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1-Year COMBO stent outcomes stratified by the PARIS bleeding prediction score: From the MASCOT registry
Get PDFBackground: The COMBO stent is a biodegradable-polymer sirolimus-eluting stent with endothelial progenitor cell capture technology for faster endothelialization. Objective: We analyzed COMBO stent outcomes in relation to bleeding risk using the PARIS bleeding score. Methods: MASCOT was an international registry of all-comers undergoing attempted COMBO stent implantation. We stratified patients as low bleeding-risk (LBR) for PARIS score 3 based on baseline age, body mass index, anemia, current smoking, chronic kidney disease and need for triple therapy. Primary endpoint was 1-year target lesion failure (TLF), composite of cardiac death, myocardial infarction (MI) not clearly attributed to a non-target vessel or clinically-driven target lesion revascularization (TLR). Bleeding was adjudicated using the Bleeding Academic Research Consortium (BARC) definition. Dual antiplatelet therapy (DAPT) cessation was independently adjudicated. Results: The study included 56% (n = 1270) LBR and 44% (n = 1009) IHBR patients. Incidence of 1-year TLF was higher in IHBR patients (4.1% vs. 2.6%, p = 0.047) driven by cardiac death (1.7% vs. 0.7%, p = 0.029) with similar rates of MI (1.8% vs. 1.1%, p = 0.17), TLR (1.5% vs. 1.6%, p = 0.89) and definite/ probable stent thrombosis (1.2% vs. 0.6%, p = 0.16). Incidence of 1-year major BARC 3 or 5 bleeding was significantly higher in IHBR patients (2.3% vs. 0.9%, p = 0.0094), as was the incidence of DAPT cessation (29.3% vs. 22.8%, p < 0.01), driven by physician-guided discontinuation. Conclusions: Patients with intermediate-to-high PARIS bleeding risk in the MASCOT registry experienced greater incidence of 1-year TLF, major bleeding and DAPT cessation than LBR patients, without significant differences in stent thrombosis
BR-BCSC Signature: The Cancer Stem Cell Profile Enriched in Brain Metastases that Predicts a Worse Prognosis in Lymph Node-Positive Breast Cancer
Get PDFBrain metastases remain an unmet clinical need in breast oncology, being frequently found in HER2-overexpressing and triple-negative carcinomas. These tumors were reported to be highly cancer stem-like cell-enriched, suggesting that brain metastases probably arise by the seeding of cancer cells with stem features. Accordingly, we found that brain-tropic breast cancer cells show increased stem cell activity and tumorigenic capacity in the chick embryo choriallantoic membrane when compared to the parental cell line. These observations were supported by a significant increase in their stem cell frequency and by the enrichment for the breast cancer stem cell (BCSC) phenotype CD44(+)CD24(-/low). Based on this data, the expression of BCSC markers (CD44, CD49f, P-cadherin, EpCAM, and ALDH1) was determined and found to be significantly enriched in breast cancer brain metastases when compared to primary tumors. Therefore, a brain (BR)-BCSC signature was defined (3-5 BCSC markers), which showed to be associated with decreased brain metastases-free and overall survival. Interestingly, this signature significantly predicted a worse prognosis in lymph node-positive patients, acting as an independent prognostic factor. Thus, an enrichment of a BCSC signature was found in brain metastases, which can be used as a new prognostic factor in clinically challenging breast cancer patients
Interactions Between the Serotonergic and Other Neurotransmitter Systems in the Basal Ganglia: Role in Parkinson's Disease and Adverse Effects of L-DOPA
Get PDFParkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra. However, other non-dopaminergic neuronal systems such as the serotonergic system are also involved. Serotonergic dysfunction is associated with non-motor symptoms and complications, including anxiety, depression, dementia, and sleep disturbances. This pathology reduces patient quality of life. Interaction between the serotonergic and other neurotransmitters systems such as dopamine, noradrenaline, glutamate, and GABA controls the activity of striatal neurons and are particularly interesting for understanding the pathophysiology of PD. Moreover, serotonergic dysfunction also causes motor symptoms. Interestingly, serotonergic neurons play an important role in the effects of L-DOPA in advanced PD stages. Serotonergic terminals can convert L-DOPA to dopamine, which mediates dopamine release as a "false" transmitter. The lack of any autoregulatory feedback control in serotonergic neurons to regulate L-DOPA-derived dopamine release contributes to the appearance of L-DOPA-induced dyskinesia (LID). This mechanism may also be involved in the development of graft-induced dyskinesias (GID), possibly due to the inclusion of serotonin neurons in the grafted tissue. Consistent with this, the administration of serotonergic agonists suppressed LID. In this review article, we summarize the interactions between the serotonergic and other systems. We also discuss the role of the serotonergic system in LID and if therapeutic approaches specifically targeting this system may constitute an effective strategy in PD
