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To verify characteristics associated with drug resistant epilepsy in children up to 36 months of age with Congenital Zika Syndrome (CZS).This is a prospective cohort study with children aged up to 36 months diagnosed with CZS. Obstetric, demographic, phenotype and other clinical signs, cranial tomography, growth and motor development of the children were collected.Of a total of 109 children diagnosed with CZS, 100 (91.7%) had epilepsy and 68 (68%) with drug resistant seizures. The types of seizures associated with drug resistant epilepsy were focal seizures from the occipital lobe, generalized tonic and generalized tonic-clonic seizures. There was an association between drug resistant epilepsy and microcephaly at birth, severe microcephaly at birth, excess nuchal skin, ventriculomegaly, reduced brain parenchyma volume, and hypoplasia or malformation of the cerebellum. Difficulty sleeping, irritability, continuous crying, dysphagia and gross motor function were clinical signs associated with drug resistant epilepsy, as were the presence of ocular abnormalities, low head circumference in the first year of life and low weight in the first six months.The prevalence of drug resistant epilepsy in children up to 36 months with CZS was 62.4% and was associated with the severity of the child's neurological damage, with emphasis on the reduction of brain parenchyma volume and damage to the cerebellum.

Background: Little is known regarding the developmental consequences of congenital Zika syndrome (CZS) without microcephaly at birth. Most previously published clinical series were descriptive and they had small sample sizes. Study design: We conducted a cohort study to compare the growth, clinical, and motor development outcomes for 110 children with CZS born with and without microcephaly up to their third birthday. Ninety-three had their head circumference (HC) at birth abstracted and they did not have hypertensive hydrocephalus at birth, where 61 were born with microcephaly and 32 without. Results: The HC z-scores decreased steeply from birth to six months of age, i.e., from –3.77 to –6.39 among those with microcephaly at birth and from –1.03 to –3.84 among those without. Thus, at 6 months of age, the mean HC z-scores for children born without microcephaly were nearly the same as those for children born with microcephaly. Children born without microcephaly were less likely to have brain damage, ophthalmic abnormalities, and drug-resistant epilepsy, but the differences in many conditions were not statistically significant. Conclusions: Children born without microcephaly were only slightly less likely to present severe neurologic impairment and to develop postnatal-onset microcephaly, and some of the original differences between the groups tended to dissipate with age.

Little is known about the evolution of head circumference (HC) in children with congenital Zika syndrome (CZS). This study aims to evaluate HC growth in children with CZS in the first three years of life and identify associated factors. HC data obtained at birth and in neuropediatric consultations from 74 children with CZS were collected from the Child’s Health Handbook, parents’ reports, and medical records. Predictors of HC z-score were investigated using different mixed-effects models; Akaike’s information criterion was used for model selection. The HC z-score decreased from -2.7 ± 1.6 at birth to -5.5 ± 2.2 at 3 months of age, remaining relatively stable thereafter. In the selected adjusted model, the presence of severe brain parenchymal atrophy and maternal symptoms of infection in the first trimester of pregnancy were associated with a more pronounced reduction in the HC z-score in the first three years of life. The decrease of HC z-score in CZS children over the first three months demonstrated a reduced potential for growth and development of the central nervous system of these children. The prognosis of head growth in the first 3 years of life is worse when maternal infection occurs in the first gestational trimester and in children who have severe brain parenchymal atrophy.

SUMMARYObjectiveTo estimate the 2020 all-cause and COVID-19 excess mortality according to sex, age, race/color, and state, and to compare mortality rates by selected causes with that of the five previous years in Brazil.MethodsData from the Mortality Information System were used. Expected deaths for 2020 were estimated from 2015 to 2019 data using a negative binomial log-linear model.ResultsExcess deaths in Brazil in 2020 amounted to 13.7%, and the ratio of excess deaths to COVID-19 deaths was 0.90. Reductions in deaths from cardiovascular diseases (CVD), respiratory diseases, and external causes, and an increase in ill-defined causes were all noted. Excess deaths were also found to be heterogeneous, being higher in the Northern, Center-Western, and Northeastern states. In some states, the number of COVID-19 deaths was lower than that of excess deaths, whereas the opposite occurred in others. Moreover, excess deaths were higher in men, in those aged 20 to 59, and in black, yellow, or indigenous individuals. Meanwhile, excess mortality was lower in women, individuals aged 80 years or older, and in whites. Additionally, deaths among those aged 0 to 19 were 7.2% lower than expected, with reduction in mortality from respiratory diseases and external causes. There was also a drop in mortality due to external causes in men and in those aged 20 to 39 years. Furthermore, reductions in deaths from CVD and neoplasms were noted in some states and groups.ConclusionThere is evidence of underreporting of COVID-19 deaths and of the possible impact of restrictive measures in the reduction of deaths from external causes and respiratory diseases. The impacts of COVID-19 on mortality were heterogeneous among the states and groups, revealing that regional, demographic, socioeconomic, and racial differences expose individuals in distinct ways to the risk of death from both COVID-19 and other causes.

