Diagnosis of obstructive coronary artery disease using computed tomography angiography in patients with stable chest pain depending on clinical probability and in clinically important subgroups: Meta-analysis of individual patient data

Objective To determine whether coronary computed tomography angiography (CTA) should be performed in patients with any clinical probability of coronary artery disease (CAD), and whether the diagnostic performance differs between subgroups of patients. Design Prospectively designed meta-analysis of individual patient data from prospective diagnostic accuracy studies. Data sources Medline, Embase, and Web of Science for published studies. Unpublished studies were identified via direct contact with participating investigators. Eligibility criteria for selecting studies Prospective diagnostic accuracy studies that compared coronary CTA with coronary angiography as the reference standard, using at least a 50% diameter reduction as a cutoff value for obstructive CAD. All patients needed to have a clinical indication for coronary angiography due to suspected CAD, and both tests had to be performed in all patients. Results had to be provided using 2×2 or 3×2 cross tabulations for the comparison of CTA with coronary angiography. Primary outcomes were the positive and negative predictive values of CTA as a function of clinical pretest probability of obstructive CAD, analysed by a generalised linear mixed model; calculations were performed including and excluding non-diagnostic CTA results. The no-treat/treat threshold model was used to determine the range of appropriate pretest probabilities for CTA. The threshold model was based on obtained post-test probabilities of less than 15% in case of negative CTA and above 50% in case of positive CTA. Sex, angina pectoris type, age, and number of computed tomography detector rows were used as clinical variables to analyse the diagnostic performance in relevant subgroups. Results Individual patient data from 5332 patients from 65 prospective diagnostic accuracy studies were retrieved. For a pretest probability range of 7-67%, the treat threshold of more than 50% and the no-treat threshold of less than 15% post-test probability were obtained using CTA. At a pretest probability of 7%, the positive predictive value of CTA was 50.9% (95% confidence interval 43.3% to 57.7%) and the negative predictive value of CTA was 97.8% (96.4% to 98.7%); corresponding values at a pretest probability of 67% were 82.7% (78.3% to 86.2%) and 85.0% (80.2% to 88.9%), respectively. The overall sensitivity of CTA was 95.2% (92.6% to 96.9%) and the specificity was 79.2% (74.9% to 82.9%). CTA using more than 64 detector rows was associated with a higher empirical sensitivity than CTA using up to 64 rows (93.4% v 86.5%, P=0.002) and specificity (84.4% v 72.6%, P<0.001). The area under the receiver-operating-characteristic curve for CTA was 0.897 (0.889 to 0.906), and the diagnostic performance of CTA was slightly lower in women than in with men (area under the curve 0.874 (0.858 to 0.890) v 0.907 (0.897 to 0.916), P<0.001). The diagnostic performance of CTA was slightly lower in patients older than 75 (0.864 (0.834 to 0.894), P=0.018 v all other age groups) and was not significantly influenced by angina pectoris type (typical angina 0.895 (0.873 to 0.917), atypical angina 0.898 (0.884 to 0.913), non-anginal chest pain 0.884 (0.870 to 0.899), other chest discomfort 0.915 (0.897 to 0.934)). Conclusions In a no-treat/treat threshold model, the diagnosis of obstructive CAD using coronary CTA in patients with stable chest pain was most accurate when the clinical pretest probability was between 7% and 67%. Performance of CTA was not influenced by the angina pectoris type and was slightly higher in men and lower in older patients. Systematic review registration PROSPERO CRD42012002780

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

The global burden of cancer attributable to risk factors, 2010–19: a systematic analysis for the Global Burden of Disease Study 2019

