Graphene Sensor Arrays for Rapid and Accurate Detection of Pancreatic Cancer Exosomes in Patients' Blood Plasma Samples.

Biosensors based on graphene field effect transistors (GFETs) have the potential to enable the development of point-of-care diagnostic tools for early stage disease detection. However, issues with reproducibility and manufacturing yields of graphene sensors, but also with Debye screening and unwanted detection of nonspecific species, have prevented the wider clinical use of graphene technology. Here, we demonstrate that our wafer-scalable GFETs array platform enables meaningful clinical results. As a case study of high clinical relevance, we demonstrate an accurate and robust portable GFET array biosensor platform for the detection of pancreatic ductal adenocarcinoma (PDAC) in patients' plasma through specific exosomes (GPC-1 expression) within 45 min. In order to facilitate reproducible detection in blood plasma, we optimized the analytical performance of GFET biosensors via the application of an internal control channel and the development of an optimized test protocol. Based on samples from 18 PDAC patients and 8 healthy controls, the GFET biosensor arrays could accurately discriminate between the two groups while being able to detect early cancer stages including stages 1 and 2. Furthermore, we confirmed the higher expression of GPC-1 and found that the concentration in PDAC plasma was on average more than 1 order of magnitude higher than in healthy samples. We found that these characteristics of GPC-1 cancerous exosomes are responsible for an increase in the number of target exosomes on the surface of graphene, leading to an improved signal response of the GFET biosensors. This GFET biosensor platform holds great promise for the development of an accurate tool for the rapid diagnosis of pancreatic cancer.

Physicochemical, calorimetric and texture profile characteristics of various gluten-free flours.

It is important to understand how the composition and structure of proteins from other flours differ from proteins in wheat, in order to have a better option to substitute gluten products with gluten-free food products. The aim of this study was the characterization of gluten-free flours and comparison of their rheological and calorimetric properties against wheat flour, for its use as gluten-free alternative. Chemical composition analysis, water solubility index (WSI), water absorption index (WAI), texture and calorimetric profile were determined. The closest WAI to wheat flour (1.45 g gel/g sample) was corn flour (2.41 g gel/g sample), while the WSI of chickpea flour was 5.51% approaching that of wheat flour of 5.88%. The hardness and adhesiveness values closest to wheat (1.65 kgf and 0.03 mJ) were amaranth flour with 0.85 kgf and 0.01 mJ, respectively. The phenolic content and antioxidant capacity were higher in the corn and bean flours with 244.4 mg GAE/100 g, 148 mg GAE/100 g and 190 mg AAE/100 g and 170 mg AAE/100 g, respectively. The combination of these non-conventional flours can be an innovative source of gluten-free formulas.

High-resolution line-scan Brillouin microscopy for live imaging of mechanical properties during embryo development.

Brillouin microscopy can assess mechanical properties of biological samples in a three-dimensional (3D), all-optical and hence non-contact fashion, but its weak signals often lead to long imaging times and require an illumination dosage harmful for living organisms. Here, we present a high-resolution line-scanning Brillouin microscope for multiplexed and hence fast 3D imaging of dynamic biological processes with low phototoxicity. The improved background suppression and resolution, in combination with fluorescence light-sheet imaging, enables the visualization of the mechanical properties of cells and tissues over space and time in living organism models such as fruit flies, ascidians and mouse embryos.

Multicenter prospective comparison of conventional and high-power short duration radiofrequency application for pulmonary vein isolation: the high-power short-duration radiofrequency application for faster and safer pulmonary vein ablation (POWER FAST III) trial.

BACKGROUND: Electrical isolation of pulmonary veins (PV) with high-power short-duration (HPSD) radiofrequency application (RFa) may reduce the duration of atrial fibrillation (AF) ablation, without compromising the procedural efficacy and safety in comparison with the conventional approach. This hypothesis has been generated in several observational studies; the POWER FAST III will test it in a randomized multicenter clinical trial. METHODS: It is a multicenter randomized, open-label and non-inferiority clinical trial with two parallel groups. AF ablation using 70 W and 9-10 s RFa is compared with the conventional technique using 25-40 W RFa guided by numerical lesion indexes. The main efficacy objective is the incidence of atrial arrhythmia recurrences electrocardiographically documented during 1-year follow-up. The main safety objective is the incidence of endoscopically detected esophageal thermal lesions (EDEL). This trial includes a substudy of incidence of asymptomatic cerebral lesions detected by magnetic resonance imaging (MRI) after ablation. RESULTS: A randomized clinical trial compares for the first time high-power short-duration and conventional ablation in order to obtain data about the efficacy and safety of the high-power technique in an adequate methodological context. CONCLUSIONS: The results of the POWER FAST III could support the use of the high-power short-duration ablation in clinical practice. REGISTRATION: ClinicalTrials.gov: NTC04153747.