Background Descriptions of the techniques for condylectomies via minimally invasive surgery (MIS) to treat interdigital helomas of the lesser toes are scarce in the literature. This study aimed to define and describe this surgical technique. Methods This observational study was performed using the Delphi method. We collected the anonymous opinions of a multidisciplinary international panel of ten experts by answering a 43-items questionnaire via e-mail. Statements with an average score ≥ 3 were included in the next round, as were those in which none of the three statements reached the minimum score of 3 within the same item. Results Response rate: 90%. Three rounds were needed to reach consensus on proposed items. A new statement that combined two statements was proposed in round 3. Eleven recommendations regarding the incision and instruments used to perform this surgical technique were obtained based on the expert consensus. Conclusions A longitudinal incision to the distal pulp of the toe or an incision to the centre of the plantar aspect of the head of the proximal phalanx should be performed according to the affectation, and a Beaver 64 scalpel blade, a blunt elevator and a Shannon-Isham burr are the most acceptable tools for this kind of surgery.

Background Minimally invasive surgery (MIS) procedures cause less trauma to the patient and might improve recovery. This study aimed to determine the efficacy and safety of condylectomy with MIS to treat interdigital corns of the lesser toes. Methods This prospective cohort study was conducted in seven podiatry centers. Patients with interdigital corns of the lesser toes, progressing for more than a year, with one or more recurrences in the last year following conservative treatments were eligible. The recruited patients were classified according to their treatment: conservative or surgical (condylectomy with MIS) and were compared. Patient satisfaction, pain, the clinical and functional status of the foot and the appearance of sequelae were assessed at 3 and 6 months after treatment. Results At 6 months, patients in the surgical treatment group showed no pain on pressure, which significantly differed from the conservative treatment group (p Conclusions Condylectomy with MIS is effective and safe to treat interdigital corns of the lesser toes.

OBJECTIVES: To estimate the prevalence and factors associated with hesitancy in getting the vaccine against SARS-CoV-2 in Maranhão, Brazil. METHODS: This is a cross-sectional population-based study conducted from October 19 to 30, 2020. The estimates were calculated based on clustering, stratification, and non-response. A three-stage sampling was adopted, considering stratum, census tracts, and domicile. After systematic analysis, thirty sectors were selected in each stratum, totaling 150 sectors. Each sector contained a fixed number of 34 households, thus totaling 5,100 households. One individual within each household (resident for at least six months and aged one year or more) was selected by a simple random sampling. We questioned participants about their vaccination intention. Univariate association between independent variables and the outcome were verified using descriptive analysis (weighted frequencies) and Pearson's chi-square test (p < 0.05). Robust multivariate analysis was performed using a three-level hierarchical model. RESULTS: We found 17.5% (95%CI 16.1–19.1%) of the 4,630 individuals interviewed to report hesitancy to be vaccinated against covid-19. After final model adjustment, vaccination hesitancy was statistically higher among residents of the cities of Imperatriz (24.0%; RP = 1.48; IC95% 1.09–2.02) and municipalities of the Grande Ilha de São Luís (20.7%; RP = 1.34; 95%CI 1.02–1.76), female individuals (19.8%; RP = 1.44; 95%CI 1.20–1.75), older adults (22.8%; RP = 1.79; IC95% 1.30–2.46), evangelicals (24.1%; RP = 1.49; 95%CI 1.24–1.79), and those without reported symptoms (18.6%; RP = 1.24; 95%CI 1.02–1.51). We found no statistical differences for other socioeconomic and demographic characteristics, as well as variables related to the labor market, behaviors, and health conditions of the interviewees. CONCLUSION: The prevalence of vaccine hesitancy in Maranhão and its association with individual, contextual, and clinical factors enable us to identify the groups and contexts of greatest resistance, requiring special attention from public strategies to ensure wide vaccination.

