Hereditary angioedema in Spain: medical care and patient journey.

BACKGROUND: Hereditary angioedema due to C1 inhibitor deficiency (HAE-C1INH) is a genetic rare disease characterized by recurrent, transient and unpredictable episodes of cold, non-pruriginous oedema without associated urticaria. The characteristics of the disease have a considerable impact on the quality of life of patients. The aim of this study was to increase understanding of the patient journey of HAE in Spain. METHODS: A multidisciplinary committee of 16 HAE experts (allergy, immunology, emergency department, hospital pharmacy and nursing) and 3 representatives of the Spanish Hereditary Angioedema Patient Association (AEDAF) who were patients or caregivers participated in the study. A review of the publications on HAE treatment was performed. Semi-structured interviews were performed to HAE experts, patients, or caregivers. Three meetings with the experts, patients and caregivers were held to share, discuss, and validate data obtained from literature and interviews and to build the model. RESULTS: Throughout the project, the patient journey has been drawn up, dividing it into the stages of pre-diagnosis, diagnosis and treatment/follow-up. Some areas for improvement have been identified. Firstly, there is a need to enhance awareness and training on HAE among healthcare professionals, with a particular emphasis on primary care and emergency department personnel. Secondly, efforts should be made to minimize patient referral times to allergy/immunology specialists, ensuring timely access to appropriate care. Thirdly, it is crucial to encourage the study of the relatives of diagnosed patients to early identify potential cases. Fourthly, equitable access to self-administered treatments should be ensured, facilitated by systems that enable medication delivery at home and proper education and training for patients. Equitable access to long-term prophylactic treatment should also be prioritized for all patients in need. To standardize HAE management, the development of consensus guidelines that reduce variability in clinical practice is essential. Lastly, promoting research studies to enhance knowledge of the disease and align its treatment with new developments in the healthcare field should be encouraged. CONCLUSIONS: The knowledge of the patient journey in HAE allowed us to identify improvement areas with the final aim to optimize the disease management.

Effectiveness of an Interactive mHealth App (EVITE) in Improving Lifestyle After a Coronary Event: Randomized Controlled Trial.

BACKGROUND: Coronary heart disease is one of the leading causes of mortality worldwide. Secondary prevention is essential, as it reduces the risk of further coronary events. Mobile health (mHealth) technology could become a useful tool to improve lifestyles. OBJECTIVE: This study aimed to evaluate the effect of an mHealth intervention on people with coronary heart disease who received percutaneous coronary intervention. Improvements in lifestyle regarding diet, physical activity, and smoking; level of knowledge of a healthy lifestyle and the control of cardiovascular risk factors (CVRFs); and therapeutic adherence and quality of life were analyzed. METHODS: This was a randomized controlled trial with a parallel group design assigned 1:1 to either an intervention involving a smartphone app (mHealth group) or to standard health care (control group). The app was used for setting aims, the self-monitoring of lifestyle and CVRFs using measurements and records, educating people with access to information on their screens about healthy lifestyles and adhering to treatment, and giving motivation through feedback about achievements and aspects to improve. Both groups were assessed after 9 months. The primary outcome variables were adherence to the Mediterranean diet, frequency of food consumed, patient-reported physical activity, smoking, knowledge of healthy lifestyles and the control of CVRFs, adherence to treatment, quality of life, well-being, and satisfaction. RESULTS: The study analyzed 128 patients, 67 in the mHealth group and 61 in the control group; most were male (92/128, 71.9%), with a mean age of 59.49 (SD 8.97) years. Significant improvements were observed in the mHealth group compared with the control group regarding adherence to the Mediterranean diet (mean 11.83, SD 1.74 points vs mean 10.14, SD 2.02 points; P<.001), frequency of food consumption, patient-reported physical activity (mean 619.14, SD 318.21 min/week vs mean 471.70, SD 261.43 min/week; P=.007), giving up smoking (25/67, 75% vs 11/61, 42%; P=.01), level of knowledge of healthy lifestyles and the control of CVRFs (mean 118.70, SD 2.65 points vs mean 111.25, SD 9.05 points; P<.001), and the physical component of the quality of life 12-item Short Form survey (SF-12; mean 45.80, SD 10.79 points vs mean 41.40, SD 10.78 points; P=.02). Overall satisfaction was higher in the mHealth group (mean 48.22, SD 3.89 vs mean 46.00, SD 4.82 points; P=.002) and app satisfaction and usability were high (mean 44.38, SD 6.18 out of 50 points and mean 95.22, SD 7.37 out of 100). CONCLUSIONS: The EVITE app was effective in improving the lifestyle of patients in terms of adherence to the Mediterranean diet, frequency of healthy food consumption, physical activity, giving up smoking, knowledge of healthy lifestyles and controlling CVRFs, quality of life, and overall satisfaction. The app satisfaction and usability were excellent. TRIAL REGISTRATION: Clinicaltrials.gov NCT04118504; https://clinicaltrials.gov/study/NCT04118504.

