Transcriptomic Analysis of Extracellular Vesicles in the Search for Novel Plasma and Thrombus Biomarkers of Ischemic Stroke Etiologies.

Accurate etiologic diagnosis provides an appropriate secondary prevention and better prognosis in ischemic stroke (IS) patients; still, 45% of IS are cryptogenic, urging us to enhance diagnostic precision. We have studied the transcriptomic content of plasma extracellular vesicles (EVs) (n = 21) to identify potential biomarkers of IS etiologies. The proteins encoded by the selected genes were measured in the sera of IS patients (n = 114) and in hypertensive patients with (n = 78) and without atrial fibrillation (AF) (n = 20). IGFBP-2, the most promising candidate, was studied using immunohistochemistry in the IS thrombi (n = 23) and atrium of AF patients (n = 13). In vitro, the IGFBP-2 blockade was analyzed using thromboelastometry and endothelial cell cultures. We identified 745 differentially expressed genes among EVs of cardioembolic, atherothrombotic, and ESUS groups. From these, IGFBP-2 (cutoff > 247.6 ng/mL) emerged as a potential circulating biomarker of embolic IS [OR = 8.70 (1.84-41.13) p = 0.003], which was increased in patients with AF vs. controls (p < 0.001) and was augmented in cardioembolic vs. atherothrombotic thrombi (p < 0.01). Ex vivo, the blockage of IGFBP-2 reduced clot firmness (p < 0.01) and lysis time (p < 0.001) and in vitro, diminished endothelial permeability (p < 0.05) and transmigration (p = 0.06). IGFBP-2 could be a biomarker of embolic IS and a new therapeutic target involved in clot formation and endothelial dysfunction.

Preparative Fractionation of Brazilian Red Propolis Extract Using Step-Gradient Counter-Current Chromatography.

Propolis is a resinous bee product with a very complex composition, which is dependent upon the plant sources that bees visit. Due to the promising antimicrobial activities of red Brazilian propolis, it is paramount to identify the compounds responsible for it, which, in most of the cases, are not commercially available. The aim of this study was to develop a quick and clean preparative-scale methodology for preparing fractions of red propolis directly from a complex crude ethanol extract by combining the extractive capacity of counter-current chromatography (CCC) with preparative HPLC. The CCC method development included step gradient elution for the removal of waxes (which can bind to and block HPLC columns), sample injection in a single solvent to improve stationary phase stability, and a change in the mobile phase flow pattern, resulting in the loading of 2.5 g of the Brazilian red propolis crude extract on a 912.5 mL Midi CCC column. Three compounds were subsequently isolated from the concentrated fractions by preparative HPLC and identified by NMR and high-resolution MS: red pigment, retusapurpurin A; the isoflavan 3(R)-7-O-methylvestitol; and the prenylated benzophenone isomers xanthochymol/isoxanthochymol. These compounds are markers of red propolis that contribute to its therapeutic properties, and the amount isolated allows for further biological activities testing and for their use as chromatographic standards.

Modified Rapid Emergency Medicine Score-Lactate (mREMS-L) performance to screen non-anticipated 30-day-related-mortality in emergency department.

BACKGROUND: The aim of this study was to compare the ability to predict 30-day in-hospital mortality of lactate versus the modified Rapid Emergency Medicine Score (mREMS) versus the arithmetic sum of the mREMS plus the numerical value of lactate (mREMS-L). METHODS: A prospective, multicentric, emergency department delivery, pragmatic study was conducted. To determine the predictive capacity of the scales, lactate was measured and the mREMS and mREMS-L were calculated in adult patients (aged>18 years) transferred with high priority by ambulance to the emergency department in five hospitals of Castilla y Leon between 1 January 2020 and 31 December 2021. The area under the receiver operating characteristic (ROC) curve of each of the scales was calculated in terms of mortality for 30 days. RESULTS: A total of 5371 participants were included, and the in-hospital mortality rate at 30 days was of 11.4% (615 cases). The best cut-off point determined in the mREMS was 7.0 points (sensitivity of 67% and specificity of 84%), and for lactate, the cut-off point was 1.4 mmol/L (sensitivity of 88% and specificity of 67%). Finally, the combined mREMS-L showed a cut-off point of 7.9 (sensitivity of 83% and a specificity of 83%). The area under the ROC curve of the mREMS, lactate and mREMS-L for 30-day mortality was 0.851, 0.853, and 0.903, respectively (p < 0.001 in all cases). CONCLUSIONS: The new score generated, mREMS-L, obtained better statistical results than its components (mREMS and lactate) separately.