OBJECTIVE: To estimate the seroprevalence of SARS-CoV-2 in the state of Maranhão, Brazil. METHODS: A population-based household survey was performed, from July 27, 2020 to August 8, 2020. The estimates considered clustering, stratification and non-response. Qualitative detection of IgM and IgG antibodies was performed in a fully-automated Elecsys® Anti-SARS-CoV-2 electrochemiluminescence immunoassay on the Cobas® e601 analyzer (Roche Diagnostics). RESULTS: In total, 3,156 individuals were interviewed. Seroprevalence of total antibodies against SARS-CoV-2 was 40.4% (95%CI 35.6-45.3). Population adherence to non-pharmaceutical interventions was higher at the beginning of the pandemic than in the last month. SARS-CoV-2 infection rates were significantly lower among mask wearers and among those who maintained social and physical distancing in the last month compared to their counterparts. Among the infected, 26.0% were asymptomatic. The infection fatality rate (IFR) was 0.14%, higher for men and older adults. The IFR based on excess deaths was 0.28%. The ratio of estimated infections to reported cases was 22.2. CONCLUSIONS: To the best of our knowledge, the seroprevalence of SARS-CoV-2 estimated in this population-based survey is one of the highest reported. The local herd immunity threshold may have been reached or might be reached soon.

This study describes the COVID-19 death reporting delay in the city of São Luís, Maranhão State, Brazil, and shows its impact on timely monitoring and modeling of the COVID-19 pandemic, while seeking to ascertain how nowcasting can improve death reporting delay. We analyzed COVID-19 death data reported daily in the Epidemiological Bulletin of the State Health Secretariat of Maranhão and calculated the reporting delay from March 23 to August 29, 2020. A semi-mechanistic Bayesian hierarchical model was fitted to illustrate the impact of death reporting delay and test the effectiveness of a Bayesian Nowcasting in improving data quality. Only 17.8% of deaths were reported without delay or the day after, while 40.5% were reported more than 30 days late. Following an initial underestimation due to reporting delay, 644 deaths were reported from June 7 to August 29, although only 116 deaths occurred during this period. Using the Bayesian nowcasting technique partially improved the quality of mortality data during the peak of the pandemic, providing estimates that better matched the observed scenario in the city, becoming unusable nearly two months after the peak. As delay in death reporting can directly interfere with assertive and timely decision-making regarding the COVID-19 pandemic, the Brazilian epidemiological surveillance system must be urgently revised and notifying the date of death must be mandatory. Nowcasting has proven somewhat effective in improving the quality of mortality data, but only at the peak of the pandemic.

Objective Maranhão State—Northeast Brazil–has the world’s highest incidence of penile cancer. This study describes the epidemiological, histopathological and clinical profile of patients stricken across that Brazilian state. The study is aimed at providing new data on neoplasia. Data description 402 men stricken with penile cancer were studied from January 2004 to December 2018. A retrospective stage was developed with collection of physical and electronic records. A prospective stage was performed with collection of clinical and epidemiological information through a questionnaire. The surgical material was looked into by a uropathologist, and the lesions were evaluated for macroscopic characteristics and various microscopic parameters. Three articles using this data have already been published.