Cardiac resynchronization therapy in non-ischemic cardiomyopathy: a comparative non-randomized study of His Bundle pacing versus biventricular pacing.

BACKGROUND: Cardiac resynchronization therapy (CRT) via permanent His bundle pacing (pHBP) has gained acceptance globally, but robust studies comparing pHBP-CRT with classic CRT are lacking. In this study, we aimed to compare the improvement in left ventricular ejection fraction (LVEF) after pHBP-CRT versus classic CRT. METHODS: This was a single-center study comparing a prospective series of pHBP-CRT with a historical series of CRT via classic biventricular pacing (BVP). Patients with non-ischemic cardiomyopathy, baseline LVEF < 35%, left bundle branch block (LBBB), and CRT indications were selected. RESULTS: Fifty-one patients underwent classic CRT and 52 patients underwent pHBP-CRT. In the classic CRT group, the median (interquartile range) basal LVEF was 30% (IQR, 29-35%) before implantation and 40% (35-48%) at follow-up. In the pHBP-CRT group, the median basal LVEF was 30% (28-34%) before implantation and 55% (45-60%) at follow-up, with significant differences between both modalities at follow-up (p = 0.001). The median long term His recruitment threshold with LBBB correction was 1.25 (1-2.5) V at 0.4 ms in cases of pHBP-CRT, compared to a left ventricular coronary sinus threshold of 1.25 (1-1.75) V in cases of classic CRT (p = 0.48). After CRT, the median paced QRS was 135 (120-145) ms for pHBP-CRT versus 140 (130-150) ms for BVP-CRT (p = 0.586). CONCLUSIONS: The improvement in LVEF was superior with pHBP-CRT than with classic CRT. The thresholds at follow-up were similar in both groups.

Ultrasensitive detection of SARS-CoV-2 spike protein by graphene field-effect transistors.

COVID-19, caused by the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), originated a global health crisis, causing over 2 million casualties and altering human daily life all over the world. This pandemic emergency revealed the limitations of current diagnostic tests, highlighting the urgency to develop faster, more precise and sensitive sensors. Graphene field effect transistors (GFET) are analytical platforms that enclose all these requirements. However, the design of a sensitive and robust GFET is not a straightforward objective. In this work, we report a GFET array biosensor for the detection of SARS-CoV-2 spike protein using the human membrane protein involved in the virus internalisation: angiotensin-converting enzyme 2 (ACE2). By finely controlling the graphene functionalisation, by tuning the Debye length, and by deeply characterising the ACE2-spike protein interactions, we have been able to detect the target protein with an extremely low limit of detection (2.94 aM). This work set the basis for a new class of analytical platforms, based on human membrane proteins, with the potential to detect a broad variety of pathogens, even before their isolation, being a powerful tool in the fight against future pandemics.

Impacts of intrathecal fentanyl on the incidence of postoperative nausea/vomiting: Systematic review and meta-analysis of randomized studies.

Post-operative nausea and vomiting (PONV) is an event of multifactorial origin with an incidence of 30% in the general population. Opioids such as fentanyl are being used as adjuvant to local anesthetic for its antiemetic effect. In this context, with this study we aimed to evaluate the impact of spinal fentanyl as an adjuvant on the incidence of PONV compared with a placebo, and shivering. A systematic search of randomized controlled trials that evaluated the use of spinal fentanyl in the prevention of PONV and shivering was conducted in different databases, of which 32 studies met the inclusion criteria. A total of 2116 patients scheduled for various surgeries, including cesarean section, orthopedic surgery in the lower limb, hysterectomy, and transurethral resection of the prostate, were included in the final analysis. The meta-analysis estimated the relative risk of incidence of PONV in the first 24 hours after surgery and secondary outcomes included the shivering symptom. The use of intrathecal fentanyl was associated with lower incidence of PONV, but not statistically significant when compared to the placebo (RR: 0.74 CI95%: 0.55-1.01 P = 0.06). Subgroup analysis showed a statistically significant reduction in PONV incidences with lower doses between 10 and 15 µg (RR: 0.44 CI95%: 0.35-0.55 P < 0.00001, I2 = 0%) but not with higher doses 20-25 µg. Secondary outcomes showed a decrease in incidence with the use of fentanyl vs the placebo (RR: 0.49, CI95% 0.33-0.72 P = 0.0003). Current evidence shows that the use of spinal fentanyl decreases the incidence of PONV, an effect favored using low doses.

