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- Out-of-hospital cardiac arrest in the Algarve region of Portugal: a retrospective registry trial with outcome dataPublication . Carvalho, Nuno Mourão; Martins, Cláudia; Cartaxo, Vera; Marreiros, Ana; Justo, Emília; Raposo, Carlos; Binnie, AlexandraBackground and importanceOut-of-hospital cardiac arrest is a leading cause of death in Europe. An understanding of region-specific factors is essential for informing strategies to improve survival. DesignThis retrospective observational study included all out-of-hospital cardiac arrest patients attended by the Emergency Medical Service of the Algarve in 2019. Outcome data were derived from hospital records. Main resultsIn 2019, there were 850 out-of-hospital cardiac arrests treated with cardiopulmonary resuscitation in the Algarve, representing a population incidence of 189/100 000. Return of spontaneous circulation occurred in 83 patients (9.8%), of whom 17 (2.0%) had survival to hospital discharge and 15 (1.8%) had survival with good neurologic outcome. Among patients in the Utstein comparator group, survival to hospital discharge was 21.4%. Predictors of return of spontaneous circulation were age, witnessed arrest, initial shockable rhythm, time of year, time to cardiopulmonary resuscitation, and time to advanced life support. Predictors of survival to hospital discharge were age, initial shockable rhythm, time to rhythm analysis, and time to advanced life support. Predictors of survival with good neurologic outcome were age, initial shockable rhythm, and time to return of spontaneous circulation. ConclusionsThe incidence of out-of-hospital cardiac arrest with cardiopulmonary resuscitation in the Algarve was higher than in other jurisdictions while return of spontaneous circulation, survival to hospital discharge, and survival with good neurologic outcome were comparatively low. An aging population, a geographically diverse region, and a low incidence of bystander cardiopulmonary resuscitation may have contributed to these outcomes. These results confirm the importance of early cardiopulmonary resuscitation, early rhythm assessment, and early advanced life support, all of which are potentially modifiable through public education, broadening of the defibrillator network and increased availability of advanced life support teams.
- CRISPR-based strategies in infectious disease diagnosis and therapyPublication . Binnie, Alexandra; Fernandes, Emanuel; Almeida‑Lousada, Helder; De Mello, Ramon Andrade; Castelo-Branco, PedroCRISPR gene-editing technology has the potential to transform the diagnosis and treatment of infectious diseases, but most clinicians are unaware of its broad applicability. Derived from an ancient microbial defence system, these so-called "molecular scissors" enable precise gene editing with a low error rate. However, CRISPR systems can also be targeted against pathogenic DNA or RNA sequences. This potential is being combined with innovative delivery systems to develop new therapeutic approaches to infectious diseases.
- Twenty articles that critical care clinicians should read about COVID-19Publication . Tsang, Jennifer L. Y.; Binnie, Alexandra; Fowler, Robert A.Infection with the severe acute respiratory syndrome coronavirus- 2 (SARS-CoV-2) was first identified in December 2019 and has since become a worldwide pandemic, challenging and sometimes overwhelming healthcare systems as well as causing more than a million deaths thus far. In just 10 months, over 80,000 indexed publications have appeared that reference SARS-CoV-2 and the associated Coronavirus disease 2019 (COVID-19). In this article, we highlight 20 papers that are of particular relevance to the critical care clinician. The papers are divided into four broad topics: manifestations of severe COVID- 19 disease, pharmacological therapy for COVID-19, ventilatory support for COVID-19 acute respiratory distress syndrome (ARDS), and healthcare system and worker stress. This list is not designed to be comprehensive but rather to give the reader an overview of important early papers and their findings.
- Epigenetic therapy in urologic cancers: an update on clinical trialsPublication . Faleiro, Inês; Leão, Ricardo; Binnie, Alexandra; De Mello, Ramon Andrade; Maia, Ana Teresa; Castelo-Branco, PedroEpigenetic dysregulation is one of many factors that contribute to cancer development and progression. Numerous epigenetic alterations have been identified in urologic cancers including histone modifications, DNA methylation changes, and microRNA expression. Since these changes are reversible, efforts are being made to develop epigenetic drugs that restore the normal epigenetic patterns of cells, and many clinical trials are already underway to test their clinical potential. In this review we analyze multiple clinical trials (n=51) that test the efficacy of these drugs in patients with urologic cancers. The most frequently used epigenetic drugs were histone deacetylase inhibitors followed by antisense oligonucleotides, DNA methyltransferase inhibitors and histone demethylase inhibitors, the last of which are only being tested in prostate cancer. In more than 50% of the clinical trials considered, epigenetic drugs were used as part of combination therapy, which achieved the best results. The epigenetic regulation of some cancers is still matter of research but will undoubtedly open a window to new therapeutic approaches in the era of personalized medicine. The future of therapy for urological malignancies is likely to include multidrug regimens in which epigenetic modifying drugs will play an important role.