N6-methyladenosine (m

FAPEMA (Fundacao de Amparo a Pesquisa e ao Desenvolvimento Cientifico e Tecnologico do Maranhao) Background: Rhinosporidiosis is a rare chronic infection of the mucous membranes caused by the Rhinosporidium seeberi. Approximately 15% of cases of rhinosporidiosis are ocular, occurring mainly in the tarsal conjunctiva. There are only 11 cases of scleral melt with staphyloma formation associated with bulbar conjuctival oculosporidiosis and none of them was associated with partial regression of the scleral ectasia after a corneoscleral tectonic graft. Case presentation: a 13-year-old girl with a progressively increasing black mass in the upper nasal part above the cornea of the left eye. The biomicroscopy revealed an oval, bluish mass measuring 10x10x5 mm with congestion of the overlying conjunctiva. Conjunctival biopsy showed sporoblasts of Rinosporidium seeberi. Treatment was conducted by conjunctival resection and tectonic corneoscleral graft (13x13mm) over the staphyloma. Within 1 year of follow-up the patient presented a partial staphyloma reduction, 9x9x2.5 mm, and the patch detached from the lesion. A novel surgical approach was done reducing the corneal patch and no recurrence was seen after 9 months. Conclusions: This case is one of the largest anterior scleral staphylomas secondary to rhinosporidiosis described in the literature. Scleral anterior staphyloma partial regression is an unusual outcome after a tectonic corneoscleral graft. Infection resolution and graft covering of thinned area contributed to scleral reepithelization. Univ Fed Maranhao, Dept Med 1, Praca Goncalves Dias 21 Ctr, BR-65020240 Sao Luis, MA, Brazil Univ Fed Sao Paulo, Dept Oftalmol, Rua Botucatu,821 Vila Clementino, BR-04023062 Sao Paulo, SP, Brazil Univ Fed Sao Paulo, Dept Oftalmol, Rua Botucatu,821 Vila Clementino, BR-04023062 Sao Paulo, SP, Brazil Web of Science

Background Infections and primary graft dysfunction are devastating complications in the immediate postoperative period following lung transplantation. Nowadays, reliable diagnostic tools are not available. Biomarkers could improve early infection diagnosis. Methods Multicentre prospective observational study that included all centres authorized to perform lung transplantation in Spain. Lung infection and/or primary graft dysfunction presentation during study period (first postoperative week) was determined. Biomarkers were measured on ICU admission and daily till ICU discharge or for the following 6 consecutive postoperative days. Results We included 233 patients. Median PCT levels were significantly lower in patients with no infection than in patients with Infection on all follow up days. PCT levels were similar for PGD grades 1 and 2 and increased significantly in grade 3. CRP levels were similar in all groups, and no significant differences were observed at any study time point. In the absence of PGD grade 3, PCT levels above median (0.50 ng/ml on admission or 1.17 ng/ml on day 1) were significantly associated with more than two- and three-fold increase in the risk of infection (adjusted Odds Ratio 2.37, 95% confidence interval 1.06 to 5.30 and 3.44, 95% confidence interval 1.52 to 7.78, respectively). Conclusions In the absence of severe primary graft dysfunction, procalcitonin can be useful in detecting infections during the first postoperative week. PGD grade 3 significantly increases PCT levels and interferes with the capacity of PCT as a marker of infection. PCT was superior to CRP in the diagnosis of infection during the study period.

Objective To prepare a protocol for the treatment of retinopathy of prematurity (ROP) agreed by the majority of Spanish ophthalmologists dedicated to this topic. Material and method A draft of the protocol was produced taking into account the experience of the participants and up to date publications. This draft was corrected by all the ophthalmologists participating in the project, and the final document was agreed by all of them. Results We present general guidelines as an aid for the treatment of ROP, including treatment criteria, treatment methods, a calendar of action, and follow-up. Conclusions It is important to have a common working protocol for the treatment of ROP to improve care and to avoid mistakes. Although individual Hospitals may adapt the protocol to their daily activity, it is recommended that there is a minimal working protocol agreed by most of professionals dedicated to pediatric ophthalmology in Spain.

Objective To prepare a retinopathy of prematurity (ROP) screening program as agreed by most of Spanish ophthalmologists dedicated to this topic. Materials and methods A draft of the protocol was produced taking into account the experience of the participants and current publications. This draft was corrected by all the ophthalmologists participating in the project and the final document produced was agreed by all of them. Results We present general guidelines to help in the screening of ROP, including treatment criteria, treatment methods, and a calendar of action. Conclusions It is important to have a common working protocol in the screening of ROP to improve the action and to avoid mistakes. Although individual hospitals may adapt the protocol to their daily activity, it is recommended that there is a minimal working protocol agreed by most of professionals dedicated to pediatric ophthalmology in Spain.

— Nodular regenerative hyperplasia of the liver was found at liver biopsy and at autopsy in a 61-year-old woman with severe cholestasis. Increased bilirubin levels persisted over a follow-up period of 4 years. Microscopic findings included hyperplastic hepatocytic nodules, interlobular bile duct lesions, fibrous medial and intimal thickening of small arterial branches and portal veins, and recanalization of a thrombus in a major portal branch related to an area of focal nodular hyperplasia of the liver. Bile duct and small vessel changes were prominent in the present case. Their role as contributing factors to the development of nodular regenerative hyperplasia of the liver is discussed.

