Indeterminate Form Research Articles

Disulfiram repurposing in the combined chemotherapy of Chagas disease

Abstract Background: Chagas disease (CD) has high morbimortality and the available trypanocidal treatment, including benznidazole (BZ), has limited efficacy in chronic patients. Furthermore, BZ causes adverse effects (AE) that prevent treatment completion in up to 30% of patients. The use of repositioned drugs or drug combination may provide an effective trypanocidal treatment. Disulfiram (DF) may enhance BZ activity and decrease BZ related AE. This study aims to assess the safety of a new combination of drugs for CD therapy, assuming BZ as the drug of choice plus DF as repositioned drug. Methods: This single-centre, open-label, phase I/II clinical trial was designed to evaluate the safety of the combined use of BZ plus DF for CD therapy. Participants are adults with indeterminate form of chronic CD, both sexes, aged from 18 to 70 years old and Trypanosoma cruzi polymerase chain reaction-positive. The primary outcome will be the occurrence of serious AE. The secondary outcome will be post-treatment Trypanosoma cruzi polymerase chain reaction negativization. Six groups of 9 patients will be sequentially tested. The first group will be allocated to receive BZ 100 mg/d + DF 250 mg/d for 60 days. Upon safety confirmation (<1/3 of participants with serious AE), the combination dose will be gradually increased and dispensed to 5 groups (group II:BZ 200 mg/day+DF 250 mg/d; group III:BZ 300 mg/d + DF 250 mg/d; group IV:BZ 100 mg/d + DF 500 mg/d; group V:BZ 200 mg/d + DF 500 mg/d; group VI: BZ 300 mg/d + DF 500 mg/d) for 60 days in order to determine the maximum tolerated dose. Discussion: Our hypothesis is that the drug combination will be well tolerated and allow the proposal of phase II trials in larger scale to test the efficacy of the new drug combination in CD. We expect that the studied combination will have less AEs with an efficacy similar or superior to the current treatment. This will allow the successful treatment of a greater number of patients while decreasing the treatment cost as less patients will need treatment for AEs. Trial registration: This study was registered on the Brazilian Clinical Trials Database - REBEC (RBR-5n4htp). Registered 7 January 2020. UTN Number: U1111-1246-1293. http://www.ensaiosclinicos.gov.br/rg/RBR-5n4htp/

IgG Subclass Analysis in Patients with Chagas Disease 4Years After Benznidazole Treatment.

In humans, Trypanosoma cruzi infection is controlled by a complex immune response. Immunoglobulin G (IgG) is important for opsonizing blood trypomastigotes, activating the classic complement pathway, and reducing parasitemia. The trypanocidal activity of benznidazole is recognized, but its effects on the prevention and progression of Chagas disease is not well understood OBJECTIVE: We aimed to evaluate the levels of total IgG and cross-specific IgG subclasses in patients with chronic Chagas disease of different clinical forms before and after 4years of benznidazole treatment. Eight individuals with the indeterminate form and nine with the cardiac form who completed the treatment protocol were evaluated. The levels of total IgG and IgG1, IgG2, IgG3, and IgG4 isotypes were quantified in the serum of each individual using the fluorescent immunosorbent assay. The results are expressed as relative fluorescence unit. Patients with chronic Chagas disease presented decreased levels of total IgG at 48months after benznidazole treatment. Increased IgG1 and decreased IgG3 levels were observed in patients with the cardiac form and those with exacerbated clinical forms. In addition, a decrease in the IgG3/IgG1 ratio was observed in individuals with the cardiac form of Chagas disease. Benznidazole administration in the chronic phase differentially changes IgG subclasses in patients with cardiac and indeterminate forms, and monitoring the IgG3 level may indicate the possible prognosis to the cardiac form or worsening of the already established clinical form.

Intra-Discrete Typing Unit TcV Genetic Variability of Trypanosoma cruzi in Chronic Chagas' Disease Bolivian Immigrant Patients in Barcelona, Spain.