Dual FGFR-targeting and pH-activatable ruthenium-peptide conjugates for targeted therapy of breast cancer.

Dysregulation of Fibroblast Growth Factor Receptors (FGFRs) signaling has been associated with breast cancer, yet employing FGFR-targeted delivery systems to improve the efficacy of cytotoxic agents is still sparsely exploited. Herein, we report four new bi-functional ruthenium-peptide conjugates (RuPCs) with FGFR-targeting and pH-dependent releasing abilities, envisioning the selective delivery of cytotoxic Ru complexes to FGFR(+)-breast cancer cells, and controlled activation at the acidic tumoral microenvironment. The antiproliferative potential of the RuPCs and free Ru complexes was evaluated in four breast cancer cell lines with different FGFR expression levels (SKBR-3, MDA-MB-134-VI, MCF-7, and MDA-MB-231) and in human dermal fibroblasts (HDF), at pH 6.8 and pH 7.4 aimed at mimicking the tumor microenvironment and normal tissues/bloodstream pHs, respectively. The RuPCs showed higher cytotoxicity in cells with higher level of FGFR expression at acidic pH. Additionally, RuPCs showed up to 6-fold higher activity in the FGFR(+) breast cancer lines compared to the normal cell line. The release profile of Ru complexes from RuPCs corroborates the antiproliferative effects observed. Remarkably, the cytotoxicity and releasing ability of RuPCs were shown to be strongly dependent on the conjugation of the peptide position in the Ru complex. Complementary molecular dynamic simulations and computational calculations were performed to help interpret these findings at the molecular level. In summary, we identified a lead bi-functional RuPC that holds strong potential as a FGFR-targeted chemotherapeutic agent.

Impact of mHealth application on adherence to cardiac rehabilitation guidelines after a coronary event: Randomised controlled clinical trial protocol.

Background: Coronary disease is the main cause of death around the world. mHealth technology is considered attractive and promising to promote behavioural changes aimed at healthy lifestyle habits among coronary patients. The purpose of this study is to evaluate the efficacy of an mHealth intervention regarding improved results in secondary prevention in patients after an acute myocardial infarction (AMI) or angina in terms of lifestyle, clinical variables and therapeutic compliance. Methods: Randomised clinical trial with 300 patients who underwent a percutaneous coronary intervention (PCI) with stent implant. They will be assigned to either the mHealth group, subject to a self-monitored educational intervention involving an internet application installed on their mobile phone or tablet, or to a control group receiving standard healthcare (150 patients in each arm). The primary outcome variables will be adherence to the Mediterranean diet, physical activity, smoking, therapeutic compliance, knowledge acquired, user-friendliness and satisfaction with the application. Measurements of blood pressure, heart rate, body weight, waist circumference (WC) and the 6-min walk test will be taken. Furthermore, the blood lipid profile, glucose and HbA1c will be evaluated. Clinical interview will be conducted, and validated questionnaires completed. The primary quantitative results will be compared using an analysis of covariance adjusted for age and sex. A multivariate analysis will be performed to examine the association of the intervention with lifestyle habits, the control of cardiovascular risk factors (CDRFs) and the results after the hospital discharge (major adverse events, treatment compliance and lifestyle). Conclusions: The study will provide evidence about the effectiveness of an mHealth intervention at improving the lifestyle of the participants and could be offered to patients with coronary disease to complement existing services. Trial registration: NCT05247606. [https://ClinicalTrials.gov]. 21/02/2022.

