Diseño y justificación del estudio clínico aleatorizado BA-SCAD (bloqueadores beta y agentes antiplaquetarios en pacientes con disección arterial coronaria espontánea) / Rationale and design of the BA-SCAD (Beta-blockers and Antiplatelet agents in patients with Spontaneous Coronary Artery Dissection) randomized clinical trial

Introducción y objetivos: La disección coronaria espontánea (DCE) es una causa rara de síndrome coronario agudo. La mayor parte de los pacientes con DCE son tratados empíricamente con bloqueadores beta (BB) y antiagregantes plaquetarios (AP). El estudio BA-SCAD (bloqueadores beta y agentes antiplaquetarios en pacientes con disección coronaria espontánea) es un ensayo clínico académico, pragmático, diseñado con metodología PROBE (prospective randomized open blinded endpoint), con el patrocinio de la Sociedad Española de Cardiología, para conocer la eficacia del tratamiento farmacológico en pacientes con DCE. Métodos: Mediante un diseño factorial 2 × 2, se aleatorizará a 600 pacientes (1:1/1:1) a: a) BB (sí/no) y b) tratamiento con AP «corto» (1 mes) frente a tratamiento antiagregante plaquetario doble y «prolongado» (12 meses). Se aleatorizará a BB (sí/no) solo a los pacientes con fracción de eyección del ventrículo izquierdo conservada, ya que a los pacientes con fracción de eyección reducida se los tratará con BB de acuerdo con las guías actuales. De modo similar, se aleatorizará al estrato de AP solo a los pacientes en tratamiento conservador (sin revascularización), ya que los que requieran intervención coronaria recibirán tratamiento antiagregante plaquetario doble durante 1 año. El objetivo primario de valoración incluye muerte, infarto de miocardio, accidente cerebrovascular, revascularización coronaria, DCE recurrente y hospitalización no planeada por síndrome coronario agudo o insuficiencia cardiaca al año de seguimiento. El objetivo de seguridad es la hemorragia. Todos los pacientes serán seguidos anualmente. Se desarrollará un programa exhaustivo de subestudios adicionales (clínicos, de imagen, de revascularización, de biomarcadores, inflamatorios, inmunológicos, farmacogenéticos y genéticos) para garantizar una visión completa de esta entidad tan especial y compleja (AU)

introduction y objectives: Spontaneous coronary artery dissection (SCAD) is a rare cause of acute coronary syndrome. Most patients are empirically treated with beta-blockers and antiplatelet drugs. The Beta-blockers and Antiplatelet agents in patients with Spontaneous Coronary Artery Dissection (BA-SCAD) is an academic, pragmatic, prospective, randomized, open-label, blinded-endpoint clinical trial, performed under the auspices of the Spanish Society of Cardiology, to assess the efficacy of pharmacological therapy in patients with SCAD. Methods: Using a 2 x 2 factorial design, 600 patients will be randomized (1:1/1:1) to: a) beta-blockers (yes/no) and b) “short” (1 month) vs “prolonged” (12 months) antiplatelet therapy. Only patients with preserved left ventricular ejection fraction will be randomized to beta-blockers (yes/no) because patients with reduced left ventricular ejection fraction will receive beta-blockers according to current guidelines. Similarly, only conservatively managed patients (ie, no coronary intervention) will be randomized to the antiplatelet stratum, as patients requiring coronary interventions will receive 1-year dual antiplatelet therapy. The primary efficacy endpoint includes a composite of death, myocardial infarction, stroke, coronary revascularization, recurrent SCAD, and unplanned hospitalization for acute coronary syndrome or heart failure at 1 year. The primary safety endpoint will be bleeding. All patients will be clinically followed up yearly. A comprehensive set of additional substudies (clinical, imaging, revascularization, biomarkers, inflammatory, immunologic, pharmacogenetics, and genetic) will be conducted to ensure a holistic view of this unique and challenging clinical entity.Conclusions: The results of the BA-SCAD randomized clinical trial will advance our knowledge in the treatment of patients with SCAD (AU)

Autoimmune polyendocrine syndrome type 1 (APECED) in the Indian population: case report and review of a series of 45 patients.