A reductionist approach to the study of infection does not lend itself to an appraisal of the interactions that occur between 2 or more organisms that infect a host simultaneously. In reality, hosts are subject to multiple simultaneous influences from multiple pathogens along the spectrum from symbiotic microflora to virulent pathogen. In this review, we draw from our own work on Fasciola hepatica and that of others studying helminth co-infection to give examples of how such interactions can influence not only the outcome of infection but also its diagnosis and control. The new tools of systems biology, including both the “omics” approaches and mathematical biology, have significant promise in unraveling the as yet largely unexplored complexities of co-infection.

Aims Following CRT, atrioventricular (AV) optimization is not routinely practised. To evaluate its clinical utility, we examined the effect of AV delay optimization on the prognostic biomarker NT-proBNP. Methods and results We prospectively studied 72 patients (mean age 73 ± 12.5 years, 70.8% male, 55.6% ischaemic) undergoing iterative AV optimization. Patients were divided into those whose nominal setting appeared ideal and not changed (Group 1, n = 22) and those whose AV delay was optimized (Group 2, n = 50). All patients underwent NT-proBNP assessment prior to CRT, and pre- and a median 5 days post-optimization. Compared with Group 1, NT-proBNP fell significantly in Group 2 patients (median 474 pg/mL) following optimization (P = 0.00001). A significant change in filling pattern (defined as a change in AV delay >50 ms) was required in 30% of patients, and it was this subgroup that derived the greater reduction in NT-proBNP levels [–1407 pg/mL, interquartile range (IQR) –3042 to –346 pg/mL] compared with those requiring

BACKGROUND: Physiological shortening of the atrioventricular (AV) interval with increasing heart rate is well documented in normal human beings and is an established component of dual-chamber pacing for bradycardia. OBJECTIVES: To assess the effect of exercise on optimal AV delay and the impact of a patient-specific rate-adaptive AV delay (RAAVD) on exercise capacity in patients with heart failure following cardiac resynchronization therapy. METHODS: Phase 1: We performed iterative AV optimization at rest and exercise in 52 cardiac resynchronization therapy patients in atrial-sensed mode (mean age 71.6 ± 9.2 years, 25% females). Phase 2: Subsequently, 20 consecutive volunteers from this group (mean age 69.2 ± 9.6 years, 15% females) underwent cardiopulmonary exercise testing with RAAVD individually programmed ON (RAAVD-ON) or OFF (RAAVD-OFF). RESULTS: Phase 1: In 94% of the patients, there was a marked reduction (mean 50%) in optimal AV delay with exercise. The optimal resting vs exercise AV delay was 114.2 ± 29 ms at a heart rate of 64.4 ± 7.1 beats/min vs 57 ± 31 ms at a heart rate of 103 ± 13 beats/min (P < .001). No patients required an increase in AV delay with exercise, and 3 (6%) showed no change. Phase 2: With RAAVD-ON, significantly better exercise times were achieved (8.7 ± 3.2 minutes) compared with RAAVD-OFF (7.9 ± 3.2 minutes; P = .003), and there was a significant improvement in Vo(2)max (RAAVD-ON 16.1 ± 4.0 vs RAAVD-OFF 14.9 ± 3.7 mL/(kg · min); P = .024). CONCLUSIONS: There was a dramatic reduction in optimal AV delay with physiological exercise in the majority of this heart failure cardiac resynchronization therapy cohort. Replicating this physiological response with a programmable RAAVD translated into a 10% improvement in exercise capacity.

Blood samples from 24 patients infested with Schistosoma mansoni were drawn immediately before and 2 days after the administration of a single therapeutic dose of 12-15 mg/kg oral oxaminiquine. Two-day lymphocyte cultures were obtained and about 100 mitoses from each blood sample were analyzed for chromosome aberrations. No significant differences were observed between the "before" and "after" cultures in the frequencies of aberrations resulting from spindle, chromatidic, or chromosome events. It is concluded that there is no reason to fear harmful effects on the chromosomes of patients from treatment with oxaminiquine.

