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"Personalized Medicine"
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Promises and challenges of personalized medicine to guide ARDS therapy
Identifying new effective treatments for the acute respiratory distress syndrome (ARDS), including COVID-19 ARDS, remains a challenge. The field of ARDS investigation is moving increasingly toward innovative approaches such as the personalization of therapy to biological and clinical sub-phenotypes. Additionally, there is growing recognition of the importance of the global context to identify effective ARDS treatments. This review highlights emerging opportunities and continued challenges for personalizing therapy for ARDS, from identifying treatable traits to innovative clinical trial design and recognition of patient-level factors as the field of critical care investigation moves forward into the twenty-first century.
Journal Article
Socio-economics of personalized medicine in Asia
\"The second decade of the 21st century has witnessed a new surge in emphasis on personalized medicine based on analysis of an individual's unique genetic make-up as a means to enable more precise diagnosis, treatment and prevention of diseases. This book attempts to contribute to this growing body of literature by tracing and analyzing \"personalized medicine\" as it unfolds in Asia, and in so doing, illustrating various social forces shaping the \"co-production\" of science and social order in transnational settings. The book shows that there are inextricable transnational linkages between developing and developed countries and also provides a theoretically guided and empirically grounded understanding of the formation and usage of particular human taxonomies in transnational settings\"-- Provided by publisher.
Book
Identification of a sub-group of critically ill patients with high risk of intensive care unit-acquired infections and poor clinical course using a transcriptomic score
Background
The development of stratification tools based on the assessment of circulating mRNA of genes involved in the immune response is constrained by the heterogeneity of septic patients. The aim of this study is to develop a transcriptomic score based on a pragmatic combination of immune-related genes detected with a prototype multiplex PCR tool.
Methods
As training cohort, we used the gene expression dataset obtained from 176 critically ill patients enrolled in the REALISM study (NCT02638779) with various etiologies and still hospitalized in intensive care unit (ICU) at day 5–7. Based on the performances of each gene taken independently to identify patients developing ICU-acquired infections (ICU-AI) after day 5–7, we built an unweighted score assuming the independence of each gene. We then determined the performances of this score to identify a subgroup of patients at high risk to develop ICU-AI, and both longer ICU length of stay and mortality of this high-risk group were assessed. Finally, we validated the effectiveness of this score in a retrospective cohort of 257 septic patients.
Results
This transcriptomic score (TScore) enabled the identification of a high-risk group of patients (49%) with an increased rate of ICU-AI when compared to the low-risk group (49% vs. 4%, respectively), with longer ICU length of stay (13 days [95% CI 8–30] vs. 7 days [95% CI 6–9],
p
< 0.001) and higher ICU mortality (15% vs. 2%). High-risk patients exhibited biological features of immune suppression with low monocytic HLA-DR levels, higher immature neutrophils rates and higher IL10 concentrations. Using the TScore, we identified 160 high-risk patients (62%) in the validation cohort, with 30% of ICU-AI (vs. 18% in the low-risk group,
p
= 0.06), and significantly higher mortality and longer ICU length of stay.
Conclusions
The transcriptomic score provides a useful and reliable companion diagnostic tool to further develop immune modulating drugs in sepsis in the context of personalized medicine.
Journal Article
Detection of COVID-19-related biomarkers by electrochemical biosensors and potential for diagnosis, prognosis, and prediction of the course of the disease in the context of personalized medicine
As a more efficient and effective way to address disease diagnosis and intervention, cutting-edge technologies, devices, therapeutic approaches, and practices have emerged within the personalized medicine concept depending on the particular patient's biology and the molecular basis of the disease. Personalized medicine is expected to play a pivotal role in assessing disease risk or predicting response to treatment, understanding a person's health status, and, therefore, health care decision-making. This work discusses electrochemical biosensors for monitoring multiparametric biomarkers at different molecular levels and their potential to elucidate the health status of an individual in a personalized manner. In particular, and as an illustration, we discuss several aspects of the infection produced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as a current health care concern worldwide. This includes SARS-CoV-2 structure, mechanism of infection, biomarkers, and electrochemical biosensors most commonly explored for diagnostics, prognostics, and potentially assessing the risk of complications in patients in the context of personalized medicine. Finally, some concluding remarks and perspectives hint at the use of electrochemical biosensors in the frame of other cutting-edge converging/emerging technologies toward the inauguration of a new paradigm of personalized medicine.