Development of an online calculator for the prediction of seizure freedom following pediatric hemispherectomy using the Hemispherectomy Outcome Prediction Scale (HOPS).

OBJECTIVES: Although hemispheric surgeries are among the most effective procedures for drug-resistant epilepsy (DRE) in the pediatric population, there is a large variability in seizure outcomes at the group level. A recently developed HOPS score provides individualized estimation of likelihood of seizure freedom to complement clinical judgement. The objective of this study was to develop a freely accessible online calculator that accurately predicts the probability of seizure freedom for any patient at 1-, 2-, and 5-years post-hemispherectomy. METHODS: Retrospective data of all pediatric patients with DRE and seizure outcome data from the original Hemispherectomy Outcome Prediction Scale (HOPS) study were included. The primary outcome of interest was time-to-seizure recurrence. A multivariate Cox proportional-hazards regression model was developed to predict the likelihood of post-hemispheric surgery seizure freedom at three time points (1-, 2- and 5- years) based on a combination of variables identified by clinical judgment and inferential statistics predictive of the primary outcome. The final model from this study was encoded in a publicly accessible online calculator on the International Network for Epilepsy Surgery and Treatment (iNEST) website (https://hops-calculator.com/). RESULTS: The selected variables for inclusion in the final model included the five original HOPS variables (age at seizure onset, etiologic substrate, seizure semiology, prior non-hemispheric resective surgery, and contralateral fluorodeoxyglucose-positron emission tomography [FDG-PET] hypometabolism) and three additional variables (age at surgery, history of infantile spasms, and magnetic resonance imaging [MRI] lesion). Predictors of shorter time-to-seizure recurrence included younger age at seizure onset, prior resective surgery, generalized seizure semiology, FDG-PET hypometabolism contralateral to the side of surgery, contralateral MRI lesion, non-lesional MRI, non-stroke etiologies, and a history of infantile spasms. The area under the curve (AUC) of the final model was 73.0%. SIGNIFICANCE: Online calculators are useful, cost-free tools that can assist physicians in risk estimation and inform joint decision-making processes with patients and families, potentially leading to greater satisfaction. Although the HOPS data was validated in the original analysis, the authors encourage external validation of this new calculator.

Added value of corpus callosotomy following vagus nerve stimulation in children with Lennox-Gastaut syndrome: A multicenter, multinational study.

OBJECTIVE: Lennox-Gastaut syndrome (LGS) is a severe form of epileptic encephalopathy, presenting during the first years of life, and is very resistant to treatment. Once medical therapy has failed, palliative surgeries such as vagus nerve stimulation (VNS) or corpus callosotomy (CC) are considered. Although CC is more effective than VNS as the primary neurosurgical treatment for LGS-associated drop attacks, there are limited data regarding the added value of CC following VNS. This study aimed to assess the effectiveness of CC preceded by VNS. METHODS: This multinational, multicenter retrospective study focuses on LGS children who underwent CC before the age of 18 years, following prior VNS, which failed to achieve satisfactory seizure control. Collected data included epilepsy characteristics, surgical details, epilepsy outcomes, and complications. The primary outcome of this study was a 50% reduction in drop attacks. RESULTS: A total of 127 cases were reviewed (80 males). The median age at epilepsy onset was 6 months (interquartile range [IQR] = 3.12-22.75). The median age at VNS surgery was 7 years (IQR = 4-10), and CC was performed at a median age of 11 years (IQR = 8.76-15). The dominant seizure type was drop attacks (tonic or atonic) in 102 patients. Eighty-six patients underwent a single-stage complete CC, and 41 an anterior callosotomy. Ten patients who did not initially have a complete CC underwent a second surgery for completion of CC due to seizure persistence. Overall, there was at least a 50% reduction in drop attacks and other seizures in 83% and 60%, respectively. Permanent morbidity occurred in 1.5%, with no mortality. SIGNIFICANCE: CC is vital in seizure control in children with LGS in whom VNS has failed. Surgical risks are low. A complete CC has a tendency toward better effectiveness than anterior CC for some seizure types.

