Large deletions and small insertions and deletions in the factor VIII gene predict unfavorable immune tolerance induction outcome in people with severe hemophilia A and high-responding inhibitors.

INTRODUCTION: Hemophilia A is an inherited bleeding disorder caused by pathogenic variants in the factor VIII gene (F8), which leads to factor VIII (FVIII) deficiency. Immune tolerance induction (ITI) is a therapeutic approach to eradicate alloantibodies (inhibitors) against exogenous FVIII in people with inherited hemophilia A. Few studies have evaluated the role of F8 variants on ITI outcome. MATERIAL AND METHODS: We included people with severe hemophilia A (FVIII ˂ 1 international units/dL) and high-responding inhibitors (≥ 5 Bethesda units/mL lifelong) who underwent a first course of ITI. Socio-demographic, clinical and laboratory data were collected. ITI outcomes were defined as total, partial successes, and failure. Detection of intron 1 and 22 inversions was performed by polymerase-chain reaction, followed by F8 sequencing. RESULTS: We included 168 people with inherited hemophilia A and high-responding inhibitors, median age 6 years at ITI start. Intron 22 inversion was the most prevalent variant (53.6 %), followed by nonsense (16.1 %), small insertion/deletion (11.3 %), and large deletion (10.7 %). In comparison with intron 22 inversion, the odds of ITI failure were 15.5 times higher (odds ratio [OR] 15.50; 95 % confidence interval [95 % CI] 4.59-71.30) and 4.25 times higher (95 % CI, 1.53-12.3) among carriers of F8 large deletions and small insertions and deletions, respectively. CONCLUSION: F8 large deletions and small insertions/deletions predicted ITI failure after a first course of ITI in patients with severe hemophilia A and high-responding inhibitors. This is the first study to show F8 large deletions and small insertions/deletions as predictors of ITI failure.

American registry of ambulatory and acute decompensated heart failure (AMERICCAASS registry): Rationale and design.

AIMS: Heart failure (HF) is a highly prevalent and progressive condition associated with significant morbidity and mortality rates. Acute decompensated HF precipitates millions of hospitalizations each year. Despite therapeutic advances, the overall prognosis of HF is poor. The varying clinical courses and outcomes of patients with this disease may be due to region-specific gaps and since most HF studies are conducted in developed countries, the participation of Latin American and Caribbean countries is low. Considering this, the American Registry of Ambulatory and Acute Decompensated Heart Failure (AMERICCAASS) aims to characterize the population with ambulatory and acute decompensated HF in the American continent and to determine rehospitalization and survival outcomes during the 12 months of follow-up. METHODS AND RESULTS: AMERICCAASS Registry is an observational, prospective, and hospital-based registry recruiting patients with ambulatory or acute decompensated HF. The registry plans to include between two and four institutions per country from at least 20 countries in the Americas, and at least 60 patients recruited from each participant institution regardless of their ambulatory or acutely decompensated condition. Ambulatory patients with confirmed HF diagnosis or inpatients presenting with acute decompensated HF will be included. Follow-up will be performed at 12 months in ambulatory patients or 1, 6, and 12 months after hospital discharge in acutely decompensated HF patients. This ongoing study began on 1 April 2022, with recruitment scheduled to end on 30 November 2023, and follow-up on 31 January 2025. Ethics approval was obtained from the Biomedical Research Ethics Committee of Fundación Valle del Lili. Data collected in the AMERICCAASS registry is being stored on the electronic platform REDCap (Research Electronic Data Capture), which allows different forms for patient groups to enable unbiased analyses. For quantitative variables comparison, we will use the Student's t-test or non-parametric tests accordingly. Categorical variables will be presented as proportions, and groups will be compared with Fisher's exact test. The significance level will be <0.05 for comparisons. Readmissions and post-discharge mortality will be calculated as proportions at 1, 6, and 12 months, with a survival analysis by conditional probability and the Kaplan-Meier method. CONCLUSIONS: AMERICCAASS Registry is intended to be the most important registry of the continent for obtaining important information about demographics, aetiology, co-morbidities, and treatment received, either ambulatory or hospitalized. This registry may contribute to the optimization of national and regional evidence and public policies for the diagnosis and treatment of HF disease.