Oncogenic driver mutations predict outcome in a cohort of head and neck squamous cell carcinoma (HNSCC) patients within a clinical trial
Get PDF234 diagnostic formalin-fixed paraffin-embedded (FFPE) blocks from homogeneously treated patients with locally advanced head and neck squamous cell carcinoma (HNSCC) within a multicentre phase III clinical trial were characterised. The mutational spectrum was examined by next generation sequencing in the 26 most frequent oncogenic drivers in cancer and correlated with treatment response and survival. Human papillomavirus (HPV) status was measured by p16INK4a immunohistochemistry in oropharyngeal tumours. Clinicopathological features and response to treatment were measured and compared with the sequencing results. The results indicated TP53 as the most mutated gene in locally advanced HNSCC. HPV-positive oropharyngeal tumours were less mutated than HPV-negative tumours in TP53 (p < 0.01). Mutational and HPV status influences patient survival, being mutated or HPV-negative tumours associated with poor overall survival (p < 0.05). No association was found between mutations and clinicopathological features. This study confirmed and expanded previously published genomic characterization data in HNSCC. Survival analysis showed that non-mutated HNSCC tumours associated with better prognosis and lack of mutations can be identified as an important biomarker in HNSCC. Frequent alterations in PI3K pathway in HPV-positive HNSCC could define a promising pathway for pharmacological intervention in this group of tumours
High Prevalence of ST131 Subclades C2-H30Rx and C1-M27 Among Extended-Spectrum beta-Lactamase-Producing Escherichia coli Causing Human Extraintestinal Infections in Patients From Two Hospitals of Spain and France During 2015
Get PDFThe present study was carried out to evaluate the prevalence of sequence type 131 (ST131) among 188 extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-EC) collected in 2015 in Lucus Augusti University hospital (Lugo, Spain) and AP-HP Beaujon hospital (Clichy, France) with regard to other STs and to characterize, the types of ESBL produced, serotypes, virulence factor (VF)-encoding genes and the ST131 clades and subclades. ST131 was detected in 33 (39.1%) and 46 (47.9%) of the isolates in Lucus Augusti and Beaujon, respectively. The 109 remaining isolates displayed 57 other STs, the following STs being displayed by at least three isolates: ST10 (8 isolates), ST23 (3), ST38 (4), ST58 (3), ST88 (5), ST95 (4), ST167 (3), ST354 (5), ST361 (3), ST410 (6), ST648 (4), ST744 (3), and ST1615 (6). ST354, ST410, and ST1615 were significantly (P < 0.05) more frequent in Lucus Augusti (5.4%, 6.5%, and 6.5%) than in Beaujon (0% for the three STs). The new globally emerging clone ST1193 among extraintestinal clinical ESBL-EC was identified in one isolate from France and one from Spain. CTX-M-15 was the commonest ESBL detected in the two hospitals (44.6% in Lucus Augusti and 50.0% in Beaujon). CTX-M-14 was significantly (P = 0.0003) more frequent in Lucus Augusti (31.5%) than in Beaujon (10.4%), whereas CTX-M-1 (20.8 vs. 7.6%; P = 0.008) and CTX-M-27 (15.6 vs. 6.5%; P = 0.0389) were more frequent in Beaujon than in Lucus Augusti. The ST131 isolates showed a higher virulence score (mean 13.367) compared with the non-ST131 isolates (mean 7.661) (P < 0.001). Among the 79 ST131 isolates, most of them (52; 65.8%) belonged to subclade C2 (also known as subclone H30Rx) followed by those belonging to subclade C1 (cluster C1-M27: 16 isolates, 20.3%; cluster non-C1-M27: 6 isolates, 7.6%) and clade A (4 isolates; 5.1%). The C2 subclade isolates showed a higher VF-encoding gene score (mean 14.250) compared with the C1-M27 cluster isolates (mean 10.875) (P < 0.001). In conclusion, this study highlights the epidemiological differences between the ESBL-EC isolated from two hospitals of France and Spain obtain in 2015 and reports, for the first time, the presence of clone ST1193 in Spain
Genomic Characterization of Escherichia coli Isolates Belonging to a New Hybrid aEPEC/ExPEC Pathotype O153:H10-A-ST10 eae-beta1 Occurred in Meat, Poultry, Wildlife and Human Diarrheagenic Samples