Validation of the General and Sport Nutrition Knowledge Questionnaire (GeSNK) in Spanish Adolescents.

The General and Sport Nutrition Knowledge Questionnaire (GeSNK) is an instrument that has been developed and validated to assess the level of nutrition knowledge in adolescents and young adults. The aim of the present study was to validate the GeSNK questionnaire in a group of Spanish adolescents in the framework of a Nutrition Education Programme in Secondary Schools in Andalusia, Spain. This cross-sectional questionnaire validation study was developed in two phases: translation-cultural adaptation and validation. A total of 305 adolescents aged 11 to 17 years, studying from the first to the third year of compulsory secondary education, participated on a voluntary basis. The GeSNK questionnaire consists of 62 items: 29 items for the General Nutrition section and 33 items for the Sports Nutrition section. Cronbach's alpha coefficient for the complete questionnaire (GeSNK Total) was: 0.934; for the GeSNK General Nutrition section it was 0.918; and for the GeSNK Sports Nutrition section it was 0.856. The stability measured by the correlation coefficient for the General Nutrition section was 0.406 (p = 0.000); for the Sports Nutrition section it was 0.198 (p = 0.017); and for GeSNK Total the stability was 0.545 (p = 0.000). The questionnaire also demonstrated adequate construct validity. We therefore conclude that the Spanish version of the GeSNK questionnaire is a valid instrument to measure the level of knowledge in general nutrition and sports nutrition in adolescents.

Effectiveness of mHealth Interventions in the Control of Lifestyle and Cardiovascular Risk Factors in Patients After a Coronary Event: Systematic Review and Meta-analysis.

BACKGROUND: Coronary artery disease is the main cause of death and loss of disability-adjusted life years worldwide. Information and communication technology has become an important part of health care systems, including the innovative cardiac rehabilitation services through mobile phone and mobile health (mHealth) interventions. OBJECTIVE: In this study, we aimed to determine the effectiveness of different kinds of mHealth programs in changing lifestyle behavior, promoting adherence to treatment, and controlling modifiable cardiovascular risk factors and psychosocial outcomes in patients who have experienced a coronary event. METHODS: A systematic review of the literature was performed following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. A thorough search of the following biomedical databases was conducted: PubMed, Embase, Web of Science, SciELO, CINAHL, Scopus, The Clinical Trial, and Cochrane. Articles that were randomized clinical trials that involved an intervention consisting of an mHealth program using a mobile app in patients after a coronary event were included. The articles analyzed some of the following variables as outcome variables: changes in lifestyle behavior, cardiovascular risk factors, and anthropometric and psychosocial variables. A meta-analysis of the variables studied was performed with the Cochrane tool. The risk of bias was assessed using the Cochrane Collaboration tool; the quality of the evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation tool; and heterogeneity was measured using the I2 test. RESULTS: A total of 23 articles were included in the review, and 20 (87%) were included in the meta-analysis, with a total sample size of 4535 patients. Exercise capacity measured using the 6-minute walk test (mean difference=21.64, 95% CI 12.72-30.55; P<.001), physical activity (standardized mean difference [SMD]=0.42, 95% CI 0.04-0.81; P=.03), and adherence to treatment (risk difference=0.19, 95% CI 0.11-0.28; P<.001) were significantly superior in the mHealth group. Furthermore, both the physical and mental dimensions of quality of life were better in the mHealth group (SMD=0.26, 95% CI 0.09-0.44; P=.004 and SMD=0.27, 95% CI 0.06-0.47; P=.01, respectively). In addition, hospital readmissions for all causes and cardiovascular causes were statistically higher in the control group than in the mHealth group (SMD=-0.03, 95% CI -0.05 to -0.00; P=.04 vs SMD=-0.04, 95% CI -0.07 to -0.00; P=.05). CONCLUSIONS: mHealth technology has a positive effect on patients who have experienced a coronary event in terms of their exercise capacity, physical activity, adherence to medication, and physical and mental quality of life, as well as readmissions for all causes and cardiovascular causes. TRIAL REGISTRATION: PROSPERO (International Prospective Register of Systematic Reviews) CRD42022299931; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=299931.