High levels of anti-factor VIII immunoglobulin G4 and immunoglobulin G total are associated with immune tolerance induction failure in people with congenital hemophilia A and high-responding inhibitors.

Background: Immune tolerance induction (ITI) is the treatment of choice to eradicate neutralizing anti-factor (F)VIII alloantibodies (inhibitors) in people with inherited hemophilia A. However, it is not successful in 10% to 40% of the cases. The biological mechanisms and biomarkers associated with ITI outcome are largely unknown. Objectives: The aim of this study was to investigate the association of plasma cytokines (interferon-γ, tumor necrosis factor, interleukin [IL]-2, IL-4, IL-5, IL-6, IL-10, and IL-17A), chemokines (IL-8/CXCL8, RANTES/CCL5, MIG/CXCL9, MCP-1/CCL2, and IP-10/CXCL10), and anti-FVIII immunoglobulin (Ig) G total, IgG1, and IgG4 with ITI outcome. Methods: In this cross-sectional analysis of the Brazilian Immune Tolerance Study, we assessed plasma levels of anti-FVIII IgGs using an enzyme-linked immunosorbent assay with plasma-derived FVIII and recombinant FVIII as target antigens, immobilized in microplates. Results: We assayed 98 plasma samples of moderately severe and severe (FVIII activity, <2%) people with hemophilia A after completion of a first ITI course. Levels of anti-recombinant FVIII IgG total and IgG4 were higher in people with hemophilia A who failed ITI (IgG total optical density [OD], 0.37; IQR, 0.15-0.73; IgG4 OD, 2.19; IQR, 0.80-2.52) than in those who had partial (IgG total OD, 0.03; IQR, 0.00-0.14; IgG4 OD, 0.39; IQR, 0.09-1.11; P < .0001 for both) or complete success (IgG total OD, 0.04; IQR, 0.00-0.07; IgG4 OD, 0.07; IQR, 0.06-0.40; P < .0001 for both). Plasma cytokines, chemokines, and anti-FVIII IgG1 were not associated with ITI outcome. Conclusion: Our results show that high levels of plasma anti-FVIII IgG4 and IgG total are associated with ITI failure.

Enhancing the Efficiency of Resilient Multipath-Routed Elastic Optical Networks: A Novel Approach for Coexisting Protected and Unprotected Services with Idle Slot Reuse.

In this paper, we investigate a scenario in which protected and unprotected services coexist in an elastic optical network under dynamic traffic. In the investigated scenario, unprotected services can reuse the reserved idle bandwidth to provide protection to the protected services. Under this scenario, we propose a new heuristic algorithm that enables such reuse as well as define and introduce a new assignment problem in elastic optical networks, named a Transmission Spectrum Assignment (T-SA) problem. In this paper, we consider a scenario in which services may be routed using the multipath routing approach. Additionally, protection using bandwidth squeezing is also considered. We assess our proposal through simulations on three different network topologies and compare our proposal against the classical protection approach, in which bandwidth reuse is not allowed. For the simulated range of network loads, the maximum (minimum) blocking probability reduction obtained by our proposal is approximately 48% (10%) in the European topology, 46% (7%) in the NSFNET topology, and 32% (6%) in the German topology.

Prediction of inhibitor development in previously untreated and minimally treated children with severe and moderately severe hemophilia A using a machine-learning network.

BACKGROUND: Prediction of inhibitor development in patients with hemophilia A (HA) remains a challenge. OBJECTIVES: To construct a predictive model for inhibitor development in HA using a network of clinical variables and biomarkers based on the individual similarity network. METHODS: Previously untreated and minimally treated children with severe/moderately severe HA, participants of the HEMFIL Cohort Study, were followed up until reaching 75 exposure days (EDs) without inhibitor (INH-) or upon inhibitor development (INH+). Clinical data and biological samples were collected before the start of factor (F)VIII replacement (T0). A predictive model (HemfilNET) was built to compare the networks and potential global topological differences between INH- and INH+ at T0, considering the network robustness. For validation, the "leave-one-out" cross-validation technique was employed. Accuracy, precision, recall, and F1-score were used as evaluation metrics for the machine-learning model. RESULTS: We included 95 children with HA (CHA), of whom 31 (33%) developed inhibitors. The algorithm, featuring 37 variables, identified distinct patterns of networks at T0 for INH+ and INH-. The accuracy of the model was 74.2% for CHA INH+ and 98.4% for INH-. By focusing the analysis on CHA with high-risk F8 mutations for inhibitor development, the accuracy in identifying CHA INH+ increased to 82.1%. CONCLUSION: Our machine-learning algorithm demonstrated an overall accuracy of 90.5% for predicting inhibitor development in CHA, which further improved when restricting the analysis to CHA with a high-risk F8 genotype. However, our model requires validation in other cohorts. Yet, missing data for some variables hindered more precise predictions.