Prehospital seizures: Short-term outcomes and risk stratification based in point-of-care testing.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Can specific virtual reality combined with conventional rehabilitation improve poststroke hand motor function? A randomized clinical trial.

TRIAL OBJECTIVE: To verify whether conventional rehabilitation combined with specific virtual reality is more effective than conventional therapy alone in restoring hand motor function and muscle tone after stroke. TRIAL DESIGN: This prospective single-blind randomized controlled trial compared conventional rehabilitation based on physiotherapy and occupational therapy (control group) with the combination of conventional rehabilitation and specific virtual reality technology (experimental group). Participants were allocated to these groups in a ratio of 1:1. The conventional rehabilitation therapists were blinded to the study, but neither the participants nor the therapist who applied the virtual reality-based therapy could be blinded to the intervention. PARTICIPANTS: Forty-six patients (43 of whom completed the intervention period and follow-up evaluation) were recruited from the Neurology and Rehabilitation units of the Hospital General Universitario of Talavera de la Reina, Spain. INTERVENTION: Each participant completed 15 treatment sessions lasting 150 min/session; the sessions took place five consecutive days/week over the course of three weeks. The experimental group received conventional upper-limb strength and motor training (100 min/session) combined with specific virtual reality technology devices (50 min/session); the control group received only conventional training (150 min/session). RESULTS: As measured by the Ashworth Scale, a decrease in wrist muscle tone was observed in both groups (control and experimental), with a notably larger decrease in the experimental group (baseline mean/postintervention mean: 1.22/0.39; difference between baseline and follow-up: 0.78; 95% confidence interval: 0.38-1.18; effect size = 0.206). Fugl-Meyer Assessment scores were observed to increase in both groups, with a notably larger increase in the experimental group (total motor function: effect size = 0.300; mean: - 35.5; 95% confidence interval: - 38.9 to - 32.0; wrist: effect size = 0.290; mean: - 5.6; 95% confidence interval: - 6.4 to - 4.8; hand: effect size = 0.299; mean: - -8.9; 95% confidence interval: - 10.1 to - 7.6). On the Action Research Arm Test, the experimental group quadrupled its score after the combined intervention (effect size = 0.321; mean: - 32.8; 95% confidence interval: - 40.1 to - 25.5). CONCLUSION: The outcomes of the study suggest that conventional rehabilitation combined with a specific virtual reality technology system can be more effective than conventional programs alone in improving hand motor function and voluntary movement and in normalizing muscle tone in subacute stroke patients. With combined treatment, hand and wrist functionality and motion increase; resistance to movement (spasticity) decreases and remains at a reduced level. TRIALS REGISTRY: International Clinical Trials Registry Platform: ISRCTN27760662 (15/06/2020; retrospectively registered).

Changes in the epidemiology of hepatitis A: Clinical and preventive implications. / Cambios en la epidemiología de la hepatitis A: repercusiones clínicas y preventivas.

INTRODUCTION AND OBJECTIVES: Hepatitis A Virus Infection (HAI) has been related to the hygienic-sanitary situation of an area, the changes in the epidemiology of HAI in the province of Guadalajara between 1991 and 2017 are analyzed. MATERIALS AND METHODS: Cases of HAI declared between 1991 and 2017 in Guadalajara were included. The variables analyzed were age, sex, environment, risk factors for HAI and need for hospitalization. The incidence was compared in three periods: 1991-1999, 2000-2008 and 2009-2017. RESULTS: Two hundred and thirty-three cases of HAI were declared, the average incidence rate was 4.27 cases/100,000 inhabitants, highest between 1991 and 1999 (6.93) and lowest between 2009 and 2017 (1.92), with an increment in 2017 (5.5). The median age was 16 years (IR: 8.5-28.5 years), 58.4% were male, and the highest incidence occurred between 5 and 14 years in both sexes. The most frequent risk factors were family and non-family contact and trips to endemic areas (18.6%, 17.3% and 18.2%, respectively). The last risk factor increased after 2000 (P=.001), as did the incidence in urban areas. The MSM group showed an increase in the last period (P<.001). Hospital admissions increased progressively from the first to the third period studied (P=.001). CONCLUSIONS: HAI has a low incidence in our area. More cases related to travel or sexual practices are observed. This should be considered when establishing prevention policies, including vaccination of the most exposed people.