Appropriateness of the dialysis modality selection process: A cross-sectional study.

Studies that specifically quantify the appropriateness of the process of dialysis modality selection are lacking. Peritoneal dialysis (PD) offers clinical and social advantages over hemodialysis (HD), but may be underused. We aimed to determine the appropriateness of the process of dialysis modality selection and quantify the percentage of patients who could potentially have been PD candidates. We performed a cross-sectional study that included adult patients from a hospital Nephrology Department in Barcelona who started dialysis between 2014 and 2015. We assessed the appropriateness of dialysis modalities selection by defining 3 sequential domains based on 3 critical steps in choosing a dialysis modality: eligibility for either treatment, information about modalities, and shared decision-making. We obtained data using medical records and a patient questionnaire. The dialysis modality selection process was considered appropriate when patients had no contraindications for the selected option, received complete information about both modalities, and voluntarily chose the selected option. A total of 141 patients were included in this study. The median age was 72 years (interquartile range 63-82 years), and 65% of the patients were men. The dialysis modality selection process was potentially inappropriate in 22% of the participants because of problems related to information about dialysis modalities (15%) or shared decision-making (7%). Appropriate PD use can potentially increase from 17% to 38%. Patient age and lack of information regarding dialysis options were independently associated with the potential degree of inappropriate dialysis modality selection. Our findings indicate areas for improvement in the selection of dialysis modalities. With better education and shared decision-making, the number of patients with PD could potentially double. The analysis of appropriateness is a helpful approach for studying renal replacement treatment patterns and identifying strategies to optimize their use.

Expanded hemodialysis: Is anticoagulation of the dialysis circuit different from online hemodiafiltration and high-flux hemodialysis?

Expanded hemodialysis (HDx) has a high capacity for removing medium and medium-large molecules; however, there are no specific recommendations during HDx for anticoagulation of the dialysis circuit. We aimed to evaluate the differences in the efficacy of anticoagulation procedures using the venous port and 40 mg enoxaparin in HDx compared to high-flux hemodialysis (HF-HD) and postdilution online hemodiafiltration (HDF). We compared anticoagulant activity in 11 patients in HDx, HF-HD, and HDF under similar dialysis conditions. In the 33 dialysis sessions, 40 mg enoxaparin was administered through the venous port, and pre- and postdialysis antifactor Xa activity (aXa) and activated partial thromboplastin time (APTT), postdialysis clotting time of the vascular access, visual clotting score of the dialyzer, and any complications with the extracorporeal circuit or bleeding were registered. APTT postdialysis in HDx was not significantly different from that in HF-HD and HDF. Postdialysis aXa in HDx was not significantly different from that in HF-HD and HDF. We found no significant differences in visual clotting score of the dialyzer. Enoxaparin administered through the venous port was sufficient for anticoagulation within the extracorporeal circuit in HDx, HF-HD, and HDF. There were no differences in postdialysis aXa or APTT, most likely because when low molecular-weight heparin is applied through venous port, lesser enoxaparin concentration reaches the dialyzer. Thus, we conclude that the dose of enoxaparin administered through the venous port should not be adjusted according to dialysis technique.

Corrected and Republished: Impacts of intrathecal fentanyl on the incidence of postoperative nausea/vomiting: Systematic review and meta-analysis of randomized studies.