Background: Trypanosoma cruzi has a high rate of biological and genetic variability, and its population structure is divided into seven distinct genetic groups (TcI-TcVI and Tcbat). Due to immigration, Chagas disease (ChD), caused by T. cruzi, has become a serious global health problem including in Europe. Therefore, the aim of this study was to evaluate the existence of genetic variability within discrete typing unit (DTU) TcV of T. cruzi in Bolivian patients with chronic ChD residing in Barcelona, Spain.Methods: The DNA was extracted from the peripheral blood of 27 patients infected with T. cruzi DTU TcV and the fragments of the genetic material were amplificated through the low stringency single primer-polymerase chain reaction (LSSP-PCR). The data generated after amplification were submitted to bioinformatics analysis.Results: Of the 27 patients evaluated in the study, 8/27 (29.6%) were male and 19/27 (70.4%) female, 17/27 (62.9%) were previously classified with the indeterminate clinical form of Chagas disease and 10/27 (37.1%) with Chagas cardiomyopathy. The LSSP-PCR detected 432 band fragments from 80 to 1,500 bp. The unweighted pair-group method analysis and principal coordinated analysis data demonstrated the existence of three distinct genetic groups with moderate-high rates of intraspecific genetic variability/diversity that had shared parasite's alleles in patients with the indeterminate and cardiomyopathy forms of ChD.Conclusions: This study demonstrated the existence of a moderate to high rate of intra-DTU TcV variability in T. cruzi. Certain alleles of the parasite were associated with the absence of clinical manifestations in patients harboring the indeterminate form of ChD. These results support the need to search for increasingly specific targets in the genome of T. cruzi to be correlated with its main biological properties and clinical features in patients with chronic ChD.

Prediction of echocardiographic parameters in Chagas disease using heart rate variability and machine learning

ObjectiveInvestigate whether heart rate variability (HRV) indices can be used to predict morpho-functional parameters obtained from the echocardiogram in a population of patients with Chagas disease (CD). MethodsSixty-three patients with CD and a recent echocardiogram had their ECG and respiratory signals recorded for 15 min. The cardiac interval series were generated from the ECG and 27 HRV indices, plus the respiratory frequency, were calculated. The correlation between HRV and echocardiographic variables was estimated. The HRV indices were also utilized as inputs in four machine learning schemes to create predictive models for numeric and categorical echocardiographic parameters. Attribute selection schemes were also performed to identify the subset of HRV indices that best represent each parameter for each machine learning algorithm. ResultsOnly three echocardiographic parameters had no HRV index significantly correlated to them. The most frequently selected HRV index in the attribute selection process was the fractal short-term scaling exponent. The regression models (numeric parameters) reached reasonable performance (R > 0.5) for all except two parameters, while the classification models (categorical variables) achieved better performance, with precision and recall values higher than 0.74. ConclusionHRV indices, both isolated and combined, are associated with cardiac morpho-functional properties in patients with CD, and may be used to predict echocardiographic parameters. SignificanceThe possibility of modeling the cardiac morpho-functional parameters in patients with CD using HRV indices opens the possibility to use HRV for risk assessment in patients with CD, especially those harboring the indeterminate form of the disease.

Phototransferred thermoluminescence of tanzanite: A matrix-based analysis of time-response profiles and competition effects

We report the phototransferred thermoluminescence of tanzanite induced by 470 nm blue light. A glow curve measured after irradiation to 120 Gy and heating at 1 °C s−1 shows three nominal peaks at 86 °C (peak I) and two secondary peaks at 160 °C and 320 °C. The latter two peaks are collocated peaks with each one consisting of multiple components. Phototransferred thermoluminescence is only reproduced at peak I. Although this work addresses phototransfer, the system studied is unconventional in that the phototransferred TL is associated with an indeterminate number of donors. A matrix-based method has been used to analyse the time-response profiles of the phototransferred thermoluminescence. Competition effects, where putative donor electron traps act in competition with acceptor electron traps, have been studied using empirical models.