Heart failure in chronic kidney disease: the emerging role of myocardial fibrosis.

Heart failure (HF) is one of the main causes of morbidity and mortality in patients with chronic kidney disease (CKD). Decreased glomerular filtration rate is associated with diffuse deposition of fibrotic tissue in the myocardial interstitium [i.e. myocardial interstitial fibrosis (MIF)] and loss of cardiac function. MIF results from cardiac fibroblast-mediated alterations in the turnover of fibrillary collagen that lead to the excessive synthesis and deposition of collagen fibres. The accumulation of stiff fibrotic tissue alters the mechanical properties of the myocardium, thus contributing to the development of HF. Accumulating evidence suggests that several mechanisms are operative along the different stages of CKD that may converge to alter fibroblasts and collagen turnover in the heart. Therefore, focusing on MIF might enable the identification of fibrosis-related biomarkers and targets that could potentially lead to a new strategy for the prevention and treatment of HF in patients with CKD. This article summarizes current knowledge on the mechanisms and detrimental consequences of MIF in CKD and discusses the validity and usefulness of available biomarkers to recognize the clinical-pathological variability of MIF and track its clinical evolution in CKD patients. Finally, the currently available and potential future therapeutic strategies aimed at personalizing prevention and reversal of MIF in CKD patients, especially those with HF, will be also discussed.

Use of Mobile Applications to Increase Therapeutic Adherence in Adults: A Systematic Review.

Failure to comply with therapeutic treatments implies negative repercussions for the patient's quality of life, their social environment, and health system. The use of information and communication technologies, especially mobile applications, has favored the increase in global therapeutic adherence figures. The objective of this study is to characterize the use of mobile applications as a strategy to increase therapeutic adherence in adults. A systematic literature review in Web of Science and Scopus was performed following the Preferred Information elements for Systematic Reviews and Meta-analysis. Information such as: the year of publication, the study population, the medical conditions of the participants, the main characteristics or functionalities of the mobile applications, and the methods or tools used to measure treatment adherence were extracted from each included article. The risk of bias was assessed. Twelve randomized controlled trials (RCTs), published in English from 1996 to May 2021, were included. Chronic diseases have been mostly addressed through interventions with mobile applications. The most reported functions of mobile applications were reminders, educational modules, two-way communication, and games. Tools such as: "Morisky Medication Adherence Scale of eight items"; "Medication adherence questionnaire"; "Self-reported adherence"; among others, were used to evaluate and report the treatment adherence. In conclusion, including treatment interventions using mobile applications in clinical practice has proven to be beneficial to improve therapeutic adherence. However, it is necessary to develop high-quality clinical trials (size and duration) to generalize results and justify their use in conventional health services.

Lactate improves the predictive ability of the National Early Warning Score 2 in the emergency department.

AIMS: The aim of this study was to compare the ability to predict 2-, 7-, 14-, and 30-day in-hospital mortality of lactate vs the National Early Warning Score 2 (NEWS2) vs the arithmetic sum of the NEWS2 plus the numerical value of lactate (NEWS2-L). METHODS: This was a prospective, multicentric, emergency department delivery, pragmatic cohort study. To determine the predictive capacity of lactate, we calculated the NEWS2 and NEWS2-L in adult patients (aged >18 years) transferred with high priority by ambulance to the emergency department in five hospitals of Castilla y Leon (Spain) between November 1, 2019, and September 30, 2020. The area under the receiver operating characteristic curve of each of the scales was calculated in terms of mortality for every time frame (2, 7, 14, and 30 days). We determined the cut-off point of each scale that offered highest sensitivity and specificity using the Youden index. RESULTS: A total of 1716 participants were included, and the in-hospital mortality rates at 2, 7, 14, and 30 days were of 7.8% (134 cases), 11.6% (200 cases), 14.2% (243 cases), and 17.2% (295 cases), respectively. The best cut-off point determined in the NEWS2 was 6.5 points (sensitivity of 97% and specificity of 59%), and for lactate, the cut-off point was 3.3 mmol/L (sensitivity of 79% and specificity of 72%). Finally, the combined NEWS2-L showed a cut-off point of 11.7 (sensitivity of 86% and a specificity of 85%). The area under the receiver operating characteristic curve of the NEWS2, lactate, and NEWS2-L in the validation cohort for 2-day mortality was 0.889, 0.856, and 0.923, respectively (p<0.001 in all cases). CONCLUSIONS: The new score generated, NEWS2-L, obtained better statistical results than its components (NEWS2 and lactate) separately.