- Measuring healthy ageing: current and future toolsPublication . Silva, Nádia; Rajado, Ana Teresa; Esteves, Filipa; Brito, David V.C.; Apolónio, Joana; Roberto, Vânia; Binnie, Alexandra; Araújo, Inês Maria; Nóbrega, Clévio; Bragança, José; Castelo-Branco, PedroHuman ageing is a complex, multifactorial process characterised by physiological damage, increased risk of age-related diseases and inevitable functional deterioration. As the population of the world grows older, placing significant strain on social and healthcare resources, there is a growing need to identify reliable and easy-to-employ markers of healthy ageing for early detection of ageing trajectories and disease risk. Such markers would allow for the targeted implementation of strategies or treatments that can lessen suffering, disability, and dependence in old age. In this review, we summarise the healthy ageing scores reported in the literature, with a focus on the past 5 years, and compare and contrast the variables employed. The use of approaches to determine biological age, molecular biomarkers, ageing trajectories, and multi-omics ageing scores are reviewed. We conclude that the ideal healthy ageing score is multisystemic and able to encompass all of the potential alterations associated with ageing. It should also be longitudinal and able to accurately predict ageing complications at an early stage in order to maximize the chances of successful early intervention.
- The impact of small-group virtual patient simulator training on perceptions of individual learning process and curricular integration: a multicentre cohort study of nursing and medical studentsPublication . Mestre, André; Muster, Marek; El Adib, Ahmed Rhassane; Ösp Egilsdottir, Hugrun; Byermoen, Kirsten R.; Padilha, Miguel; Aguilar, Thania; Tabagari, Nino; Betts, Lorraine; Sales, Leila; Garcia, Pedro; Ling, Luo; Café, Hugo; Binnie, Alexandra; Marreiros, AnaThe COVID-19 pandemic has precipitated rapid changes in medical education to protect students and patients from the risk of infection. Virtual Patient Simulators (VPS) provide a simulated clinical environment in which students can interview and examine a patient, order tests and exams, prioritize interventions, and observe response to therapy, all with minimal risk to themselves and their patients. Like high-fdelity simulators (HFS), VPS are a tool to improve curricular integration. Unlike HFS, VPS require limited infrastructure investment and can be used in lowresource settings. Few studies have examined the impact of VPS training on clinical education. This international, multicenter cohort study was designed to assess the impact of small-group VPS training on individual learning process and curricular integration from the perspective of nursing and medical students.
- COVID-19 research in critical care: the good, the bad, and the uglyPublication . Salluh, Jorge I. F.; Arabi, Yaseen M.; Binnie, AlexandraThe extraordinary pace of research on coronavirus disease 2019 (COVID-19) has been one of the major success stories of the pandemic. Therapeutic trials involving thousands of patients, which usually take years to complete, have been reported in a matter of months. National and international registries and networks have reported on tens of thousands of patients in near real time. However, there have also been many challenges: hundreds of trials have been underpowered, duplicated, or of poor quality; excessive bureaucracy has complicated study initiation; and only a small percentage of eligible patients worldwide have been enrolled in studies, while many others have been treated with off-label, unproven therapies. All of this has been complicated by an “infodemic” of low-quality medical information, accelerated by social media.