American Registry of Ambulatory or acutely decompensated heart failure (AMERICCAASS Registry): First 1000 patients.

BACKGROUND: About 80% of cardiovascular diseases (including heart failure [HF]) occur in low-income and developing countries. However, most clinical trials are conducted in developed countries. HYPOTHESIS: The American Registry of Ambulatory or Acutely Decompensated Heart Failure (AMERICCAASS) aims to describe the sociodemographic characteristics of HF, comorbidities, clinical presentation, and pharmacological management of patients with ambulatory or acutely decompensated HF in America. METHODOLOGY: Descriptive, observational, prospective, and multicenter registry, which includes patients >18 years with HF in an outpatient or hospital setting. Collected information is stored in the REDCap electronic platform. Quantitative variables are defined according to the normality of the variable using the Shapiro-Wilk test. RESULTS: This analysis includes data from the first 1000 patients recruited. 63.5% were men, the median age of 66 years (interquartile range 56.7-75.4), and 77.6% of the patients were older than 55 years old. The percentage of use of the four pharmacological pillars at the time of recruitment was 70.7% for beta-blockers (BB), 77.4% for angiotensin-converting enzyme inhibitor (ACEI)/angiotensin II receptor blocker (ARB II)/angiotensin receptor-neprilysin inhibitor (ARNI), 56.8% for mineralocorticoid receptor antagonists (MRA), and 30.7% for sodium-glucose cotransporter type-2 inhibitors (SGLT2i). The main cause of decompensation in hospitalized patients was HF progression (64.4%), and the predominant hemodynamic profile was wet-warm (68.3%). CONCLUSIONS: AMERICCAASS is the first continental registry to include hospitalized or outpatient patients with HF. Regarding optimal medical therapy, approximately a quarter of the patients still need to receive BB and ACEI/ARB/ARNI, less than half do not receive MRA, and more than two-thirds do not receive SGLT2i.

Recomendaciones de terapia Antihipertensiva: la importancia de las combinaciones Avalado por la Sociedad Centroamericana y del Caribe de Cardiología / Antihypertensive therapy recommendations: the importance of combinations Endorsed by the Central American and Caribbean Society of Cardiology

RESUMEN El presente trabajo es el resultado de una iniciativa para analizar, resumir y mostrar la evidencia científica más reciente sobre el tema de la hipertensión y la implementación de las mejores terapéuticas disponibles. Este documento fue creado con la colaboración conjunta de médicos especialistas para dar una perspectiva local a la gestión basada en la mejor evi- dencia científica y en el contexto de la región de Centroamérica y el Caribe. Este artículo cuenta con el respaldo científico y académico de la Sociedad Centroamericana y del Caribe de Cardiología y es el primero de su tipo en abordar el problema y tema de la hipertensión. Se desarrolló a partir de una revisión detallada de la evidencia científica utilizando los principales buscadores médicos, seleccionando los estudios pivotales y poblacionales con mayor nivel de evidencia disponible. La in- tención es brindar información sencilla, con recomendaciones fáciles de implementar en el manejo diario de los pacientes con hipertensión arterial. Este documento contó con el apoyo logístico del Laboratorio Servier, tanto con los autores como en su edición; sin embargo, la información clínica presentada no estuvo condicionada por el laboratorio. Este material es responsabilidad de los autores.

