The availability of multiple treatments for type 1 Gaucher disease increases the need for real-life studies to evaluate treatment efficacy and safety and provide clinicians with more information to ...choose the best personalized therapy for their patients.
To determine whether treatment with eliglustat produces, in adult GD1 patients, ans optimal response in daily clinical practice.
We designed a real-life study with 2 years of follow-up (TRAZELGA GEE-ELI-2017-01) to uniformly evaluate the response and adverse events to eliglustat treatment. This study, conducted in 30 patients across Spain and previously treated with other therapies, included the evaluation of safety and efficacy by assessing visceral enlargement, bone disease (DEXA and T and Z scores), concomitant treatments and adverse events, as well as a quality of life evaluation (SF-36). In addition, the quantification of classical biomarkers (chitotriosidase activity, CCL18/PARC and glucosylsphingosine (GluSph)) and new candidates for GD biomarkers (YKL-40, cathepsin S, hepcidin and lipocalin-2 determined by immunoassay) were also assessed. Non-parametric statistical analysis was performed and p < 0.05 was considered statistically significant.
Thirty patients were enrolled in the study. The median age was 41.5 years and the male-female ratio was 1.1:1. 84% of the patients had received ERT and 16% SRT as previous treatment. The most common symptoms at baseline were fatigue (42%) and bone pain (38%), no patient had a bone crisis during the study, and two years after switching, 37% had reduced their use of analgesics. Patient-reported outcomes showed a significant increase in physical function scores (p = 0.027) and physical pain scores (p = 0.010). None of the enrolled patients discontinued treatment due to adverse events, which were mild and transient in nature, mainly gastrointestinal and skin dryness. None of the biomarkers show a significant increase or decompensation after switching. CCL18/PARC (p = 0.0012), YKL-40 (p = 0.00004) and lipocalin-2 (p = 0.0155) improved after two years and GluSph after one year (p = 0.0008) and two years (p = 0.0245) of oral therapy.
In summary, this real-life study, showed that eliglustat maintains stability and can improve quality of life with few side effects. Significant reductions in classic and other novel biomarkers were observed after two years of therapy.
Information for treatment or hospital derivation of prehospital seizures is limited, impairing patient condition and hindering patients risk assessment by the emergency medical services (EMS). This ...study aimed to determine the associated factors to clinical impairment, and secondarily, to determine risk factors associated to cumulative in-hospital mortality at 2, 7 and 30 days, in patients presenting prehospital seizures.
Prospective, multicentre, EMS-delivery study involving adult subjects with prehospital seizures, including five advanced life support units, 27 basic life support units and four emergency departments in Spain. All bedside variables: including demographic, standard vital signs, prehospital laboratory tests and presence of intoxication or traumatic brain injury (TBI), were analysed to construct a risk model using binary logistic regression and internal validation methods.
A total of 517 patients were considered. Clinical impairment was present in 14.9%, and cumulative in-hospital mortality at 2, 7 and 30-days was 3.4%, 4.6% and 7.7%, respectively. The model for the clinical impairment indicated that respiratory rate, partial pressure of carbon dioxide, blood urea nitrogen, associated TBI or stroke were risk factors; higher Glasgow Coma Scale (GCS) scores mean a lower risk of impairment. Age, potassium, glucose, prehospital use of mechanical ventilation and concomitant stroke were risk factors associated to mortality; and oxygen saturation, a high score in GCS and haemoglobin were protective factors.
Our study shows that prehospital variables could reflect the clinical impairment and mortality of patients suffering from seizures. The incorporation of such variables in the prehospital decision-making process could improve patient outcomes.
Background
Heart failure (HF) admission in chronic coronary syndrome (CCS) patients has a prognostic impact. Stratification schemes have been described for predicting this endpoint, but none of them ...has been externally validated.
Objectives
Our aim was to develop point scores for predicting incident HF admission with data from previous studies, to perform an external validation in an independent prospective cohort and to compare their discriminative ability for this event.