Molecular recognition of a membrane-anchored HIV-1 pan-neutralizing epitope.

Antibodies against the carboxy-terminal section of the membrane-proximal external region (C-MPER) of the HIV-1 envelope glycoprotein (Env) are considered as nearly pan-neutralizing. Development of vaccines capable of producing analogous broadly neutralizing antibodies requires deep understanding of the mechanism that underlies C-MPER recognition in membranes. Here, we use the archetypic 10E8 antibody and a variety of biophysical techniques including single-molecule approaches to study the molecular recognition of C-MPER in membrane mimetics. In contrast to the assumption that an interfacial MPER helix embodies the entire C-MPER epitope recognized by 10E8, our data indicate that transmembrane domain (TMD) residues contribute to binding affinity and specificity. Moreover, anchoring to membrane the helical C-MPER epitope through the TMD augments antibody binding affinity and relieves the effects exerted by the interfacial MPER helix on the mechanical stability of the lipid bilayer. These observations support that addition of TMD residues may result in more efficient and stable anti-MPER vaccines.

Examining Topoisomers of a Snake-Venom-Derived Peptide for Improved Antimicrobial and Antitumoral Properties.

Ctn[15-34], the C-terminal section of crotalicidin (Ctn), a cathelicidin from a South American pit viper, is an antimicrobial and antitumoral peptide with remarkably longer stability in human serum than the parent Ctn. In this work, a set of topoisomers of both Ctn and Ctn[15-34], including the retro, enantio, and retroenantio versions, were synthesized and tested to investigate the structural requirements for activity. All topoisomers were as active as the cognate sequences against Gram-negative bacteria and tumor cells while slightly more toxic towards normal cells. More importantly, the enhanced serum stability of the D-amino-acid-containing versions suggests that such topoisomers must be preferentially considered as future antimicrobial and anticancer peptide leads.

Design and Validation of a Scale of Knowledge of Cardiovascular Risk Factors and Lifestyle after Coronary Event.

BACKGROUND: It is important for health professionals to have tools available to assess patients' knowledge of lifestyle and cardiovascular risk factors after they have suffered a coronary event and determine whether educational interventions are effective. This study aims to design and validate a scale to evaluate this knowledge. METHODS: Four-phase instrument design: (A) Conceptual review. (B) Review by experts. (C) Pilot test-retest. (D) Psychometric validation of the final version of the questionnaire with 24 items. A panel of experts performed the content validity. The reliability of the scale was measured using Cronbach's alpha score and criterion validity was evaluated by comparing the total scores for knowledge obtained by the participants among the three education level groups. The construct and dimensional structure validity were assessed using exploratory factor analysis. RESULTS: A total of 143 people participated, 30 in the pilot study and 113 (68% male, 60.2 ± 9 years) in the psychometric validation of version 3 of the scale. A Cronbach's alpha score of 0.887 was reached for this version. The factor analysis showed that the items were distributed into five factors that explained 57% of the variance. Significant differences were observed in the level of knowledge among the patients of the three levels of education (low, moderate and high) (99.20 ± 11.93, 105.92 ± 7.85, 109.78 ± 8.76 points, p = 0.003), as there was a negative correlation between age and knowledge level (r = -0.213, p = 0.024). CONCLUSIONS: The scale presents psychometric properties that are evidence of its reliability and validity. The relationship demonstrated between the level of knowledge and age, sex and level of education shows the importance of emphasizing educational interventions for elderly people and those with a lower level of education.

Structural basis of Nrd1-Nab3 heterodimerization.