A proportion of CD4+ T cells from patients with chronic Chagas disease undergo a dysfunctional process, which is partially reversed by benznidazole treatment

Signs of senescence and the late stages of differentiation associated with the more severe forms of Chagas disease have been described in the Trypanosoma cruzi antigen-specific CD4+ T-cell population. However, the mechanisms involved in these functions are not fully known. To date, little is known about the possible impact of benznidazole treatment on the T. cruzi-specific functional response of CD4+ T cells. The functional capacity of CD4+ T cells was analyzed by cytometric assays in chronic Chagas disease patients, with indeterminate form (IND) and cardiac alterations (CCC) (25 and 15, respectively) before and after benznidazole treatment. An increase in the multifunctional capacity (expression of IFN-γ, IL-2, TNF-α, perforin and/or granzyme B) of the antigen-specific CD4+ T cells was observed in indeterminate versus cardiac patients, which was associated with the reduced coexpression of inhibitory receptors (2B4, CD160, CTLA-4, PD-1 and/or TIM-3). The functional profile of these cells shows statistically significant differences between IND and CCC (p<0.001), with a higher proportion of CD4+ T cells coexpressing 2 and 3 molecules in IND (54.4% versus 23.1% and 4.1% versus 2.4%, respectively). A significant decrease in the frequencies of CD4+ T cells that coexpress 2, 3 and 4 inhibitory receptors was observed in IND after 24-48 months of treatment (p<0.05, p<0.01 and p<0.05, respectively), which was associated with an increase in antigen-specific multifunctional activity. The IND group showed, at 9-12 months after treatment, an increase in the CD4+ T cell subset coproducing three molecules, which were mainly granzyme B+, perforin+ and IFN-γ+ (1.4% versus 4.5%). A CD4+ T cell dysfunctional process was detected in chronic Chagas disease patients, being more exacerbated in those patients with cardiac symptoms. After short-term benznidazole treatment (9-12 months), indeterminate patients showed a significant increase in the frequency of multifunctional antigen-specific CD4+ T cells.

Neutrophils from patients with the cardiac clinical form of Chagas disease release less NETs than neutrophils from healthy individuals

Chagas disease (CD) is a global health concern with approximately 12000 deaths per year worldwide. In the chronic phase, about 30% of patients develop the cardiac clinical form, which presents symptoms associated with the presence of inflammatory cells in the cardiac tissue. Neutrophils are inflammatory cells able to modulate the chronic immune response against pathogens. These cells are capable of interacting with Trypanosoma cruzi, the aetiological agent of CD, and perform several effector functions, such as NET release. However, few studies have been carried out to investigate the role of these cells in the disease. To investigate the release of NETs by neutrophils from CD patients by measuring the amount of DNA and elastase released. Measurement of DNA release by neutrophils from chronic CD patients presenting the indeterminate (IND group; n=18) and cardiac (CARD group; n=15) clinical forms and nonchagasic subjects (n=18) stimulated with soluble antigen of T.cruzi was quantified using the Quant-iT™ PicoGreen® dsDNA assay kit. Patients from CARD group release less DNA (117.3±21.85ng/mL; *P=.0131) than neutrophils from control (177.7±58.41ng/mL). Elastase enzyme degranulation was measured using the substrate N-methoxysuccinyl-Ala-Ala-Pro-Val p-nitroanilide (SAAVNA). Absorbance values of elastase degranulation activity showed that only cells from healthy individuals presented a high release profile of elastase. Also, we found a negative correlation between DNA released concentration and risk of death (r=-.6574; *P=.0173); the lower the neutrophil DNA release from chagasic patients with cardiac event, the higher the risk of death. These preliminary data show that patients with the cardiac form of CD release less NETs than nonchagasic individuals, raising the possibility that lower release of NETs enhances risk of death in CD patients with cardiac events.

Factors related to the discontinuation and mortality rates of a cardiac rehabilitation programme in patients with Chagas disease: a 6-year experience in a Brazilian tertiary centre.