Post-operative nausea and vomiting (PONV) is an event of multifactorial origin with an incidence of 30% in the general population. Opioids such as fentanyl are being used as adjuvant to local anesthetic for its antiemetic effect. In this context, with this study we aimed to evaluate the impact of spinal fentanyl as an adjuvant on the incidence of PONV compared with a placebo, and shivering. A systematic search of randomized controlled trials that evaluated the use of spinal fentanyl in the prevention of PONV and shivering was conducted in different databases, of which 32 studies met the inclusion criteria. A total of 2116 patients scheduled for various surgeries, including cesarean section, orthopedic surgery in the lower limb, hysterectomy, and transurethral resection of the prostate, were included in the final analysis. The meta-analysis estimated the relative risk of incidence of PONV in the first 24 hours after surgery and secondary outcomes included the shivering symptom. The use of intrathecal fentanyl was associated with lower incidence of PONV, but not statistically significant when compared to the placebo (RR: 0.74 CI95%: 0.55-1.01 P = 0.06). Subgroup analysis showed a statistically significant reduction in PONV incidences with lower doses between 10 and 15 µg (RR: 0.44 CI95%: 0.35-0.55 P < 0.00001, I2 = 0%) but not with higher doses 20-25 µg. Secondary outcomes showed a decrease in incidence with the use of fentanyl vs the placebo (RR: 0.49, CI95% 0.33-0.72 P = 0.0003). Current evidence shows that the use of spinal fentanyl decreases the incidence of PONV, an effect favored using low doses.

Fast Energy Dependent Scatter Correction for List-Mode PET Data.

Improvements in energy resolution of modern positron emission tomography (PET) detectors have created opportunities to implement energy-based scatter correction algorithms. Here, we use the energy information of auxiliary windows to estimate the scatter component. Our method is directly implemented in an iterative reconstruction algorithm, generating a scatter-corrected image without the need for sinograms. The purpose was to implement a fast energy-based scatter correction method on list-mode PET data, when it was not possible to use an attenuation map as a practical approach for the scatter degradation. The proposed method was evaluated using Monte Carlo simulations of various digital phantoms. It accurately estimated the scatter fraction distribution, and improved the image contrast in the simulated studied cases. We conclude that the proposed scatter correction method could effectively correct the scattered events, including multiple scatters and those originated in sources outside the field of view.

[Monoclonal gammopathy of undetermined significance and evolution to myeloma: Experience in 153 patients]. / Gammapatía monoclonal de significado incierto y evolución a mieloma múltiple: Experiencia en 153 pacientes.

INTRODUCTION: Based on risk factors, the Mayo Clinic Multiple Myeloma Group (MCMMG) established a model of progression from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) at 20 years. It is also described that MGUS with a progressive increase of monoclonal protein (M-protein) and/or immunoparesis (IMP) may be more predisposed to progress to myeloma. Our objective was to make a review of MGUS, to see how those who presented IMP and/or progression of their M-protein, contrasting them with MGUS that presented intermediate/high and high risk according to MCMMG. METHODOLOGY AND MATERIALS: A review of the MGUS objectified during the realization of a serum proteinogram (SPEP) was carried out during 2010-2014, in our area. Serum immunoglobulins, serum immunofixation (IFs), and serum free light chain ratio (FLCr) were determined for all MGUS. RESULTS: Of the 153 MGUS that are followed up for 4 years, 6 progress to MM. Of these 6 MM, 5 progress from MGUS with intermediate/high risk taking into account the MCMMG. Of these 5, 3 have IMP or progression of their M-protein. 2 present IMP plus progression of their M-protein. The sixth MM evolves from a MGUS without any risk factor, but with progression of its M-protein plus IMP. CONCLUSIONS: IMP and/or M-protein progression are important risk factors to be taken into account in the MGUS, in the first years after diagnosis, due to their possible evolution to MM.

Efficacy of enoxaparin in preventing coagulation during high-flux haemodialysis, expanded haemodialysis and haemodiafiltration.