Heterodimerization of RNA binding proteins Nrd1 and Nab3 is essential to communicate the RNA recognition in the nascent transcript with the Nrd1 recognition of the Ser5-phosphorylated Rbp1 C-terminal domain in RNA polymerase II. The structure of a Nrd1-Nab3 chimera reveals the basis of heterodimerization, filling a missing gap in knowledge of this system. The free form of the Nrd1 interaction domain of Nab3 (NRID) forms a multi-state three-helix bundle that is clamped in a single conformation upon complex formation with the Nab3 interaction domain of Nrd1 (NAID). The latter domain forms two long helices that wrap around NRID, resulting in an extensive protein-protein interface that would explain the highly favorable free energy of heterodimerization. Mutagenesis of some conserved hydrophobic residues involved in the heterodimerization leads to temperature-sensitive phenotypes, revealing the importance of this interaction in yeast cell fitness. The Nrd1-Nab3 structure resembles the previously reported Rna14/Rna15 heterodimer structure, which is part of the poly(A)-dependent termination pathway, suggesting that both machineries use similar structural solutions despite they share little sequence homology and are potentially evolutionary divergent.

Comparison of the real-world effectiveness of vertical versus lateral functional hemispherotomy techniques for pediatric drug-resistant epilepsy: A post hoc analysis of the HOPS study.

OBJECTIVE: This study was undertaken to determine whether the vertical parasagittal approach or the lateral peri-insular/peri-Sylvian approach to hemispheric surgery is the superior technique in achieving long-term seizure freedom. METHODS: We conducted a post hoc subgroup analysis of the HOPS (Hemispheric Surgery Outcome Prediction Scale) study, an international, multicenter, retrospective cohort study that identified predictors of seizure freedom through logistic regression modeling. Only patients undergoing vertical parasagittal, lateral peri-insular/peri-Sylvian, or lateral trans-Sylvian hemispherotomy were included in this post hoc analysis. Differences in seizure freedom rates were assessed using a time-to-event method and calculated using the Kaplan-Meier survival method. RESULTS: Data for 672 participants across 23 centers were collected on the specific hemispherotomy approach. Of these, 72 (10.7%) underwent vertical parasagittal hemispherotomy and 600 (89.3%) underwent lateral peri-insular/peri-Sylvian or trans-Sylvian hemispherotomy. Seizure freedom was obtained in 62.4% (95% confidence interval [CI] = 53.5%-70.2%) of the entire cohort at 10-year follow-up. Seizure freedom was 88.8% (95% CI = 78.9%-94.3%) at 1-year follow-up and persisted at 85.5% (95% CI = 74.7%-92.0%) across 5- and 10-year follow-up in the vertical subgroup. In contrast, seizure freedom decreased from 89.2% (95% CI = 86.3%-91.5%) at 1-year to 72.1% (95% CI = 66.9%-76.7%) at 5-year to 57.2% (95% CI = 46.6%-66.4%) at 10-year follow-up for the lateral subgroup. Log-rank test found that vertical hemispherotomy was associated with durable seizure-free progression compared to the lateral approach (p = .01). Patients undergoing the lateral hemispherotomy technique had a shorter time-to-seizure recurrence (hazard ratio = 2.56, 95% CI = 1.08-6.04, p = .03) and increased seizure recurrence odds (odds ratio = 3.67, 95% CI = 1.05-12.86, p = .04) compared to those undergoing the vertical hemispherotomy technique. SIGNIFICANCE: This pilot study demonstrated more durable seizure freedom of the vertical technique compared to lateral hemispherotomy techniques. Further studies, such as prospective expertise-based observational studies or a randomized clinical trial, are required to determine whether a vertical approach to hemispheric surgery provides superior long-term seizure outcomes.

Rationally Modified Antimicrobial Peptides from the N-Terminal Domain of Human RNase 3 Show Exceptional Serum Stability.

Multidrug resistance against conventional antibiotics poses an important threat to human health. In this context, antimicrobial peptides (AMPs) have been extensively studied for their antibacterial activity and promising results have been shown so far. However, AMPs tend to be rather vulnerable to protease degradation, which offsets their therapeutic appeal. Here, we demonstrate how replacing functional residues in the antimicrobial region of human RNase 3-also named eosinophil cationic protein-by non-natural amino acids increases stability in human serum. These changes were also shown to reduce the hemolytic effect of the peptides in general terms, whereas the antimicrobial activity was reasonably preserved. Digestion profiles enabled us to design new peptides with superior stability and lower toxicity that could become relevant candidates to reach clinical stages.