To describe the clinical and sociodemographic characteristics of participants as well as discontinuation and mortality rates in a cardiac rehabilitation programme (CRP) tailored to Chagas disease (CD). Participants underwent functional capacity, anthropometry and cardiac function evaluations before beginning a CRP. Univariate and multivariate Cox proportional hazards models were performed to investigate the associations between clinical and sociodemographic characteristics at baseline with discontinuation rates and deaths. Forty-two patients were enrolled in the CRP (61.9% men, mean age of 58.1±11.8years). During a median follow-up period of 10.8months, 74% discontinued and 14% died while enrolled in CRP. 34% of the patients who discontinued CRP died during follow-up. White race (HR=0.09; 95% CI 0.01-1.00), right ventricular systolic dysfunction (HR=10.54; 95% CI 1.24-89.50) and oxygen pulse (HR=0.69; 95% CI 0.48-0.99) were independently associated with death while enrolled in CRP. Married status (HR=0.44; 95% CI 0.21-0.95) was independently associated with discontinuation rates from CRP. VO2 peak (HR=0.85; 95% CI 0.74-0.98) and CRP discontinuation due to CD-related reasons (HR=8.33; 95% CI 1.91-36.27) were the variables independently associated with death after discontinuation of CRP. In this population, sociodemographic aspects and severity of CD were important determinants of CRP discontinuation and mortality.

Indeterminate form of Chagas disease: historical, conceptual, clinical, and prognostic aspects

Chagas disease (CD) remains a serious endemic disease in Latin America and a major public health problem. Because of globalization, the disease has spread to non-endemic areas in the northern hemisphere. In the chronic phase of the disease, most patients present with the indeterminate form (IF), characterized by positive serology for Trypanosoma cruzi, absence of clinical findings, and normal findings in electrocardiogram (ECG). IF was not recognized as a clinical entity until decades after the discovery of the disease, and only in the 1940-50s, it was categorized as a form of CD, and its conceptual definition was ratified in the 1980s. Children, adolescents, and young adults with the IF benefit from etiological treatment and tend to have less progression to heart disease in the long term than the untreated ones. IF patients have an essentially benign clinical condition, and their prognosis can be compared to that of healthy individuals with normal ECG findings. Currently, because of aging, patients with the IF have comorbidities that require attention in health services.

Temporal changes in the clinical-epidemiological profile of patients with Chagas disease at a referral center in Brazil.

INTRODUCTION We aimed to describe the sociodemographic, epidemiological, and clinical characteristics of patients with chronic Chagas disease (CD) at an infectious disease referral center. Changes in patient profiles over time were also evaluated. METHODS This retrospective study included patients with CD from November 1986-December 2019. All patients underwent an evaluation protocol that included sociodemographic profile; epidemiological history; anamnesis; and physical, cardiologic, and digestive examinations. Trend differences for each 5-year period from 1986 to 2019 were tested using a nonparametric trend test for continuous and generalized linear models with binomial distribution for categorical variables. RESULTS A total of 2,168 patients (52.2% women) were included, with a mean age of 47.8 years old. White patients with low levels of education predominated. The reported transmission mode was vectorial in 90.2% of cases. The majority came from areas with a high prevalence (52.2%) and morbidity (67.8%) of CD. The most common clinical presentation was the indeterminate form (44.9%). The number of patients referred gradually decreased and the age at admission increased during the study period, as did the patients’ levels of education. CONCLUSIONS The clinical profile of CD is characterized by a predominance of the indeterminate form of the disease. Regarding the patients who were followed up at the referral center, there was a progressive increase in the mean age and a concomitant decrease in the number of new patients. This reflects the successful control of vector and transfusion transmission in Brazil as well as the aging population of patients with CD.