Get PDFDifferent surveillance studies (2005-2015) in northwest Spain revealed the presence of eae-positive isolates of Escherichia coli O153:H10 in meat for human consumption, poultry farm, wildlife and human diarrheagenic samples. The aim of this study was to explore the genetic and genomic relatedness between human and animal/meat isolates, as well as the mechanism of its persistence. We also wanted to know whether it was a geographically restricted lineage, or whether it was also reported elsewhere. Conventional typing showed that 32 isolates were O153:H10-A-ST10 fimH54, fimAvMT78, traT and eae-beta1. Amongst these, 21 were CTX-M-32 or SHV-12 producers. The PFGE XbaI-macrorestriction comparison showed high similarity (>85%). The plasmidome analysis revealed a stable combination of IncF (F2:A-:B-), IncI1 (STunknown) and IncX1 plasmid types, together with non-conjugative Col-like plasmids. The core genome investigation based on the cgMLST scheme from EnteroBase proved close relatedness between isolates of human and animal origin. Our results demonstrate that a hybrid MDR aEPEC/ExPEC of the clonal group O153:H10-A-ST10 (CH11-54) is circulating in our region within different hosts, including wildlife. It seems implicated in human diarrhea via meat transmission, and in the spreading of ESBL genes (mainly of CTX-M-32 type). We found genomic evidence of a related hybrid aEPEC/ExPEC in at least one other country
The social return on investment of a new approach to heart failure in the Spanish National Health System
Get PDFAIMS: We aim to agree on a set of proposals to improve the current management of heart failure (HF) within the Spanish National Health System (SNHS) and apply the social return on investment (SROI) method to measure the social impact that these proposals would generate. METHODS AND RESULTS: A multidisciplinary working team of 16 experts was set up, with representation from the main stakeholders regarding HF: medical specialists (cardiologists, internal medicine physicians, general practitioners, and geriatric physicians), nursing professionals, health management professionals, patients, and informal caregivers. This team established a set of proposals to improve the management of HF according to the main areas of HF care: emergency and hospitalization, primary care, cardiology, and internal medicine. A forecast-type SROI method, with a 1-year time frame, was applied to measure the social impact resulting from the implementation of these proposals. The required investment and social return were estimated and summarized into a ratio indicating how much social return could be generated for each euro invested. Intangible returns were included and quantified through financial proxies. The approach to improve the management of HF consisted of 28 proposals, including the implementation of a case management nurse network, standardization of operational protocols, psychological support, availability of echocardiography machines at emergency departments, stationary units and primary care, early specialist visits after hospital discharge, and cardiac rehabilitation units, among others. These proposals would benefit not only patients and their informal caregivers but also the SNHS. Regarding patients, proposals would increase their autonomy in everyday activities, decrease anxiety, increase psychological and physical well-being, improve pharmacological adherence and self-care, enhance understanding of the disease, delay disease progression, expedite medical assessment, and prevent the decrease in work productivity associated with HF management. Regarding informal caregivers, proposals would increase their quality of life; improve their social, economic, and emotional well-being; and reduce their care burden. The SNHS would benefit from shorter stays of HF patients at intensive care units and reduction of hospitalizations and admissions to emergency departments. The investment needed to implement these proposals would amount to euro548m and yield a social return of euro1932m, that is, euro3.52 for each euro invested. CONCLUSIONS: The current management of HF could be improved by a set of proposals that resulted in an overall positive social return, varying between areas of analysis. This may guide the allocation of healthcare resources and improve the quality of life of patients with HF
Points to consider in cardiovascular disease risk management among patients with rheumatoid arthritis living in South Africa, an unequal middle income country