BACKGROUND: Low-molecular-weight heparins (LMWHs) are easily dialysable with high-flow membranes; however, it is not clear whether the LMWH dose should be adjusted according to the membrane type and dialysis technique. This study aimed to evaluate the influence of the dialyser on anticoagulation of the extracorporeal dialysis circuit. METHODS: Thirteen patients received the same dose of LMWH through the arterial port via three dialysis techniques: high-flux haemodialysis (HF-HD), online haemodiafiltration (HDF) and expanded haemodialysis (HDx). All dialysis was performed under similar conditions: duration, 4 h; blood flow, 400 mL/min; and dialysate flow, 500 mL/min. Antifactor Xa (aXa) activity and activated partial thromboplastin time (APTT) were measured before and after the dialysis. Clotting time of the vascular access site after haemodialysis, visual clotting score of the dialyser and any complications with the extracorporeal circuit or bleeding were registered. RESULTS: Post-dialysis aXa activity in HF-HD (0.26 ± 0.02 U/mL) was significantly different from that in HDF (0.21 ± 0.02 U/mL, P = 0.024), and there was a trend in HDx (0.22 ± 0.01 U/mL, P = 0.05). APTT post-dialysis in HF-HD (30.5 ± 0.7 s) was significantly different from that in HDx (28.2 ± 0.64 s, P = 0.009) and HDF (28.8 ± 0.73 s, P = 0.009). CONCLUSIONS: AXa activity in HDF was significantly lower than that in HF-HD, possibly because of more losses of LMWH through the dialyser. Given the higher anticoagulant loss in HDF and probably in HDx than in HF-HD, the enoxaparin dose administered may be adjusted according to the dialysis technique.

Intradialytic hypotension and relationship with cognitive function and brain morphometry.

BACKGROUND: The haemodynamic stress brought about by dialysis could justify the loss of structural and functional integrity of the central nervous system (CNS). The main objective of this study was to analyse the relationship between intradialytic hypotension (IDH) and cognitive function and brain morphometry. METHODS: The cross-sectional KIDBRAIN study (Cohort Study of Morphological Changes of the Brain by MRI in Chronic Kidney Disease Patients) included 68 prevalent patients with no history of neurological disorders (cerebrovascular disease and cognitive impairment) undergoing haemodialysis (HD). We analysed 18 non-consecutive dialysis sessions (first three of each month over a 6-month period) and various definitions of IDH were recorded. Global cognitive function (GCF) was assessed using the Mini-Mental State Examination (MMSE) and parameters of structural integrity of the CNS were obtained using volume morphometry magnetic resonance imaging analysis [grey matter (GM), white matter (WM) and hippocampus). RESULTS: A greater number of sessions with IDH were associated with less volume of WM (r = -0.359,P = 0.003) and hippocampus (r = -0.395, P = 0.001) independent of cardiovascular risk factors according to multivariable linear regression models (ß = -0.198, P = 0.046 for WM; ß = -0.253, P = 0.017 for hippocampus). The GCF by the MMSE was 27.3 ± 7.3.1 and was associated with WM volume (ß = 0.403, P = 0.001) independent of GM and hippocampus volume. Symptomatic IDH was associated with GCF (r = -0.420, P < 0.001) in adjusted analysis (ß = -0.339, P = 0.008). CONCLUSIONS: Even when asymptomatic, IDH is associated with a lower WM and hippocampus volume and reduced GCF in patients undergoing HD, thus suggesting greater vulnerability of the brain to the haemodynamic stress that may be generated by a dialysis session.

Effectiveness and safety of AV node ablation after His bundle pacing in patients with uncontrolled atrial arrhythmias.

INTRODUCTION: In patients with uncontrolled atrial fibrillation, atrioventricular (AV) node ablation after permanent His bundle pacing (p-HBP) could be a therapeutic option for heart rate (HR) control. We aimed to demonstrate the advantages of AV node ablation with p-HBP, and to describe its effectiveness and safety. METHODS: This descriptive observational study included patients with uncontrolled permanent atrial arrhythmias who were candidates for HR control (January 2019 to July 2020) and underwent p-HBP and AV node ablation. RESULTS: A total of 39 patients were included. The median left ventricular ejection fraction (LVEF) was 55% (45-60); 46.1% in NYHA class II and 43.6% in NYHA class III. p-HBP was achieved in 92.3% (n = 36), and AV node ablation was successfully performed in all patients. The LVEF improved in patients with reduced LVEF (baseline, 35% [23.8-45.3%]; follow-up, 40% [35-56.5%], p < 0.05); the NYHA class also showed improvement (baseline, 71.4% patients in class III and 7.1% in class II, and at follow-up, 78.6% patients in class II and 14.3% in class I). In patients with previously normal LVEF, LVEF remained stable; nevertheless, a significant NYHA class improvement was observed (baseline, 63.6% class II and 31.8% class III patients; follow-up, 54.5% class I and 45.5% class II patients). The His thresholds and lead parameter values did not significantly change during the follow-up and remained stable. CONCLUSIONS: In patients with uncontrolled atrial arrhythmias who underwent AV node ablation after p-HBP, the NYHA class improved and the LVEF increased in those with reduced baseline LVEF. The values of pacing parameters were acceptable and remained stable during the follow-up.