ABSTRACT Antihypertensive therapy recommendations: the importance of combinations Endorsed by the Central American and Caribbean Society of Cardiology The present work is the result of an initiative to analyze, summarize, and show the latest scientific evidence on the subject of hypertension and the implementation of the best available therapeutics. This document was created with the joint collaboration of medical specialists to give a local perspective to the management based on the best scientific evidence and in the context of the Central American and Caribbean region. This paper has the scientific and academic support of the Central American and Caribbean Society of Cardiology and is the first of its kind to address the problem and topic of hypertension. It was developed from a detailed review of the scientific evidence using the main medical search engines, selecting the pivotal and population-based studies with the highest level of evidence available. The intention is to provide simple information, with easy-to-implement recommendations to implement in the daily management of patients with arterial hypertension. This document had the logistic support of Servier Laboratory, both with the authors as well as its editing; however, the clinical information presented was not conditioned by the laboratory. This material is the responsibility of the authors.

A Fragile Image Watermarking Scheme in DWT Domain Using Chaotic Sequences and Error-Correcting Codes.

With the rapid development of digital signal processing tools, image contents can be easily manipulated or maliciously tampered with. Fragile watermarking has been largely used for content authentication purposes. This article presents a new proposal for image fragile watermarking algorithms for tamper detection and image recovery. The watermarked bits are obtained from the parity bits of an error-correcting code whose message is formed from a binary chaotic sequence (generated from a secret key known to all legitimate users) and from bits of the original image. Part of the codeword (the chaotic bits) is perfectly known to these users during the extraction phase, adding security and robustness to the watermarking method. The watermarked bits are inserted at specific sub-bands of the discrete wavelet transform of the original image and are used as authentication bits for the tamper detection process. The imperceptibility, detection, and recovery of this algorithm are tested for various common attacks over digital images. The proposed algorithm is analyzed for both grayscale and colored images. Comparison results reveal that the proposed technique performs better than some existing methods.

Efficacy of lotilaner against myiasis caused by Cochliomyia hominivorax (Diptera: Calliphoridae) in naturally infested dogs.

BACKGROUND: The New World screwworm fly, Cochliomyia hominivorax, is widely distributed across South America. This parasitic insect is a significant cause of primary myiasis in animals, including dogs. There is an urgent need for a rapid and efficient treatment to improve the recovery of affected animals. In the present study we evaluated the potential of lotilaner for the treatment of myiasis caused by C. hominivorax larvae in naturally infested dogs. Lotilaner belongs to the isoxazoline class of chemical compounds and is marketed as Credelio™ for use against ticks and fleas in dogs and cats. METHODS: Eleven dogs with naturally acquired myiasis were enrolled in this study based on the severity of lesions and the number of identified larvae. All animals received a single oral administration of lotilaner at a minimum dose of 20.5 mg/kg body weight. After treatment, the number of expelled larvae, live or dead, was determined at 2, 6 and 24 h, and the larval expulsion rate, larvicidal effect and overall efficacy were calculated. After 24 h, the remaining larvae were removed, counted and identified. The lesions were cleaned, and palliative treatment was administered when necessary, according to the animal's health status. RESULTS: All larvae were identified as C. hominivorax. The larval expulsion rate was 80.5% and 93.0% at 2 and 6 h post-treatment, respectively. Lotilaner showed an overall efficacy of 100% at 24 h post-treatment. CONCLUSIONS: Lotilaner demonstrated a rapid onset of action and a high efficacy against C. hominivorax. We therefore recommend lotilaner for the effective treatment of myiasis in dogs.

Gummies candy enriched with Konjac glucomannan reduces hunger intensity and waist circumference of overweight individuals.

Konjac glucomannan (KGM) is a herbal medicine with benefits in appetite control, body weight and biochemical parameters in overweight individuals. The objective of our work was to evaluate the effect of the consumption of gummy candy enriched with KGM on appetite, to evaluate anthropometric data, biochemical and oxidative stress markers in overweight individuals. Forty-two participants aged 18 to 45 years completed our randomized, double-blind, placebo-controlled clinical trial. Participants were randomly assigned to consume for fourteen days, 2 candies per day, containing 250 mg of KGM or identical-looking placebo candy with 250 mg of flaxseed meal, shortly after breakfast and dinner. As a result, we observed that there was a reduction in waist circumference and in the intensity of hunger/satisfaction of the participants who consumed KGM for fourteen days, and we believe that a longer consumption time as well as an increase dose of KGM contribute to even more satisfactory body results.