Methods
Independent predictive variables of HF admission in CCS patients without baseline HF were selected from four previous prospective studies (CARE, PEACE, CORONOR and CLARIFY), generating scores based on the relative magnitude of the coefficients of Cox of each variable. Finally, the scores were validated and compared in a monocentric prospective cohort.
Results
The validation cohort included 1212 patients followed for up to 17 years, with 171 patients suffering at least one HF admission in the follow‐up. Discriminative ability for predicting HF admission was statistically significant for all, and paired comparisons among them were all nonsignificant except for CORONOR score was superior to CLARIFY score (C‐statistic 0.73, 95%CI 0.69–0.76 vs. 0.69, 95% CI 0.65–0.73; p = 0.03).
Conclusion
All tested scores showed significant discriminative ability for predicting incident HF admission in this independent validation study. Their discriminative ability was similar, with significant differences only between the two scores with higher and lower performance.
All the study‐derived scores showed significant ability for predicting HF admission in this cohort. According to their discriminative ability, there were only differences between two scores.
Abstract
Whole-genome duplication and post-polyploidization genome downsizing play key roles in the evolution of land plants; however, the impact of genomic diploidization on functional traits still ...remains poorly understood. Using Dianthus broteri as a model, we compared the ecophysiological behaviour of colchicine-induced neotetraploids (4xNeo) to diploids (2x) and naturally occurring tetraploids (4xNat). Leaf gas-exchange and chlorophyll fluorescence analyses were performed in order to asses to what extent post-polyploidization evolutionary processes have affected 4xNat. Genomic diploidization and phenotypic novelty were evident. Distinct patterns of variation revealed that post-polyploidization processes altered the phenotypic shifts directly mediated by genome doubling. The photosynthetic phenotype was affected in several ways but the main effect was phenotypic diploidization (i.e. 2x and 4xNat were closer to each other than to 4xNeo). Overall, our results show the potential benefits of considering experimentally synthetized versus naturally established polyploids when exploring the role of polyploidization in promoting functional divergence.
Colchicine-induced polyploidization in Dianthus broteri demonstrates that ‘phenotypic diploidization’ occurs in functional traits, which can lead to the creative role of polyploidization being underestimated.
The functional role of SNAP23, STX3, and STX4 in Ab secretion; SNAP23, STX4 is implicated in the Ab secretion by a myeloma cell line and by normal human colon lamina propria PCs.
PCs are responsible ...for the production and secretion of antibodies, the effector molecules of the humoral immune response. The molecular mechanisms responsible for vesicle docking and secretion implicated in the antibody‐secretion process are not well‐known, as they have not been studied, but it is known that SNARE proteins are responsible for many membrane‐fusion processes in the cell. We show here that freshly isolated human colon LP‐PCs and T‐PCs from MM‐PC patients and the U266 cell line, as a model for PC secretion, contain a set of these proteins. SNAP23, STX3, and STX4 were localized mainly in the plasma membrane of PCs, and interactions of SNAP23 with STX3 and with STX4 were proven by IP. Interaction between SNAP23 and STX4 was also confirmed in situ. With the use of siRNA, as well as shRNA, the functional role of SNAP23, STX3, and STX4 in antibody secretion was also examined. The findings demonstrate that in addition to SNAP23, STX4 is implicated in the antibody secretion by a myeloma cell line and by normal human colon LP‐PCs.
Bone is the most studied tissue in the field of tissue regeneration. Even though it has intrinsic capability to regenerate upon injury, several pathologies and injuries could hamper the highly ...orchestrated bone formation and resorption process. Bone tissue engineering seeks to mimic the extracellular matrix of the tissue and the different biochemical pathways that lead to successful regeneration. For many years, the use of extrinsic factors (i.e., growth factors and drugs) to modulate these biological processes have been the preferred choice in the field. Even though it has been successful in some instances, this approach presents several drawbacks, such as safety-concerns, short release profile and half-time life of the compounds. On the other hand, the use of inorganic ions has attracted significant attention due to their therapeutic effects, stability and lower biological risks. Biomaterials play a key role in such strategies where they serve as a substrate for the incorporation and release of the ions. In this review, the methodologies used to incorporate ions in biomaterials is presented, highlighting the osteogenic properties of such ions and the roles of biomaterials in controlling their release.