Natural Compound Library Screening Identifies New Molecules for the Treatment of Cardiac Fibrosis and Diastolic Dysfunction.

BACKGROUND: Myocardial fibrosis is a hallmark of cardiac remodeling and functionally involved in heart failure development, a leading cause of deaths worldwide. Clinically, no therapeutic strategy is available that specifically attenuates maladaptive responses of cardiac fibroblasts, the effector cells of fibrosis in the heart. Therefore, our aim was to develop novel antifibrotic therapeutics based on naturally derived substance library screens for the treatment of cardiac fibrosis. METHODS: Antifibrotic drug candidates were identified by functional screening of 480 chemically diverse natural compounds in primary human cardiac fibroblasts, subsequent validation, and mechanistic in vitro and in vivo studies. Hits were analyzed for dose-dependent inhibition of proliferation of human cardiac fibroblasts, modulation of apoptosis, and extracellular matrix expression. In vitro findings were confirmed in vivo with an angiotensin II-mediated murine model of cardiac fibrosis in both preventive and therapeutic settings, as well as in the Dahl salt-sensitive rat model. To investigate the mechanism underlying the antifibrotic potential of the lead compounds, treatment-dependent changes in the noncoding RNAome in primary human cardiac fibroblasts were analyzed by RNA deep sequencing. RESULTS: High-throughput natural compound library screening identified 15 substances with antiproliferative effects in human cardiac fibroblasts. Using multiple in vitro fibrosis assays and stringent selection algorithms, we identified the steroid bufalin (from Chinese toad venom) and the alkaloid lycorine (from Amaryllidaceae species) to be effective antifibrotic molecules both in vitro and in vivo, leading to improvement in diastolic function in 2 hypertension-dependent rodent models of cardiac fibrosis. Administration at effective doses did not change plasma damage markers or the morphology of kidney and liver, providing the first toxicological safety data. Using next-generation sequencing, we identified the conserved microRNA 671-5p and downstream the antifibrotic selenoprotein P1 as common effectors of the antifibrotic compounds. CONCLUSIONS: We identified the molecules bufalin and lycorine as drug candidates for therapeutic applications in cardiac fibrosis and diastolic dysfunction.

Feasibility of a hybrid clinical trial for respiratory virus detection in toddlers during the influenza season.

BACKGROUND: Traditional clinical trials are conducted at investigator sites. Participants must visit healthcare facilities several times for the trial procedures. Decentralized clinical trials offer an interesting alternative. They use telemedicine and other technological solutions (apps, monitoring devices or web platforms) to decrease the number of visits to study sites, minimise the impact on daily routine, and decrease geographical barriers for participants. Not much information is available on the use of decentralization in randomized clinical trials with vaccines. METHODS: A hybrid clinical trial may be assisted by parental recording of symptoms using electronic log diaries in combination with home collected nasal swabs. During two influenza seasons, children aged 12 to 35 months with a history of recurrent acute respiratory infections were recruited in 12 primary health centers of the Valencia Region in Spain. Parents completed a symptom diary through an ad hoc mobile app that subsequently assessed whether it was an acute respiratory infection and requested collection of a nasal swab. Feasibility was measured using the percentage of returned electronic diaries and the validity of nasal swabs collected during the influenza season. Respiratory viruses were detected by real-time PCR. RESULTS: Ninety-nine toddlers were enrolled. Parents completed 10,476 electronic diaries out of the 10,804 requested (97%). The mobile app detected 188 potential acute respiratory infections (ARIs) and requested a nasal swab. In 173 (92%) ARI episodes a swab was taken. 165 (95.4%) of these swabs were collected at home and 144 (87.3%) of them were considered valid for laboratory testing. Overall, 152 (81%) of the ARIs detected in the study had its corresponding valid sample collected. CONCLUSIONS: Hybrid procedures used in this clinical trial with the influenza vaccine in toddlers were considered adequate, as we diagnosed most of the ARI cases on time, and had a valid swab in 81% of the cases. Hybrid clinical trials improve participant adherence to the study procedures and could improve recruitment and quality of life of the participants and the research team by decreasing the number of visits to the investigator site. This report emphasises that the conduct of hybrid CTs is a valid alternative to traditional CTs with vaccines. This hybrid CT achieved high adherence of participant to the study procedures. TRIAL REGISTRATION: 2019-001186-33 (EudraCT).