Phenotypic variation in severe hemophilia A is related to endogenous thrombin potential and plasma levels of factor VII.

Hemophilia A is a bleeding disorder caused by deficiency or low activity of circulating factor VIII characterized by prolonged blood coagulation time and often spontaneous bleeding. Patients with the severe form of the disease may present considerable heterogeneity in the occurrence of bleeding episodes and some of them have a mild hemophilia A phenotype. This study aimed to evaluate the association of biomarkers and coagulation parameters to the differential hemorrhagic profile of severe hemophilia A patients. Polymorphisms in the genes of proteins C and S, factors V and VII and prothrombin were evaluated in a group of severe hemophilia A patients with a broad spectrum of bleeding profile. Plasma levels of coagulation factors and thrombin generation were also analyzed. This study included 59 Brazilian hemophilia A patients who were allocated into low bleeding profile (LBP; n = 33) and high bleeding profile (HBP; n = 26) groups based on their joint and muscle bleeding episodes requiring treatment in the 5 years before inclusion in the study. Results evidenced that endogenous thrombin potential (ETP) and plasma factor VII levels were significantly higher in the LBP group. Results indicate a prominent importance of FVII plasma activity and endogenous thrombin potential on the differential bleeding phenotype of hemophilia A patients.

A potent inflammatory response is triggered in asymptomatic blood donors with recent SARS-CoV-2 infection.

BACKGROUND: The inflammatory response plays a significant role in the outcome of coronavirus disease (COVID-19). METHODS: We investigated plasma cytokine and chemokine concentrations in non-infected (NI), asymptomatic severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2)-infected blood donors (AS), and patients with severe COVID-19 (SC). RESULTS: The SC group showed significantly higher levels of interleukin 6 (IL-6), IL-10, and CCL5 than the AS and NI groups. The SC and AS groups had considerably greater CXCL9 and CXCL10 concentrations than the NI group. Only NI and infected people showed separate clusters in the principal component analysis. CONCLUSIONS: SC, as well as AS was characterized by an inflammatory profile.

Impact of COVID-19 on the efficacy of meeting the transfusion demand by a Brazilian blood banks network.

One of the effects of the pandemic in the hemotherapy services was the reduction in the attendance of blood donors and production of blood components. It is relevant to investigate how the capacity to meet the demand for blood components was affected, especially in blood centers located in the regions most affected by the pandemic, such as Brazil. This study aimed to describe the impact of the pandemic on the capacity to meet the demand for different types of blood components by a Brazilian blood center in 2020, compared to the historical series of 2016-2019 and to discuss the measures adopted to mitigate the effects of the pandemic. Retrospective cross-sectional study was carried out with comparative analysis of the blood components requested and attended in the period from 2016 to 2020. Data analysis was performed by Graphpad Prism 5. The spread of COVID-19 cases since March 2020 had impact on the blood components production and transfusions. The reduction in the production of blood components was observed prior to the restriction measures, in March 2020. In comparison to 2016-2019, there was a reduction in the number of transfusions performed in all months of 2020. The results suggest that the measures adopted in a Brazilian blood center to face the COVID-19 pandemic resulted in reasonable regularity in the supply of blood components. The sharing of experiences between blood banks in different regions, social and epidemiological contexts can contribute to the improvement of strategies to reduce the impact of COVID-19 in transfusion medicine.

Pro-inflammatory immune profile mediated by TNF and IFN-γ and regulated by IL-10 is associated to IgG anti-SARS-CoV-2 in asymptomatic blood donors.