Women and men with chronic coronary syndrome (CCS) have different clinical features and management, and studies on mid-term prognosis have reported conflicting results. Our objective was to ...investigate the impact of the female sex in the prognosis of the disease in the very long term.
We investigated differential features and very long-term prognosis in 1268 consecutive outpatients with CCS (337 27% women and 931 73% men). Women were older than men, more likely to have hypertension, diabetes, angina, and atrial fibrillation, and less likely to be exsmoker/active smoker and to have been treated with coronary revascularization (
< 0.05 for all). The prescription of statins, antiplatelets, and betablockers was similar in both groups. After up to 17 years of follow-up (median = 11 years, interquartile range = 4-15 years), cumulative incidences of acute myocardial infarction (10.2% vs. 11.8%) or stroke (11% vs. 10%) at median follow-up were similar, but the risks of major cardiovascular events (acute myocardial infarction, stroke, or cardiovascular death, 41.2% vs. 33.6%), hospital admission for heart failure (20.9% vs. 11.9%), or cardiovascular death (32.3% vs. 22.1%) were significantly higher for women (
< 0.0005), with a nonsignificant trend to higher overall mortality (45.2% vs. 39.1%,
= 0.07). However, after multivariate adjustment, all these differences disappeared.
Although women and men with CCS presented a different clinical profile, and crude rates of major cardiovascular events, heart failure and cardiovascular death were higher in women, female sex was not an independent prognostic factor in this study with up to 17 years of follow-up.
In potentially severe diseases in general and COVID-19 in particular, it is vital to early identify those patients who are going to progress to severe disease. A recent living systematic review ...dedicated to predictive models in COVID-19, critically appraises 145 models, 8 of them focused on prediction of severe disease and 23 on mortality. Unfortunately, in all 145 models, they found a risk of bias significant enough to finally "not recommend any for clinical use". Authors suggest concentrating on avoiding biases in sampling and prioritising the study of already identified predictive factors, rather than the identification of new ones that are often dependent on the database. Our objective is to develop a model to predict which patients with COVID-19 pneumonia are at high risk of developing severe illness or dying, using basic and validated clinical tools. We studied a prospective cohort of consecutive patients admitted in a teaching hospital during the "first wave" of the COVID-19 pandemic. Follow-up to discharge from hospital. Multiple logistic regression selecting variables according to clinical and statistical criteria. 404 consecutive patients were evaluated, 392 (97%) completed follow-up. Mean age was 61 years; 59% were men. The median burden of comorbidity was 2 points in the Age-adjusted Charlson Comorbidity Index, CRB was abnormal in 18% of patients and basal oxygen saturation on admission lower than 90% in 18%. A model composed of Age-adjusted Charlson Comorbidity Index, CRB score and basal oxygen saturation can predict unfavorable evolution or death with an area under the ROC curve of 0.85 (95% CI 0.80-0.89), and 0.90 (95% CI 0.86 to 0.94), respectively. Prognosis of COVID-19 pneumonia can be predicted without laboratory tests using two classic clinical tools and a pocket pulse oximeter.
The immunological synapse (IS) is a cell-cell junction formed between CD4.sup.+ T cells and dendritic cells (DCs). Here we show in vitro and in vivo that IS formation inhibits apoptosis of DCs. ...Consistent with these results, IS formation induced antiapoptotic signaling events, including activation of the kinase Akt1 and localization of the prosurvival transcription factor NF-κB and the proapoptotic transcription factor FOXO1 to the nucleus and cytoplasm, respectively. Inhibition of phosphatidylinositol 3-OHk inase and Akt1 partially prevented the antiapoptotic effects of IS formation. Direct stimulation of the IS component CD40 on DCs leads to the activation of Akt1, suggesting the involvement of this receptor in the antiapoptotic effects observed upon IS formation.
PDF