Effectiveness of virtual reality technology on functional mobility of older adults: systematic review and meta-analysis.

BACKGROUND: The accessibility, versatility and motivation provided by virtual reality technology (VRT) have fostered its rapid expansion as a rehabilitation technique to improve functional mobility. The aim of this study was to investigate the effectiveness of rehabilitation programmes using VRT, specific virtual reality technology (VRT-S) and non-specific virtual reality technology (VRT-NS), to improve functional mobility in individuals aged >60 years versus conventional treatment (CT) or no intervention. METHODS: Nine databases (Cochrane Library, Scopus, PEDro, Medline, CSIC, Web of Science, OT Seeker, NGCH and CINAHL) were searched to identify randomised trials up to December 2019. Results of clinical trials that used VRT-S and VRT-NS in rehabilitation were combined, using a random effects model with inverse variance weighting of the studies. GRADE was used to assess the quality of evidence. The protocol was registered in PROSPERO: CRD42019131630. Overall, there was moderate quality of evidence for the functional mobility results, which means that the estimate of effect is likely to change. RESULTS: Sixteen of the 18 studies selected (n = 568) provided data for the subgroup meta-analysis. VRT-NS was more effective in improving functional mobility than no intervention [standardised mean difference (SMD) = -1.02; 95% confidence interval (CI) -1,91 to -0,14). VRT-NS was also more effective than CT in improving resistance in ambulation (SMD = -1.20; 95% CI -1.93 to 0.46). No significant differences were found between VRT-S and CT or no intervention. Programmes in which >18 sessions were applied were more beneficial (SMD = -0.89; 95% CI -1.71 to -0.08; <0.001) than programmes with ≤18 sessions (SMD = 0.04; 95% CI -0.51 to 0.59) versus no intervention. CONCLUSIONS: Our results suggest that VRT is an effective intervention for improving functional mobility in older persons compared with CT. VRT-NS proved to be more effective than VRT-S. However, these results are still not conclusive due to the low methodological quality of the studies. Thus, new studies and analyses are required.

Electroencephalography as a Non-Invasive Biomarker of Alzheimer's Disease: A Forgotten Candidate to Substitute CSF Molecules?

Biomarkers for disease diagnosis and prognosis are crucial in clinical practice. They should be objective and quantifiable and respond to specific therapeutic interventions. Optimal biomarkers should reflect the underlying process (pathological or not), be reproducible, widely available, and allow measurements repeatedly over time. Ideally, biomarkers should also be non-invasive and cost-effective. This review aims to focus on the usefulness and limitations of electroencephalography (EEG) in the search for Alzheimer's disease (AD) biomarkers. The main aim of this article is to review the evolution of the most used biomarkers in AD and the need for new peripheral and, ideally, non-invasive biomarkers. The characteristics of the EEG as a possible source for biomarkers will be revised, highlighting its advantages compared to the molecular markers available so far.

Evaluation of the anti-inflammatory potential of Solidago microglossa (Arnica-brasileira) in vivo and its effects on PPARγ activity.

Solidago microglossa is used as an anti-inflammatory agent in traditional Brazilian medicine, and this work evaluated the anti-inflammatory potential of the crude ethanolic extract of the flowers of S. microglossa in vivo, as assayed by paw edema models induced by carrageenan, prostaglandin E2, bradykinin and compound 48/80. In the chemical profile, we identified compounds by electrospray ionization mass spectrometry and quantified them by HPLC-DAD. Additionally, this study analyzed the potential to activate the in vitro transcriptional activity of PPARγ, which is a nuclear receptor linked to the anti-inflammatory response. It was possible to identify five compounds: quinic acid, quercetin, chlorogenic acid, hyperoside, and rutin. In the paw edema evaluation, it was possible to show the potential of reducing edema during the inflammatory process. The crude ethanolic extract of the flowers of S. microglossa activated PPARγ compared to the full agonist rosiglitazone and in a dose-response manner. It is possible to conclude that the extract of the flowers of S. microglossa showed anti-inflammatory activity, and the phenolic compounds present in this species might be responsible for this activity.

Metal Oxide Laser Ionization Mass Spectrometry Imaging (MOLI MSI) Using Cerium(IV) Oxide.

Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) is a powerful technique for spatially resolved metabolomics. A variation on MALDI, termed metal oxide laser ionization (MOLI), capitalizes on the unique property of cerium(IV) oxide (CeO2) to induce laser-catalyzed fatty acyl cleavage from lipids and has been utilized for bacterial identification. In this study, we present the development and utilization of CeO2 as an MSI catalyst. The method was developed using a MALDI TOF instrument in negative ion mode, equipped with a high frequency laser. Instrument parameters for MOLI MS fatty acid catalysis with CeO2 were optimized with phospholipid standards and fatty acid catalysis was confirmed using lipid extracts from reference bacterial strains, and sample preparation was optimized using mouse brain tissue. MOLI MSI was applied to the imaging of normal mouse brain revealing differentiable fatty acyl pools in myelinated and nonmyelinated regions. Similarly, MOLI MSI showed distinct fatty acyl composition in tumor regions of a patient derived xenograft mouse model of glioblastoma. To assess the potential of MOLI MSI to detect pathogens directly from tissue, a pseudoinfection model was prepared by spotting Escherichia coli lipid extracts on mouse brain tissue sections and imaged by MOLI MSI. The spotted regions were molecularly resolved from the supporting mouse brain tissue by the diagnostic odd-chained fatty acids and reflected control bacterial MOLI MS signatures. We describe MOLI MSI for the first time and highlight its potential for spatially resolved fatty acyl analysis, characterization of fatty acyl composition in tumors, and its potential for pathogen detection directly from tissue.

Automatic 3D Nonlinear Registration of Mass Spectrometry Imaging and Magnetic Resonance Imaging Data.

Multimodal integration between mass spectrometry imaging (MSI) and radiology-established modalities such as magnetic resonance imaging (MRI) would allow the investigations of key questions in complex biological systems such as the central nervous system. Such integration would provide complementary multiscale data to bridge the gap between molecular and anatomical phenotypes, potentially revealing new insights into molecular mechanisms underlying anatomical pathologies presented on MRI. Automatic coregistration between 3D MSI/MRI is a computationally challenging process due to dimensional complexity, MSI data sparsity, lack of direct spatial-correspondences, and nonlinear tissue deformation. Here, we present a new computational approach based on stochastic neighbor embedding to nonlinearly align 3D MSI to MRI data, identify and reconstruct biologically relevant molecular patterns in 3D, and fuse the MSI datacube to the MRI space. We demonstrate our method using multimodal high-spectral resolution matrix-assisted laser desorption ionization (MALDI) 9.4 T MSI and 7 T in vivo MRI data, acquired from a patient-derived, xenograft mouse brain model of glioblastoma following administration of the EGFR inhibitor drug of Erlotinib. Results show the distribution of some identified molecular ions of the EGFR inhibitor erlotinib, a phosphatidylcholine lipid, and cholesterol, which were reconstructed in 3D and mapped to the MRI space. The registration quality was evaluated on two normal mouse brains using the Dice coefficient for the regions of brainstem, hippocampus, and cortex. The method is generic and can therefore be applied to hyperspectral images from different mass spectrometers and integrated with other established in vivo imaging modalities such as computed tomography (CT) and positron emission tomography (PET).

Association of left atrium voltage amplitude and distribution with the risk of atrial fibrillation recurrence and evolution after pulmonary vein isolation: An ultrahigh-density mapping study.

INTRODUCTION: Ultrahigh-density-voltage mapping (uHDV M) is a new tool that can add new insights into the pathophysiology of atrial fibrillation (AF). The aim of this study was to evaluate the performance of uHDV M in predicting postablation AF recurrence (AFR). METHODS AND RESULTS: We included 98 consecutive patients undergoing pulmonary vein isolation for AF (40.8% persistent) using an uHDV M system and followed for 1 year. The left atrium (LA) mean voltage (Vm ) and the Vslope (slope of the voltage histogram calculated by linear interpolation, with the relative frequency on the vertical axis and the bipolar potential on the horizontal axis) were calculated from 12 567 ± 5486 points per map. Patients with AFR (N = 29) had lower Vm and higher Vslope as compared with patients without AFR (N = 69). Receiver operating characteristic curves identified Vm as the strongest predictor of AFR, with a higher incidence of AFR in patients with Vm 0.758 mV (57.6%) or lower than patients with Vm higher than 0.758 mV (15.4%; P < .0001). Among patients with Vm  higher than 0.758 mV, patients with Vslope 0.637 or higher exhibited higher (P = .043) AFR incidence (31.3%) than patients with Vslope lower than 0.637 (10.2%). This classification showed incremental predictive value over relevant covariables. Vm values were lower and Vslope values were higher in patients that progressed from paroxysmal to persistent AF. Patients with Vslope 0.637 or higher had a 14.2% incidence of postablation atypical atrial flutter, whereas patients with Vslope lower than 0.637 did not present this outcome. CONCLUSIONS: The risk of AFR, atrial flutter, and progression from paroxysmal to persistent AF can be detected by quantitative analysis of LA uHDV M identifying diverse patterns of atrial substrate alterations.