The SARS-CoV-2 virus has infected and killed millions of people, but little is known about the risk factors that lead to the development of severe, mild or asymptomatic conditions after infection. The individual immune response and the balance of cytokines and chemokines have been shown to be important for the prognosis of patients. Additionally, it is essential to understand how the production of specific antibodies with viral neutralizing capacity is established. In this context, this study aimed to identify positive individuals for IgG anti-SARS-CoV-2 in a large population of blood donors (n = 7837) to establish their immune response profile and to evaluate its viral neutralization capacity. The prevalence found for IgG anti-SARS-CoV-2 was 5.6% (n = 441), with male blood donors (61.9%) being more prevalent among the positive ones. The results showed that positive individuals for IgG anti-SARS-CoV-2 have high serum concentrations of chemokines, TNF, IFN-γ and IL-10. The analyses showed that the positivity index for IgG anti-SARS-CoV-2 is associated with the neutralizing capacity of the antibodies, which, in turn, is significantly related to lower serum concentrations of CCL5 and CXCL10. The results allow us to hypothesize that the development and maintenance of IgG anti-SARS-CoV-2 antibodies in infected individuals occurs in a pro-inflammatory microenvironment well regulated by IL-10 with great capacity for recruiting cells from the innate and adaptive immune systems.

SARS-CoV-2 IgG Seroprevalence among Blood Donors as a Monitor of the COVID-19 Epidemic, Brazil.

During epidemics, data from different sources can provide information on varying aspects of the epidemic process. Serology-based epidemiologic surveys could be used to compose a consistent epidemic scenario. We assessed the seroprevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) IgG in serum samples collected from 7,837 blood donors in 7 cities of Brazil during March-December 2020. Based on our results, we propose a modification in a compartmental model that uses reported number of SARS-CoV-2 cases and serology results from blood donors as inputs and delivers estimates of hidden variables, such as daily values of SARS-CoV-2 transmission rates and cumulative incidence rate of reported and unreported SARS-CoV-2 cases. We concluded that the information about cumulative incidence of a disease in a city's population can be obtained by testing serum samples collected from blood donors. Our proposed method also can be extended to surveillance of other infectious diseases.

Gender-related Differences in the Impact of COVID-19 Pandemic in Cardiometabolic Patients in Latin America: The CorCOVID LATAM Gender Sub-study.

COVID-19 pandemic and lockdown measures have disrupted lifestyle habits and self-care. Gender differences in health behavior during the pandemic have not yet been fully elucidated. The aim of this study was to evaluate gender related differences in the impact of COVID-19 pandemic on patients with cardiometabolic diseases. A cross-sectional survey was administered to cardiometabolic patients in 13 Latin American countries between June 15th and July 15th, 2020. The study included 4216 participants, of which 2147 (50.9%) were women. Women reported healthier eating habits as well as lower tobacco and alcohol consumption than men but exercised less and reported increased symptoms of depression. Low income and symptoms of depression were associated with sedentarism in women. The interplay between psychological factors and sedentarism could increase the risk of cardiovascular events in this population.

HCV infection in hemophilia A patients is associated with altered cytokines and chemokines profile and might modulate the levels of FVIII inhibitor.

Prevalence of hepatitis C virus (HCV) is high in hemophilia A patients and the development of FVIII inhibitor is another challenge in the management of these individuals. The influence of HCV infection in the occurrence of inhibitors was investigated by the comparison of clinical and laboratory data from noninfected (NI, n = 96) and chronically HCV-infected (HCV, n = 58) hemophilia A patients. Concentrations of plasmatic cytokines (IL-2, IL-4, IL-6, IL-10, TNF, IFN-γ, and IL-17A) and chemokines (CCL2, CCL5, CXCL8, CXCL9, and CXCL10) were quantified from patients' samples. The results showed that older age, use of cryoprecipitate and fresh frozen plasma, and severe hemophilia were associated with HCV infection, whereas exclusive use of virus inactivated clotting factors was a protector factor to acquiring HCV infection. HCV infection was strongly associated with low levels of inhibitor (OR = 20.53, p < 0.001). Patients with a history of inhibitor (INB+) presented a mixed immune profile characterized by higher levels of pro-and anti-inflammatory cytokines than those without a history of inhibitor (INB-). The highest levels of CCL2 and CXCL8 were seen in HCVINB- , whereas CXCL9 and CXCL10 in HCVINB+ . Heatmap analysis of the set of cytokines and chemokines concentration distributed HCV patients into two distinct clusters, HCVINB+ and HCVINB- , both characterized by low concentrations of IL-4, while noninfected patients were grouped in a single block regardless of inhibitor development history (NIINB-/INB+ ). This finding suggests that the strong association between HCV infection and low levels of factor VIII inhibitors might be due to the modulation of the cytokine and chemokine network established by the antiviral response.