Impact of Serum Magnesium Levels on Kidney and Cardiovascular Prognosis and Mortality in CKD Patients.

INTRODUCTION: In the general population, hypomagnesemia has been associated with cardiovascular events and hypermagnesemia with overall mortality. In chronic kidney disease (CKD) the evidence is not so strong. The objective of our study was to investigate the relationship between serum magnesium (SMg) concentration and cardiovascular morbidity and mortality, all-cause mortality, and the progression to kidney failure in a population with CKD. METHODS: Observational study of a cohort of 746 patients with CKD. Baseline characteristics and analytical profile were collected at the first visit, and patients were followed for a mean of 42.6 months. RESULTS: A cohort of 746 patients were analyzed, age 70 ± 13 years, 62.9% were male, 45.2% had CKD grade 3, and 35.9% grade 4. The mean SMg concentration was 2.09 ± 0.33 mg/dL, with a close correlation between SMg concentration and serum creatinine, phosphorus, and intact parathyroid hormone (iPTH) values. Use of calcitriol was associated with higher SMg (SMgH) concentration, while calcium supplements and proton pump inhibitors (PPIs) were associated with lower SMg concentration. For risk of cardiovascular events, patients with hypermagnesemia had an overall higher risk on a crude analysis (Log Rank 4.83, P = .28) and adjusted analysis (HR = 1.34, CI 1.02-1.77, P = .037). For risk of all-cause mortality, patients with hypermagnesemia had an overall higher risk on crude analysis (Log Rank 13.11, P > .001) and adjusted analysis (HR = 1.5424, IC = 1.002-2.319, P = .049). After performing a propensity score matching for SMg concentration, we achieved two comparable groups of 287 patients, finding again higher all-cause mortality in the hypermagnesemia group (LogRank 15.147, P < .001), that persisted in the Cox model adjusted for calcium, phosphorus, and iPTH. No association was found between SMg concentration and initiation of kidney replacement therapy (KRT). CONCLUSIONS: Magnesium concentration increases with decreasing kidney function. Hypermagnesemia predicts cardiovascular events and all-cause mortality in this same population. Thus, magnesium supplementation should be used with caution in these patients.

Electrocardiographic patterns predictive of left bundle branch block correction with His bundle pacing.

INTRODUCTION: Permanent His bundle pacing (p-HBP) could be an alternative for traditional cardiac resynchronization therapy (CRT), but an important limitation is that p-HBP cannot always correct the left bundle branch block (LBBB). The purpose of this article is to assess electrocardiographic patterns of LBBB that can predict electrocardiographic response (QRS narrowing) to His bundle pacing. METHODS: We designed a prospective descriptive study of patients with LBBB and CRT indication proposed for CRT by p-HBP. We analyzed the correlation between the different electrocardiographic patterns and the correction of conduction disturbance (LBBB). RESULTS: We included 70 patients. Pacing at the location where His bundle electrogram was recorded narrowed the QRS in 81.4% (n = 57). Basically, we identified two electrocardiographic patterns in lead V1: QS or rS. The QS pattern was a sensitivity of 56%, a specificity of 84.6%, and a positive predictive value (PPV) of 94.1% to predict the correction of the LBBB (area under the curve [AUC] = .70). In patients with rS pattern, a ratio between the descending and the ascending S wave component duration ≥0.64 was a very good predictor of the correction of the LBBB (AUC = .968); with a value ≥0.64, the sensitivity, specificity, and PPV was 92%, 100%, and 100%, respectively. CONCLUSIONS: In patients with LBBB and CRT indication, the QS pattern in lead V1 predicts the correction of the QRS with HBP. In the case of rS pattern in lead V1, the ratio descending/ascending S wave component duration has a strong correlation with the LBBB correction.