Weighted Parameterized Correlation Coefficients of Indeterminacy Fuzzy Multisets and Their Multicriteria Group Decision Making Method with Different Decision Risks

Real-life data introduce noise, uncertainty, and imprecision to statistical projects; it is advantageous to consider strategies to overcome these information expressions and processing problems. Neutrosophic (indeterminate) numbers can flexibly and conveniently represent the hybrid information of the partial determinacy and partial indeterminacy in an indeterminate setting, while a fuzzy multiset is a vital mathematical tool in the expression and processing of multi-valued fuzzy information with different and/or same fuzzy values. If neutrosophic numbers are introduced into fuzzy sequences in a fuzzy multiset, the introduced neutrosophic number sequences can be constructed as the neutrosophic number multiset or indeterminate fuzzy multiset. Motivated based on the idea, this study first proposes an indeterminate fuzzy multiset, where each element in a universe set can be repeated more than once with the different and/or identical indeterminate membership values. Then, we propose the parameterized correlation coefficients of indeterminate fuzzy multisets based on the de-neutrosophication of transforming indeterminate fuzzy multisets into the parameterized fuzzy multisets by a parameter (the parameterized de-neutrosophication method). Since indeterminate decision-making issues need to be handled by an indeterminate decision-making method, a group decision-making method using the weighted parameterized correlation coefficients of indeterminate fuzzy multisets is developed along with decision makers’ different decision risks (small, moderate, and large risks) so as to handle multicriteria group decision-making problems in indeterminate fuzzy multiset setting. Finally, the developed group decision-making approach is used in an example on a selection problem of slope design schemes for an open-pit mine to demonstrate its usability and flexibility in the indeterminate group decision-making problem with indeterminate fuzzy multisets.

Training of legal specialists in the context of development of collective forms of judicial remedy

Introduction. One of the collective forms of judicial remedy is a class action. The institution of a class action is a new one for the Russian legal system. Nevertheless, in foreign jurisdictions it has proven as an effective remedy for large groups of persons, providing a higher level of access to judicial protection. At the moment, this institute is only just beginning to develop and being actively used. In this connection, not only issues of scientific understanding of this institute are becoming relevant, but also training of lawyers, including those specializing in the protection of collective interests. Materials and methods. The research methodology consists of general scientific research methods: analysis and synthesis; special methods, including special legal ones: formal legal and comparative legal. Results of the research and their discussion. The paper consists of two large parts. The first part examines issues related to the analysis of existing collective forms of judicial remedy, including in particular joinder of the parties, protection of an indeterminate number of persons, insolvency (bankruptcy), derivative actions, class actions. Particular emphasis is given to the research of the institute of class actions. It is analyzed in terms of access to judicial protection and its significance for the Russian legal system. Based on the conducted analysis, it is concluded that it is necessary to train lawyers specializing in class actions among other issues. Accordingly, issues of teaching of relevant disciplines and parts of courses devoted to the use of class action tools are examined in the second part of the paper. In particular, this part of the paper is devoted to the issues of teaching methods including traditional and modern methodologies and information technology. Conclusions. Based on the results of the research and their discussion, the authors come to a conclusion that a class action occupies a very important place in the system of collective judicial remedies. This fact determines not only perspectivity of scientific research in this area, but also training of relevant specialists in the field of protection of rights and legal interests of numerous groups of persons.

Benznidazole decreases the risk of chronic Chagas disease progression and cardiovascular events: A long-term follow up study.

