin.

In order to gain insights into the interplay between Cu(I) and Cu(II) in sulfur-rich protein environments, the first preparation and characterization of copper-substituted forms of the wild-type rubredoxin (Rd) from Desulfovibrio vulgaris Hildenborough are reported, as well as those of its variant C42A-Rd. The initial products appear to be tetrahedral Cu(I)(S-Cys)n species for the wild type (n=4) and the variant C42A (n=3, with an additional unidentified ligand). These species are unstable to aerial oxidation to products, whose properties are consistent with square planar Cu(II)(S-Cys)n species. These Cu(II) intermediates are susceptible to auto-reduction by ligand S-Cys to produce stable Cu(I) final products. The original Cu(I) center in the wild-type system can be regenerated by reduction, suggesting that the active site can accommodate Cu(I)(S-Cys)2 and Cys-S-S-Cys fragments in the final product. The absence of one S-Cys ligand prevents similar regeneration in the C42A-Rd system. These results emphasize the redox instability of Cu(II)-(S-Cys)n centers.

Mucormicosis rinocerebral / Rhinocerebral mucormycosis

La mucormicosis es una enfermedad micótica, cuya forma más frecuente comienza en nariz y senos paranasales y puede llegar al cerebro. Se trata de una enfermedad fulminante y a menudo fatal