- Roadmap of DNA methylation in breast cancer identifies novel prognostic biomarkersPublication . Almeida, Bernardo; Apolónio, Joana; Binnie, Alexandra; Castelo-Branco, PedroBackground Breast cancer is a highly heterogeneous disease resulting in diverse clinical behaviours and therapeutic responses. DNA methylation is a major epigenetic alteration that is commonly perturbed in cancers. The aim of this study is to characterize the relationship between DNA methylation and aberrant gene expression in breast cancer. Methods We analysed DNA methylation and gene expression profiles from breast cancer tissue and matched normal tissue in The Cancer Genome Atlas (TCGA). Genome-wide differential methylation analysis and methylation-gene expression correlation was performed. Gene expression changes were subsequently validated in the METABRIC dataset. The Oncoscore tool was used to identify genes that had previously been associated with cancer in the literature. A subset of genes that had not previously been studied in cancer was chosen for further analysis. Results We identified 368 CpGs that were differentially methylated between tumor and normal breast tissue (∆β > 0.4). Hypermethylated CpGs were overrepresented in tumor tissue and were found predominantly (56%) in upstream promoter regions. Conversely, hypomethylated CpG sites were found primarily in the gene body (66%). Expression analysis revealed that 209 of the differentially-methylated CpGs were located in 169 genes that were differently expressed between normal and breast tumor tissue. Methylation-expression correlations were predominantly negative (70%) for promoter CpG sites and positive (74%) for gene body CpG sites. Among these differentially-methylated and differentially-expressed genes, we identified 7 that had not previously been studied in any form of cancer. Three of these, TDRD10, PRAC2 and TMEM132C, contained CpG sites that showed diagnostic and prognostic value in breast cancer, particularly in estrogen-receptor (ER)-positive samples. A pan-cancer analysis confirmed differential expression of these genes together with diagnostic and prognostic value of their respective CpG sites in multiple cancer types. Conclusion We have identified 368 DNA methylation changes that characterize breast cancer tumor tissue, of which 209 are associated with genes that are differentially-expressed in the same samples. Novel DNA methylation markers were identified, of which cg12374721 (PRAC2), cg18081940 (TDRD10) and cg04475027 (TMEM132C) show promise as diagnostic and prognostic markers in breast cancer as well as other cancer types.
- Epigenetics of sepsisPublication . Binnie, Alexandra; Tsang, Jennifer L. Y.; Hu, Pingzhao; Carrasqueiro, Gabriela; Castelo-Branco, Pedro; dos Santos, Claudia C.Recent evidence from the fields of microbiology and immunology, as well as a small number of human sepsis studies, suggest that epigenetic regulation may play a central role in the pathogenesis of sepsis. The term "epigenetics" refers to regulatory mechanisms that control gene expression but are not related to changes in DNA sequence. These include DNA methylation, histone modifications, and regulation of transcription via non-coding RNAs. Epigenetic modifications, occurring in response to external stressors, lead to changes in gene expression, and thus lie at the intersection between genetics and the environment. In this review, we examine data from in vitro studies, animal studies, and the existing human sepsis studies in epigenetics to demonstrate that epigenetic mechanisms are likely central to the pathogenesis of sepsis and that epigenetic therapies may have potential in the treatment of sepsis and its associated organ failures.
- Identification of novel DNA methylation prognostic biomarkers for AML with normal cytogeneticsPublication . Cardoso, Cândida; Pestana, Daniel; Gokuladhas, Sreemol; Marreiros, Ana; Justin M. O'Sullivan; Binnie, Alexandra; Teotónio Fernandes, Mónica Alexandra; Castelo-Branco, PedroPURPOSE AML is a hematologic cancer that is clinically heterogeneous, with a wide range of clinical outcomes. DNA methylation changes are a hallmark of AML but are not routinely used as a criterion for risk stratification. The aim of this study was to explore DNA methylation markers that could risk stratify patients with cytogenetically normal AML (CN-AML), currently classified as intermediate-risk.MATERIALS AND METHODSDNA methylation profiles in whole blood samples from 77 patients with CN-AML in The Cancer Genome Atlas (LAML cohort) were analyzed. Individual 5'-cytosine-phosphate-guanine-3' (CpG) sites were assessed for their ability to predict overall survival. The output was validated using DNA methylation profiles from bone marrow samples of 79 patients with CN-AML in a separate data set from the Gene Expression Omnibus.RESULTSIn the training set, using DNA methylation data derived from the 450K array, we identified 2,549 CpG sites that could potentially distinguish patients with CN-AML with an adverse prognosis (intermediate-poor) from those with a more favorable prognosis (intermediate-favorable) independent of age. Of these, 25 CpGs showed consistent prognostic potential across both the 450K and 27K array platforms. In a separate validation data set, nine of these 25 CpGs exhibited statistically significant differences in 2-year survival. These nine validated CpGs formed the basis for a combined prognostic biomarker panel, which includes an 8-CpG Somatic Panel and the methylation status of cg23947872. This panel displayed strong predictive ability for 2-year survival, 2-year progression-free survival, and complete remission in the validation cohort.CONCLUSIONThis study highlights DNA methylation profiling as a promising approach to enhance risk stratification in patients with CN-AML, potentially offering a pathway to more personalized treatment strategies.