BackgroundChagas disease (CD) remains an important endemic disease in Latin America. However, CD became globalized in recent decades. The majority of the chronically infected individuals did not receive etiologic treatment for several reasons, among them the most conspicuous is the lack of access to diagnosis. The impact of trypanocidal treatment on CD chronic phase, without cardiac involvement (indeterminate form ICF), is yet to be determined. We aimed to evaluate the effect of trypanocidal treatment with benznidazole (BZN) on the rate of progression to Chagas heart disease in patients with ICF.MethodsThis is a retrospective cohort observational study including patients with ICF treated with BZN and compared to a group of non-treated patients matched for age, sex, region of origin, and the year of cohort entry. We reviewed the medical charts of all patients followed from May 1987 to June 2020 at the outpatient center of the Evandro Chagas National Institute of Infectious Diseases (INI) of the Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, Brazil. Patients’ follow-up included at least one annual medical visit and one annual electrocardiogram (ECG). Echocardiographic exams were performed at baseline and during the follow-up. Disease progression from ICF to cardiac form was defined by changes in baseline ECG. Cumulative incidence and the incidence rate were described in the incidence analysis. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals for the association between BZN and CD progression, cardiovascular events or death.FindingsOne hundred and fourteen treated patients met the study inclusion criteria. A comparison group of 114 non-treated patients matched for age, sex, region of origin, and the year of cohort entry was also included, totalizing 228 patients. Most patients included in the study were male (70.2%), and their mean age was 31.3 (+7.4) years. Over a median follow-up of 15.1 years (ranging from 1.0 to 32.4), the cumulative CD progression incidence in treated patients was 7.9% vs. 21.1% in the non-treated group (p = 0.04) and the CD progression rate was 0.49 per 1.000 patients/year in treated patients vs. 1.10 per 1.000 patients/year for non-treated patients (p = 0.02). BZN treatment was associated with a decreased risk of CD progression in both unadjusted (HR 0.46; 95%CI 0.21 to 0.98) and adjusted (HR 0.43; 95%CI 0.19 to 0.96) models and with a decreased risk of occurrence of the composite of cardiovascular events only in the adjusted (HR 0.15; 95%CI 0.03 to 0.80) model. No association was observed between BZN treatment and mortality.InterpretationIn a long-term follow-up, BZN treatment was associated with a decreased incidence of CD progression from ICF to the cardiac form and also with a decreased risk of cardiovascular events. Therefore, our results indicate that BZN treatment for CD patients with ICF should be implemented into clinical practice.

Metabolic and immunological evaluation of patients with indeterminate and cardiac forms of Chagas disease.

Chagas disease affects approximately 7 million people, causing disability and mortality in the most productive life stages of infected individuals. Considering the lifestyle of the world population, metabolic syndrome is a synergistic factor for an increased cardiovascular risk of patients with Chagas disease.This study transversally evaluated the metabolic and immunological profiles of patients with indeterminate (IF) and cardiac (CF) forms of Chagas disease and their correlations with left ventricular dysfunction (LVD).Clinical and electrical bioimpedance analysis, levels of cytokines (interferon [IFN]-γ, tumor necrosis factor [TNF]-α, interleukin [IL]-17, IL-10, and IL-33) and adipocytokines (adiponectin, leptin, and resistin), metabolic syndrome components, and brain natriuretic peptide (BNP) levels were assessed in 57 patients (13 IF and 44 CF) with a mean age of 61.63 ± 12.1 years. Chest x-ray, electrocardiogram, and echocardiogram were performed to classify the clinical forms.The CF group had a higher number of individuals with metabolic syndrome components blood pressure altered, while more participants in the CF group with LVD had low high-density lipoprotein (HDL) levels. The IF group had more participants with a higher waist-to-hip ratio (WHR). No significant difference was observed between metabolic syndrome, cytokine and adipocytokine level, and clinical forms of the disease or in relation to LVD.Individuals with the IF showed metabolic and immunological profiles compatible with increased disease control, whereas those with CF showed marked inflammatory immune response.

Misdiagnosis of leprosy in Brazil in the period 2003 - 2017: spatial pattern and associated factors

BackgroundLeprosy causes a range of symptoms, and most diagnoses are established based on the clinical picture. Therefore, false negative and positive diagnoses are relatively common. We analyzed the spatial pattern of leprosy misdiagnosis and associated factors in Brazil. MethodExploratory analyses of Kernel density of the new case detection rate (NCDR) and proportion of misdiagnosis in Brazil, 2003–2017. Factors associated with misdiagnosis were identified by logistic regression at the 5% significance level. ResultA total of 574,181 new leprosy cases were recorded in Brazil within the study period, of which 7,477 (1.3%) were misdiagnoses. No spatial correlation was observed between the proportion of misdiagnoses and the NCDR. The likelihood of misdiagnosis was elevated for females [OR: 1.58 (1.51–1.66)], children [OR: 1.49 (1.36–1.64)]; paucibacillary [OR: 1.08 (1.02–1.13)], indeterminate clinical forms [OR: 2.37 (2.15–2.62)], for cases diagnosed in the frame of mass screenings [OR: 3.36 (3.09– 3.73)] and contact examination [OR: 2.30 (2.13–2.49)] and for cases with affected nerves but no skin lesions [OR: 2.47 (2.19–2.77)] when compared with those presenting both skin lesion and affected nerves. ConclusionMisdiagnosis of leprosy is not correlated with the endemicity level in Brazil but rather with personal, diagnosis-related and disease characteristics.