Lifestyle and Treatment Adherence Intervention after a Coronary Event Based on an Interactive Web Application (EVITE): Randomized Controlled Clinical Trial Protocol.

Coronary heart disease is one of the main causes of morbimortality around the world. Patients that survive a coronary event suffer a high risk of readmission, relapse and mortality, attributed to the sub-optimal control of cardiovascular risk factors (CVRF), which highlights the need to improve secondary prevention strategies aimed at improving their lifestyle and adherence to treatment. Through a randomized controlled clinical trial, this study aims to evaluate the effect of an intervention involving an online health application supported by a mobile telephone or tablet (mHealth) on lifestyle (diet, physical activity, and tobacco consumption) and treatment adherence among people with coronary heart disease after percutaneous coronary intervention. The sample will comprise 240 subjects (120 in each arm: intervention and usual care). They are assessed immediately and nine months after their hospital discharge about sociodemographic, clinical, CVRF, lifestyle, and treatment adherence characteristics. The educative intervention, involving a follow-up and self-monitoring, will be performed using an online mHealth tool consisting of an application for mobile phones and tablets. The quantitative primary outcomes from the two groups will be compared using an analysis of covariance (ANCOVA) adjusted for age and gender. A multivariate analysis will be performed to examine the association of the intervention with lifestyle habits, the control of CVRFs, and outcomes after discharge in terms of the use of health services, emergency visits, cardiovascular events and readmissions.

Penetrating the Blood-Brain Barrier with New Peptide-Porphyrin Conjugates Having anti-HIV Activity.

Passing through the blood-brain barrier (BBB) to treat neurological conditions is one of the main hurdles in modern medicine. Many drugs with promising in vitro profiles become ineffective in vivo due to BBB restrictive permeability. In particular, this includes drugs such as antiviral porphyrins, with the ability to fight brain-resident viruses causing diseases such as HIV-associated neurocognitive disorders (HAND). In the last two decades, BBB shuttles, particularly peptide-based ones, have shown promise in carrying various payloads across the BBB. Thus, peptide-drug conjugates (PDCs) formed by covalent attachment of a BBB peptide shuttle and an antiviral drug may become key therapeutic tools in treating neurological disorders of viral origin. In this study, we have used various approaches (guanidinium, phosphonium, and carbodiimide-based couplings) for on-resin synthesis of new peptide-porphyrin conjugates (PPCs) with BBB-crossing and potential antiviral activity. After careful fine-tuning of the synthetic chemistry, DIC/oxyma has emerged as a preferred method, by which 14 different PPCs have been made and satisfactorily characterized. The PPCs are prepared by coupling a porphyrin carboxyl group to an amino group (either N-terminal or a Lys side chain) of the peptide shuttle and show effective in vitro BBB translocation ability, low cytotoxicity toward mouse brain endothelial cells, and low hemolytic activity. Three of the PPCs, MP-P5, P4-MP, and P4-L-MP, effectively inhibiting HIV infectivity in vitro, stand out as most promising. Their efficacy against other brain-targeting viruses (Dengue, Zika, and SARS-CoV-2) is currently under evaluation, with preliminary results confirming that PPCs are a promising strategy to treat viral brain infections.

Hemispherectomy Outcome Prediction Scale: Development and validation of a seizure freedom prediction tool.

OBJECTIVE: To develop and validate a model to predict seizure freedom in children undergoing cerebral hemispheric surgery for the treatment of drug-resistant epilepsy. METHODS: We analyzed 1267 hemispheric surgeries performed in pediatric participants across 32 centers and 12 countries to identify predictors of seizure freedom at 3 months after surgery. A multivariate logistic regression model was developed based on 70% of the dataset (training set) and validated on 30% of the dataset (validation set). Missing data were handled using multiple imputation techniques. RESULTS: Overall, 817 of 1237 (66%) hemispheric surgeries led to seizure freedom (median follow-up = 24 months), and 1050 of 1237 (85%) were seizure-free at 12 months after surgery. A simple regression model containing age at seizure onset, presence of generalized seizure semiology, presence of contralateral 18-fluoro-2-deoxyglucose-positron emission tomography hypometabolism, etiologic substrate, and previous nonhemispheric resective surgery is predictive of seizure freedom (area under the curve = .72). A Hemispheric Surgery Outcome Prediction Scale (HOPS) score was devised that can be used to predict seizure freedom. SIGNIFICANCE: Children most likely to benefit from hemispheric surgery can be selected and counseled through the implementation of a scale derived from a multiple regression model. Importantly, children who are unlikely to experience seizure control can be spared from the complications and deficits associated with this surgery. The HOPS score is likely to help physicians in clinical decision-making.