BACKGROUND: Understanding the magnitude of cancer burden attributable to potentially modifiable risk factors is crucial for development of effective prevention and mitigation strategies. We analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 to inform cancer control planning efforts globally. METHODS: The GBD 2019 comparative risk assessment framework was used to estimate cancer burden attributable to behavioural, environmental and occupational, and metabolic risk factors. A total of 82 risk–outcome pairs were included on the basis of the World Cancer Research Fund criteria. Estimated cancer deaths and disability-adjusted life-years (DALYs) in 2019 and change in these measures between 2010 and 2019 are presented. FINDINGS: Globally, in 2019, the risk factors included in this analysis accounted for 4·45 million (95% uncertainty interval 4·01–4·94) deaths and 105 million (95·0–116) DALYs for both sexes combined, representing 44·4% (41·3–48·4) of all cancer deaths and 42·0% (39·1–45·6) of all DALYs. There were 2·88 million (2·60–3·18) risk-attributable cancer deaths in males (50·6% [47·8–54·1] of all male cancer deaths) and 1·58 million (1·36–1·84) risk-attributable cancer deaths in females (36·3% [32·5–41·3] of all female cancer deaths). The leading risk factors at the most detailed level globally for risk-attributable cancer deaths and DALYs in 2019 for both sexes combined were smoking, followed by alcohol use and high BMI. Risk-attributable cancer burden varied by world region and Socio-demographic Index (SDI), with smoking, unsafe sex, and alcohol use being the three leading risk factors for risk-attributable cancer DALYs in low SDI locations in 2019, whereas DALYs in high SDI locations mirrored the top three global risk factor rankings. From 2010 to 2019, global risk-attributable cancer deaths increased by 20·4% (12·6–28·4) and DALYs by 16·8% (8·8–25·0), with the greatest percentage increase in metabolic risks (34·7% [27·9–42·8] and 33·3% [25·8–42·0]). INTERPRETATION: The leading risk factors contributing to global cancer burden in 2019 were behavioural, whereas metabolic risk factors saw the largest increases between 2010 and 2019. Reducing exposure to these modifiable risk factors would decrease cancer mortality and DALY rates worldwide, and policies should be tailored appropriately to local cancer risk factor burden

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Protein-protein interaction (ppi) network: Recent advances in drug discovery

Background: The investigation of the cellular components, their interactions and related functions constitute the major conditions in order to understand the cell as an integrated system. More specifically, the Protein-Protein Interactions and the obtained networks are very important in the majority of biological functions and processes, while most of the proteins appear to activate their functionalities through their interaction. Methods: Our in depth review analysis, include Sixty-five peer-reviewed research and review studies from several bibliographic databases. The most significant components were fully described, filtered, combined and analyzed in order to provide documented proofs on the Protein-Protein Interaction Network' applications in biomedicine. Results: The Protein-Protein Interaction Network' alignment and mapping give the opportunity of further knowledge extraction concerning the evolutionary relationships between the species through conserved pathways and protein complexes. Additionally, Protein-Protein Interaction Network information has been demonstrated to be able to predict functionally orthologous proteins within sequence homology clusters. Our review analysis concluded that, while Protein-Protein Interaction was used to be characterized just by their large and plain interacting surfaces, they were considered inapplicable for drug discovery studies for a long time. Conclusion: The present review explores multiple technologies implicated in Protein-Protein Interaction Networks, implicating their potential role in drug discovery mechanisms. © 2017 Bentham Science Publishers

Application of efficient nanoparticles for early diagnosis and treatment of cancer

Cancer is considered as a prevalent cause of human deaths and undoubtedly, is the most complex disease with multiple cellular physiological systems involved. During the last decade, the application of nanotechnological products for cancer treatment has received considerable attention. These sophisticated tools and materials treat cancer though the early diagnosis, the prediction, the prevention and the personalized therapy. This technology enabled the development of nanoscale particles that can be conjugated with one or multiple functional molecules simultaneously. Nanoparticles have the capability to be delivered directly through blood vessels to the tumor site and interact with targeted tumor-specific proteins located inside or on the surface of cancer cells, since their size is a hundred to thousand times smaller than cancer cells. In this review, comprehensive outline of all the latest scientific and technological applications such as quantum dots and gold nanoparticles alongside with their applications in cancer diagnosis and treatment have been presented. © 2015 Bentham Science Publishers