Tangent second-order homogenisation estimates for incompressible hyperelastic composites with fibrous microstructures and anisotropic phases

This work presents new estimates for the effective mechanical response of composites with fibrous microstructures and hyperelastic, anisotropic, incompressible phases. The composites are two-phase materials consisting of aligned cylindrical fibres of circular cross section that are randomly distributed in the transverse plane of the matrix phase. The proposed homogenisation is based on the tangent second-order method proposed by Avazmohammadi and Ponte Castañeda (2013), which utilises variational principles and a suitably chosen “linear comparison material” to provide estimates for effective strain energies of nonlinear materials. To take into account the incompressibility of the fibre phase, we employed an appropriate asymptotic expansion of the fibre deformation field. By doing so, a constraint pressure is identified as the consistent limit of emerging indeterminate forms in the dilatational part of the fibre stress tensor. Furthermore, we performed an asymptotic analysis to obtain regular expressions of the underlying equations in the incompressible matrix limit. While we addressed the general case of incompressible and generally anisotropic phases, we put particular emphasis on composites with transversely isotropic phases whose symmetry axes are collinear with the fibre direction. For such materials, we derived estimates for the effective strain energies in terms of macroscopic strain invariants. In addition, for composites that are described by isotropic phase energies augmented with J4-invariant-based anisotropic terms, which is the case for many biological materials, we show that the anisotropic part of the energy can be easily homogenised by means of a simple Voigt-type average. Moreover, we present closed-form results for composites with isotropic Neo-Hookean phases augmented by transversely isotropic energy contributions. Finally, it is shown that the new estimates correspond to certain exact results under longitudinal shear deformation and that they properly linearise for small strains by recovering the corresponding linear-elastic estimates.

Middle school students’ construction of quantitative unknowns

Two iterative, after school design experiments with small groups of middle school students were conducted to investigate how students constructed quantitative unknowns, conceived of as values of fixed quantities that are not known but can be determined. Students solved problems about an unknown height or length measured in two different units. Of 13 students who participated, 6 structured quantities into three levels of units. These students constructed an unknown as a height consisting of an indeterminate number of length units, each of which consisted of smaller length units, and they symbolized these relationships in their equations. The other 7 students structured quantities into two levels of units. Five of these students symbolized only the relationships between the measurement units, with two students demonstrating more basic and advanced solutions. The study shows that grappling with unknowns as measured and indeterminate is beneficial for students’ construction of variable.

Bergson's Theory of Free Will

Bergson argues that there is an incompatibility between free will and determinism: while free will has a dimension of creation, of invention, determinism corresponds to the idea that the future is fixed in advance by laws. In addition, he rejects determinism. According to him, the singularity of our deep-seated psychic states makes that their evolution cannot be governed by laws. However, Bergson does not defend classical indeterminism (of which contemporary indeterminism is only an extension) because it reduces free will to a choice between alternative possibilities, that is to say between pre-fixed futures. Such a conception does not take into account the creative dimension of free will. In fact, Bergson develops an original form of indeterminism based on a certain conception of causation. For determinism and classical indeterminism, causation is always the actualization of a pre-fixed virtual reality (single or multiple). For Bergson, causation can also be a creation, that is, the formation of something which is not pre-fixed.

Association between Trypanosoma cruzi DTU TcII and chronic Chagas disease clinical presentation and outcome in an urban cohort in Brazil.