Cognitive and behavioral profiles of pediatric surgical candidates with frontal and temporal lobe epilepsy.

BACKGROUND: We aimed to prospectively analyze memory and executive and social cognitive functioning in patients with drug-resistant frontal lobe epilepsy (FLE) and temporal lobe epilepsy (TLE) with focal lesions and isolate the impact of intellectual ability on specific deficits. METHODS: A neuropsychological evaluation was performed in 23 children with FLE, 22 children with TLE, and 36 healthy pediatric controls (HCs). Patients in the epilepsy groups had a range of lesions, including low-grade epilepsy-associated tumors (LEAT), focal cortical dysplasia (FCD) type II, and mesial temporal sclerosis (MS). RESULTS: There were no significant differences between children with FLE and TLE regarding memory, executive, or social cognitive functioning. General Ability Index (GAI) was a predictor of memory, executive function, and social cognition scores and was influenced by age at onset, duration of epilepsy, and number of antiepileptic drugs (AEDs) prescribed at the time of assessment. Working Memory Index scores of patients with TLE, which measure verbal mnesic processing, were significantly lower than those of HCs and patients with TLE. The greatest differences in both clinical groups compared to HCs were recorded in cognitive executive functions, and patients with FLE had lower scores in this domain. Regarding behavioral executive functions, patients with TLE presented impaired emotional control and impulse inhibition and patients with FLE exhibited decreased flexibility. CONCLUSION: Consistent with previous research, our findings provide further detailed evidence of small differences in cognitive performance among children with FLE and TLE. These differences emerge on analysis of the factors with which deficits are associated.

Properties of virulence emergence of Leishmania infantum isolates from Phlebotomus perniciosus collected during the human leishmaniosis outbreak in Madrid, Spain. Hepatic histopathology and immunological parameters as virulence markers in the mouse model.

Recent anthropic activity related to the construction of the Bosquesur Green Park in a large urban setting in Madrid (Spain) has resulted in the largest reported community outbreak of human leishmaniosis in Europe. Previous phylogenetic and molecular-typing studies of parasite isolates have implicated the Leishmania infantum ITS-Lombardi genotype in this outbreak. In an unusual scenario, visceral leishmaniosis (VL) is affecting a significant number of individuals, suggesting that an increase in parasite virulence has occurred. In this work, using an in vivo BALB/c model of VL, we aimed to investigate the properties of emergent virulence of the L. infantum POL2FL7 and BOS1FL1 isolates obtained from Phlebotomus perniciosus collected in the outbreak area and compare them with those of the well-characterized strain BCN150 MON-1 isolated from a dog. The P. perniciosus specimens were collected during an entomological survey conducted in the transmission season of 2012. We observed a range of virulence phenotypes from moderately to highly aggressive after 5 weeks of infection. IV challenge of mice with outbreak isolates from sand flies induced higher splenic and liver parasite burdens, higher serological titres of specific anti-Leishmania antibodies and impaired capacities to control infection, as revealed by the arginine metabolism and low ratios of Th1/Th2 cytokine profiles analysed, compared with the corresponding measures evaluated in mice infected with the BCN150 strain. The BOS1FL1 isolate showed the highest degree of virulence among the isolates, superior to that of POL2FL7, as evidenced by the analysed biomarkers and the histopathological severity of liver lesions. These results provide insight into how L. infantum isolates from sand flies collected in the outbreak area have been able to affect not only immunosuppressed patients but also middle-aged people with normal immunocompetence in the largest human VL outbreak in Europe.