Get PDFBackground: It is plausible that optimal cardiovascular disease (CVD) risk management differs in patients with rheumatoid arthritis (RA) from low or middle income compared to high income populations. This study aimed at producing evidence-based points to consider for CVD prevention in South African RA patients. Methods: Five rheumatologists, one cardiologist and one epidemiologist with experience in CVD risk management in RA patients, as well as two patient representatives, two health professionals and one radiologist, one rheumatology fellow and 11 rheumatologists that treat RA patients regularly contributed. Systematic literature searches were performed and the level of evidence was determined according to standard guidelines. Results: Eighteen points to consider were formulated. These were grouped into 6 categories that comprised overall CVD risk assessment and management (n = 4), and specific interventions aimed at reducing CVD risk including RA control with disease modifying anti-rheumatic drugs, glucocorticoids and non-steroidal anti-inflammatory drugs (n = 3), lipid lowering agents (n = 8), antihypertensive drugs (n = 1), low dose aspirin (n = 1) and lifestyle modification (n = 1). Each point to consider differs partially or completely from recommendations previously reported for CVD risk management in RA patients from high income populations. Currently recommended CVD risk calculators do not reliably identify South African black RA patients with very high-risk atherosclerosis as represented by carotid artery plaque presence on ultrasound. Conclusions: Our findings indicate that optimal cardiovascular risk management likely differs substantially in RA patients from low or middle income compared to high income populations. There is an urgent need for future multicentre longitudinal studies on CVD risk in black African patients with RA
Diagnosis and treatment outcomes of adult tuberculosis in an urban setting with high HIV prevalence in Sierra Leone: A retrospective study
Get PDFOBJECTIVE: To assess the diagnosis, treatment outcomes, and predictors of mortality in adult tuberculosis (TB) patients in an urban setting with a high HIV prevalence. METHODS: A retrospective study was conducted of adult TB patients aged >/=15 years who were treated at Connaught Hospital in Freetown, Sierra Leone from January through December 2017. Multivariate logistic regression was used to identify predictors of mortality. RESULTS: Of 1127 TB cases notified in 2017, 1105 (98%) were tested for HIV, yielding a TB/HIV co-infection rate of 32.0%. Only HIV-tested cases (n=1105) were included in the final analysis. The majority were male (69.3%), aged 25-34 years (29.2%), and had pulmonary TB (96.3%). Treatment outcomes were as follows: 29.0% cured, 29.0% completed, 0.5% treatment failure, 24.2% lost to follow-up, 12.8% transferred/not evaluated, and 4.5% died. The majority of deaths (80.0%, 40/50) occurred within 2 months of TB treatment initiation. Age 65 years or older (adjusted odds ratio 3.48, 95% confidence interval 1.15-10.56; p=0.027) and HIV-positive status (adjusted odds ratio 3.50, 95% confidence interval 1.72-7.12; p=0.001) were independent predictors of mortality. CONCLUSIONS: Suboptimal TB treatment outcomes were observed in Sierra Leone in 2017. More local and international action is warranted to help achieve the 2035 global TB elimination targets
MRI of female genital tract congenital anomalies: European Society of Urogenital Radiology (ESUR) guidelines
Get PDFOBJECTIVE: To develop imaging guidelines for the MR work-up of female genital tract congenital anomalies (FGTCA). METHODS: These guidelines were prepared based on a questionnaire sent to all members of the European Society of Urogenital Radiology (ESUR) Female Pelvic Imaging Working Group (FPI-WG), critical review of the literature and expert consensus decision. RESULTS: The returned questionnaires from 17 different institutions have shown reasonable homogeneity of practice. Recommendations with focus on patient preparation and MR protocol are proposed, as these are key to optimised examinations. Details on MR sequences and planning of uterus-orientated sequences are provided. CONCLUSIONS: The multiplanar capabilities and soft tissue resolution of MRI provide superb characterisation of the wide spectrum of findings in FGTCA. A standardised imaging protocol and method of reporting ensures that the salient features are recognised, contributing to a correct diagnosis and classification of FGTCA, associated anomalies and complications. These imaging guidelines are based on current practice among expert radiologists in the field and incorporate up to date information regarding MR protocols and essentials of recently published classification systems. KEY POINTS: * MRI allows comprehensive evaluation of female genital tract congenital anomalies, in a single examination. * A dedicated MRI protocol comprises uterus-orientated sequences and vaginal and renal evaluation. * Integration of classification systems and structured reporting helps in successful communication of the imaging findings