The specific roles of parasite characteristics and immunological factors of the host in Chagas disease progression and prognosis are still under debate. Trypanosoma cruzi genotype may be an important determinant of the clinical chronic Chagas disease form and prognosis. This study aimed to identify the potential association between T. cruzi genotypes and the clinical presentations of chronic Chagas disease. This is a retrospective study using T. cruzi isolated from blood culture samples of 43 patients with chronic Chagas disease. From 43 patients, 42 were born in Brazil, mainly in Southeast and Northeast Brazilian regions, and one patient was born in Bolivia. Their mean age at the time of blood collection was 52.4±13.2 years. The clinical presentation was as follows 51.1% cardiac form, 25.6% indeterminate form, and 23.3% cardiodigestive form. Discrete typing unit (DTU) was determined by multilocus conventional PCR. TcII (n = 40) and TcVI (n = 2) were the DTUs identified. DTU was unidentifiable in one patient. The average follow-up time after blood culture was 5.7±4.4 years. A total of 14 patients (32.5%) died and one patient underwent heart transplantation. The cause of death was sudden cardiac arrest in six patients, heart failure in five patients, not related to Chagas disease in one patient, and ignored in two patients. A total of 8 patients (18.6%) progressed, all of them within the cardiac or cardiodigestive forms. TcII was the main T. cruzi DTU identified in chronic Chagas disease Brazilian patients (92.9%) with either cardiac, indeterminate or cardiodigestive forms, born at Southeast and Northeast regions. Other DTU found in much less frequency was TcVI (4.8%). TcII was also associated to patients that evolved with heart failure or sudden cardiac arrest, the two most common and ominous consequences of the cardiac form of Chagas disease.

Early impairment of myocardial deformation assessed by regional speckle-tracking echocardiography in the indeterminate form of Chagas disease without fibrosis detected by cardiac magnetic resonance.

Chagas disease (CD) will account for 200,000 cardiovascular deaths worldwide over the next 5 years. Early detection of chronic Chagas cardiomyopathy (CCC) is a challenge. We aimed to test if speckle-tracking echocardiography (STE) can detect incipient myocardial damage in CD. METHODS: Among 325 individuals with positive serological tests, 25 (age 55±12yrs) were selected to compose the group with indeterminate form of Chagas disease (IFCD), based on stringent criteria of being asymptomatic and with normal EKG/X-ray studies. This group was compared with a group of 20 patients with CCC (55±11yrs) and a group of 20 non-infected matched control (NC) subjects (48±10yrs). CD patients and NC were submitted to STE and CD patients were submitted to cardiac magnetic resonance (CMR) with late gadolinium administration to detect cardiac fibrosis by the late enhancement technique. Global longitudinal strain (GLS), circumferential (GCS) and radial strain (GRS) were defined as the average of segments measured from three apical view (GLS) and short axis views (GRS and GCS). Regional left ventricular (LV) longitudinal strain (Reg LS) was measured from each of the 17 segments. Twist was measured as systolic peak difference between basal and apical rotation and indexed to LV length to express torsion. RESULTS: STE global indices (GLS, GCS, twist and torsion) were reduced in CCC vs NC (GLS: -14±6.3% vs -19.3±1.6%, p = 0.001; GCS: -13.6±5.2% vs -17.3 ±2.8%; p = 0.008; twist: 8±7° vs 14±7°, p = 0.01 and torsion: 0.96±1°/cm vs 1.9±1°/cm, p = 0.005), but showed no differences in IFCD vs NC. RegLS was reduced in IFCD vs NC in four LV segments: basal-inferior (-16.3±3.3% vs -18.6±2.2%, p = 0.013), basal inferoseptal (-13.1±3.4 vs -15.2±2.7, p = 0.019), mid-inferoseptal (-17.7±3.2 vs -19.4±2, p = 0.032) and mid-inferolateral (-15.2±3.5 vs -17.8±2.8, p = 0.014). These abnormalities in RegLS occurred in the absence of myocardial fibrosis detectable with CMR in nearly 92% of subjects with IFCD, while myocardial fibrosis was present in 65% with CCC. CONCLUSION: RegLS detects early regional impairment of myocardial strain that is independent from fibrosis in IFCD subjects.