Glycoproteins secreted by helminth parasites are immunogenic and represent appealing components of vaccine preparations. Our poor knowledge of the pathways that mediate protein glycosylation in parasitic flatworms hinders our understanding of how proteins are synthesised and modified, and our ability to target these pathways for parasite control. Here we provide the first detailed description of genes associated with protein glycosylation in a parasitic flatworm, focusing on the genome of the liver fluke (Fasciola hepatica), which is a globally important trematode parasite of humans and their livestock. Using 190 human sequences as search queries against currently available F. hepatica genomes, we identified 149 orthologues with putative roles in sugar uptake or nucleotide sugar synthesis, and an array of glycosyltransferase and glycosidase activities required for protein N- and O-glycosylation. We found appreciable duplication within these orthologues, describing just 87 non-redundant genes when paralogues were excluded. F. hepatica lacks many of the enzymes required to produce complex N- and O-linked glycans, which explains the genomic basis for the structurally simple glycans described by F. hepatica glycomic datasets, and predicts pervasive structural simplicity in the wider glycome. These data provide a foundation for functional genomic interrogation of these pathways with the view towards novel parasite intervention strategies.

Optical coherence tomography (OCT) is a tool that is increasingly more commonly used in the study of neuro-degenerative diseases.To analyse and correlate the thickness of the retinal nerve fibre layer (RNFL) by means of time-domain and spectral-domain OCT in patients with relapsing-remitting multiple sclerosis (MS), with and without a history of optic neuritis (ON).We conducted a cross-sectional study of the thickness (mean and by quadrants) of the RNFL of 15 disease-free subjects, 28 with MS with no prior history of ON and 18 with a history of ON. The full ophthalmologic examination included measurement of the RNFL by means of time-domain and spectral-domain tomography.Statistically significant differences are found between the two tomography scans on comparing the mean thickness of the RNFL of the control group (p = 0.000), the group with a history of ON (p = 0.000) and the group without ON (p = 0.000). We obtained a strong, statistically significant and directly proportional correlation between the mean thickness of the RNFL measured with the two types of tomography in the control group (rho = 0.842; p = 0.000), and the groups of eyes without ON (rho = 0.91; p = 0.000) and with ON (rho = 0.902; p = 0.000).There is a strong correlation between the two tomography scans in the measurement of the thickness of the RNFL in patients with MS, with and without a history of ON. Time-domain OCT quantifies greater thicknesses, and therefore both types of tomography have proven to be effective in the study of MS, although the results cannot be interchanged or extrapolated.Analisis de las diferencias cuantitativas en el grosor de la capa de fibras nerviosas retiniana entre la tomografia de coherencia optica de dominio-tiempo y de dominio-espectral en pacientes con esclerosis multiple remitente recurrente.Introduccion. La tomografia de coherencia optica (OCT) es una herramienta cada vez mas extendida en el estudio de las enfermedades neurodegenerativas. Objetivos. Analizar y correlacionar el grosor de la capa de fibras nerviosas retiniana (CFNR) mediante OCT de dominio-tiempo y dominio-espectral en pacientes con esclerosis multiple (EM) remitente recurrente, con y sin antecedente de neuritis optica (NO). Sujetos y metodos. Estudio transversal del grosor medio y por cuadrantes de la CFNR en 15 sujetos libres de enfermedad, 28 con EM sin historia previa de NO y 18 con antecedentes de NO. La exploracion oftalmologica completa incluia la medicion de la CFNR mediante tomografos de dominio-tiempo y dominio-espectral. Resultados. Existen diferencias estadisticamente significativas entre ambos tomografos al comparar el grosor medio de la CFNR en el grupo control (p = 0,000), el grupo con antecedentes de NO (p = 0,000) y el grupo sin NO (p = 0,000). Hemos obtenido una fuerte correlacion, estadisticamente significativa y directamente proporcional entre el grosor medio de la CFNR medido con ambos tomografos en el grupo control (rho = 0,842; p = 0,000), y los grupos de ojos sin NO (rho = 0,91; p = 0,000) y con NO (rho = 0,902; p = 0,000). Conclusiones. Existe una fuerte correlacion en la medicion del grosor de la CFNR entre ambos tomografos en pacientes con EM, con y sin antecedente de NO. La OCT de dominio-tiempo cuantifica grosores mayores, por lo que ambos tomografos se demuestran eficaces en el estudio de la EM, aunque los resultados no son intercambiables ni extrapolables.