Journal Article
Personalized medicine, individual choice and the common good
Hippocrates famously advised doctors 'it is far more important to know what person the disease has than what disease the person has'. Yet 2,500 years later, 'personalised medicine', based on individual genetic profiling and the achievements of genomic research, claims to be revolutionary. In this book, experts from a wide range of disciplines critically examine this claim. They expand the discussion of personalised medicine beyond its usual scope to include many other highly topical issues, including: human nuclear genome transfer ('three-parent IVF'), stem cell-derived gametes, private umbilical cord blood banking, international trade in human organs, biobanks such as the US Precision Medicine Initiative, direct-to-consumer genetic testing, health and fitness self-monitoring. Although these technologies often prioritise individual choice, the original ideal of genomic research saw the human genome as 'the common heritage of humanity'. The authors question whether personalised medicine actually threatens this conception of the common good.
Book
Point-of-care diagnosis and monitoring of fibrinolysis resistance in the critically ill: results from a feasibility study
Background
Fibrinolysisis is essential for vascular blood flow maintenance and is triggered by endothelial and platelet release of tissue plasminogen activator (t-PA). In certain critical conditions, e.g. sepsis, acute respiratory failure (ARF) and trauma, the fibrinolytic response is reduced and may lead to widespread thrombosis and multi-organ failure. The mechanisms underpinning fibrinolysis resistance include reduced t-PA expression and/or release, reduced t-PA and/or plasmin effect due to elevated inhibitor levels, increased consumption and/or clearance. This study in critically ill patients with fibrinolysis resistance aimed to evaluate the ability of t-PA and plasminogen supplementation to restore fibrinolysis with assessment using point-of-care ClotPro viscoelastic testing (VET).
Methods
In prospective, observational studies, whole-blood ClotPro VET evaluation was carried out in 105 critically ill patients. In 32 of 58 patients identified as fibrinolysis-resistant (clot lysis time > 300 s on the TPA-test: tissue factor activated coagulation with t-PA accelerated fibrinolysis), consecutive experimental whole-blood VET was carried out with repeat TPA-tests spiked with additional t-PA and/or plasminogen and the effect on lysis time determined. In an interventional study in a patient with ARF and fibrinolysis resistance, the impact of a 24 h intravenous low-dose alteplase infusion on coagulation and fibrinolysis was prospectively monitored using standard ClotPro VET.
Results
Distinct response groups emerged in the ex vivo experimental VET, with increased fibrinolysis observed following supplementation with (i) t-PA only or (ii) plasminogen and t-PA. A baseline TPA-test lysis time of > 1000 s was associated with the latter group. In the interventional study, a gradual reduction (25%) in serial TPA-test lysis times was observed during the 24 h low-dose alteplase infusion.
Conclusions
ClotPro viscoelastic testing, the associated TPA-test and the novel experimental assays may be utilised to (i) investigate the potential mechanisms of fibrinolysis resistance, (ii) guide corrective treatment and (iii) monitor in real-time the treatment effect. Such a precision medicine and personalised treatment approach to the management of fibrinolysis resistance has the potential to increase treatment benefit, while minimising adverse events in critically ill patients.
Trial registration
: VETtiPAT-ARF, a clinical trial evaluating ClotPro-guided t-PA (alteplase) administration in fibrinolysis-resistant patients with ARF, is ongoing (ClinicalTrials.gov
NCT05540834
; retrospectively registered September 15th 2022).
Journal Article
Baseline plasma IL-18 may predict simvastatin treatment response in patients with ARDS: a secondary analysis of the HARP-2 randomised clinical trial
Background
Interleukin (IL)-18 is a marker of inflammasome activation, and high baseline plasma IL-18 is associated with increased mortality in patients with sepsis-induced ARDS. The aim of this analysis was to determine if simvastatin was associated with benefit in patients with ARDS and high plasma IL-18.
Methods
In this secondary analysis of the HARP-2 study, we compared 28-day mortality and response to simvastatin according to baseline plasma IL-18 using cox proportional hazards analysis. Separately, monocyte-derived macrophages from healthy volunteers were pre-incubated with simvastatin or rosuvastatin before stimulation with ATP and LPS, and the effect on secreted IL-18 and IL-1β compared.
Results
511 patients from HARP-2 had available data. High baseline plasma IL-18 (≥ 800 pg/ml) was associated with increased 28-day mortality (high IL-18 30.6% vs. low IL-18 17.5%; HR 1.89 [95% CI 1.30–2.73];
p
= 0.001). Allocation to simvastatin in patients with high baseline plasma IL-18 was associated with a lower probability of 28-day mortality compared with placebo (24.0% vs 36.8%;
p
= 0.01). Finally, simvastatin, but not rosuvastatin, reduced stimulated macrophage secretion of IL-18 and IL-1β.
Conclusion
In patients with high baseline plasma IL-18, simvastatin is associated with a higher probability of survival, and this effect may be due to reduced inflammasome activation. These data suggest that baseline plasma IL-18 may allow a personalised treatment approach by identifying patients with ARDS who could benefit from simvastatin therapy.
Journal Article