Social and ethical impact of advanced artificial and biological enhancements

Background: While modern humans seek ways to extend life expectancy, the necessity of advanced bioengineering tools for the production of effective human enhancement applications appears as compelling as ever. Objective: The technological future of Homo sapiens has been scheduled within a quantum environment and advanced physical interventions are imperative to occur in the anatomy of modern humans, including genetic improvement and human cloning. New terminologies and latest projects such as genome editing, mind uploading and tissue engineering applications for the growth of new organs are issues of discussion in this paper. Methods: Several advanced biotechnological methods are presented in this paper, including the 14-days rule, the 2045 Initiative project and the CRISPR technique and their social and ethical implications are discussed. Results: The exponential aging of the population results in rapidly increasing demands for next-generation drugs and innovative pharmaceutical products that target individualized genetic treatment, resulting in the emergence of controversial ethical and social implications in the forthcoming post-Homo sapiens Era. Conclusion: The next-generation ethics must be clarified, an interdisciplinary debate should be initiated, and all the different perspectives must be recorded and evaluated to adopt the most efficient practices for controversial topics like the potential digital immortality. © 2020 Alexiou et al

Applications of nanotechnology in diagnostics and therapeutics of Alzheimer's and Parkinson's disease

In this paper, an extended review analysis has been presented concerning the developments in brain drug delivery through new and efficient applications of nanotechnology. Modern nanotechnological approaches for the diagnosis and treatment of Alzheimer's and Parkinson's diseases are described along with simultaneous analysis of safety and practical clinical usage of these strategies. © 2015 Bentham Science Publishers

Inmunogenicidad en terapias basadas en proteínas y péptidos: descripción general

15 páginasCurrently it is well known that all biological drugs, including those with a fully human structure, are capable of inducing a host immune response known as immunogenicity [1]. The presence of ADAs can condition the drug´s level and action, thus modifying the therapeutic effect and even the safety profile by its mechanism of action - neutralizing or non-neutralizing - and / or an increase in its clearance. Immunogenicity is a dynamic factor to be taken into account in biological therapy, especially in long-term treatments, and as a relevant aspect in the assessment of secondary response loss [2]. With the above, not only the knowledge but also the management of the immunogenicity of the different biological treatments, represent a useful instrument for optimization of the strategies of use for each drug, and in the design of predictive models of response, which finally permits a significant improvement in the efficacy and safety profile, aiming to a personalization of the therapies, especially in patients with autoimmune diseases, genetic disorders and cancer [3]. This review summarizes the events of immunogenicity that produce the biological drug, the factor that influence to immunogenicity and the assessment of immunogenicity.Actualmente es bien sabido que todos los fármacos biológicos, incluidos aquellos con estructura totalmente humana, son capaces de inducir una respuesta inmune del huésped conocida como inmunogenicidad [1]. La presencia de ADA puede condicionar el nivel y acción del fármaco, modificando así el efecto terapéutico e incluso el perfil de seguridad por su mecanismo de acción -neutralizante o no neutralizante- y/o un aumento en su aclaramiento. La inmunogenicidad es un factor dinámico a tener en cuenta en la terapia biológica, especialmente en tratamientos a largo plazo, y como aspecto relevante en la evaluación de la pérdida de respuesta secundaria [2]. Con lo anterior, no sólo el conocimiento sino también el manejo de la inmunogenicidad de los diferentes tratamientos biológicos, representan un instrumento útil para la optimización de las estrategias de uso de cada fármaco, y en el diseño de modelos predictivos de respuesta, lo que finalmente permite una mejora significativa en el perfil de eficacia y seguridad, con el objetivo de personalizar las terapias, especialmente en pacientes con enfermedades autoinmunes, trastornos genéticos y cáncer [3]. Esta revisión resume los eventos de inmunogenicidad que produce el fármaco biológico, los factores que influyen en la inmunogenicidad y la evaluación de la inmunogenicidad