Immunomodulation by adoptive regulatory T-cell transfer improves Coxsackievirus B3-induced myocarditis.

Regulatory T (Treg) cells offer new therapeutic options for controlling undesired systemic and local immune responses. The aim of the current study was to determine the impact of therapeutic Treg administration on systemic and cardiac inflammation and remodeling in coxsackievirus B3 (CVB3) -induced myocarditis. Therefore, syngeneic Treg cells were applied intravenously in CVB3-infected mice 3 d after infection. Compared with CVB3 + PBS mice, CVB3 + Treg mice exhibited lower left ventricular (LV) chemokine expression, accompanied by reduced cardiac presence of proinflammatory Ly6ChighCCR2highCx3Cr1low monocytes and higher retention of proinflammatory Ly6CmidCCR2highCx3Cr1low monocytes in the spleen. In addition, splenic myelopoiesis was reduced in CVB3 + Treg compared with CVB3 + PBS mice. Coculture of Treg cells with splenocytes isolated from mice 3 d post-CVB3 infection further demonstrated the ability of Treg cells to modulate monocyte differentiation in favor of the anti-inflammatory Ly6ClowCCR2lowCx3Cr1high subset. Treg-mediated immunomodulation was paralleled by lower collagen 1 protein expression and decreased levels of soluble and insoluble collagen in LV of CVB3 + Treg compared with CVB3 + PBS mice. In agreement with these findings, LV systolic and diastolic function was improved in CVB3 + Treg mice compared with CVB3 + PBS mice. In summary, adoptive Treg transfer in the inflammatory phase of viral-induced myocarditis protects the heart against inflammatory damage and fibrosis via modulation of monocyte subsets.-Pappritz, K., Savvatis, K., Miteva, K., Kerim, B., Dong, F., Fechner, H., Müller, I., Brandt, C., Lopez, B., González, A., Ravassa, S., Klingel, K., Diez, J., Reinke, P., Volk, H.-D., Van Linthout, S., Tschöpe, C. Immunomodulation by adoptive regulatory T-cell transfer improves Coxsackievirus B3-induced myocarditis.

Decision-making for pediatric allergy immunotherapy for aeroallergens: a narrative review.

There has been exciting progress in diagnosis and in the treatment of allergic patients. The objective of this review is to summarize the most relevant contributions in the past 10 years with a special focus on the pediatric population allergic to aeroallergens and provide the most relevant references and practical issues for the decision-making. Current guidelines on allergy diagnosis recommend a thorough clinical history as the first step, followed by allergen extract testing using an in vivo prick test and/or an in vitro specific IgE test. Molecular diagnosis is recommended when previous tests are inconclusive. In practice, the most important factors to decide the AIT treatment are the actual intensity and duration of the patient's symptoms and the availability of appropriate AIT products for the patient's sensitization profile at high allergen concentrations and with confirmed efficacy and safety from clinical trials. This document summarizes outstanding references for allergic immunotherapy decision-making and provides summary tables and figures analyzing the most important factors related to the decision for allergen immunotherapy and the safety risks related. The experts concluded that AIT is efficacious and safe for the treatment of allergic patients that is available for the most frequent aeroallergens.What is Known:• The prevalence of allergic asthma and rhinitis in children has increased in recent decades.• The efficacy and safety of allergen immunotherapy has been shown in multiple studies and systematic reviews.What is New:• This document summarizes outstanding references for allergic immunotherapy decision-making and provides summary tables and figures analyzing the most important factors related to the decision for allergen immunotherapy and the safety risks related. Recommendations of expert authors for the decision of the patients more suitable for allergen immunotherapy are included.