BACKGROUND: Autoimmune polyendocrinopathy-candidiasis-ectodermal-dystrophy (APECED) or autoimmune polyglandular syndrome type 1 (APS-1) is a rare autosomal recessive genetic disease due to mutations in the AIRE (AutoImmune REgulator) gene. The clinical diagnosis is classically based on the presence of at least two of the three main components: chronic mucocutaneous candidiasis, hypoparathyroidism and primary adrenal insufficiency. Patients often suffer from other endocrine or non-endocrine autoimmune conditions throughout life. APECED etiopathogenesis is mediated by T lymphocytes. Autoantibodies against proteins of the affected organs are found in the serum of APECED patients as well as neutralizing antibodies against cytokines. We report here the clinical and genetic characteristics of 45 Indian APECED patients in comparison to Finnish, Sardinian, Turkish and North/South American cohorts from their published results. We also report a new case of APECED of Indian origin, a 2-year old child suffering from chronic mucocutaneous candidiasis since the age of 8 months, with confirmatory AIRE homozygous mutation c.274C > T (p.R92W). CONCLUSION: With the inherent limitations of a retrospective study, analysis of Indian APECED patients suggested that compared to classic criteria, application of Ferre/Lionakis criteria validated in North/South American patients could help in earlier diagnosis in 3 of 8 (37.5%) patients for whom adequate information for evaluation was available.

CureTB and continuity of care for globally mobile patients.

BACKGROUND: In 2016, 3% of newly diagnosed patients with tuberculosis (TB) left the United States, of whom 24% moved to Mexico. Continuity of care for TB is important to ensure patients complete treatment and reduce TB transmission. CureTB provides continuity of care for patients with TB who move out of the United States by referring them for care at their destination.METHODS: Analysis of CureTB data collected between January 2012 to December 2015 to describe demographics and outcomes of referred patients and examine factors contributing to successful treatment outcomes.RESULTS: CureTB received 1347 referrals mostly from health departments and law enforcement agencies in the United States (92%). A total of 858 referrals were for patients with verified or possible TB (64%). Most patients moved to Mexico or other Latin American countries (96%) and completed treatment after departing (78%). Poor treatment outcomes were associated with being in custody (33%), not being interviewed by CureTB (30%), and not having diabetes (18%).CONCLUSION: CureTB successfully promoted transnational continuity of care for patients by exchanging information with international public health authorities and linking them directly with patients. This patient-centered strategy helps improve TB treatment success and reduce the global burden and transmission of TB.

Enteral fish oil supplementation in the resolution of parenteral nutrition associated cholestasis.

OBJECTIVE: To analyze safety, tolerance and efficacy of enteral omega-3 fatty acids (FAs) in the resolution of Parenteral Nutrition Associated Cholestasis (PNAC) and postnatal growth among preterm neonates. STUDY DESIGN: This is a single center retrospective case-control study of all neonates born less than 32 weeks of gestation and developed PNAC (Direct bilirubin >2 mg/dl). Infants who received enteral omega-3 FAs supplementation (1 g/Kg/d) served as cases and were compared with gestational age, gender and direct bilirubin level matched controls who did not receive enteral omega-3 FAs supplementation. RESULTS: A total of 48 infants were analyzed, 24 who received enteral omega-3 fatty acids were matched with 24 controls. The omega-3 FAs and control groups were similar in gestational age (weeks) and birth weight (gram). Overall there were no differences between the two groups in infants' demographics or clinical characteristics including risk factors for the development of PNAC. Infants who received enteral omega-3 FAs had significantly fewer days of cholestasis (p = 0.025) and a higher average daily weight gain (grams/day) (p = 0.011) than their controls. In a linear regression analysis with days of cholestasis as the dependent variable and Ursodeoxycholic acid (UDCA) and Omega-3 FAs as independent variables, enteral omega-3 FAs remained associated with a shorter duration of cholestasis, p < 0.001. CONCLUSION: Enteral fish oil is inexpensive, safe & well tolerated in preterm neonates with no contraindications to enteral feeding. Enteral omega-3 FAs are easy to administer and help in rapid resolution of PNAC while promoting postnatal weight gain in preterm infants.

First isolation of Candida metapsilosis in Kuwait, an emerging global opportunistic pathogen.

Invasive infections due to uncommon and rare yeast species are increasing worldwide in prevalence and are associated with high mortality rates. Here, we describe the first isolation and characterization of Candida metapsilosis cultured from the blood sample of a 10-year-old Saudi girl, who suffered from a neurodegenerative disorder, in Kuwait. The yeast isolate was identified by sequencing of ITS region and D1/D2 domains of rDNA. The report extends the geographic distribution of C. metapsilosis to the Middle East and highlights the emerging role of uncommon yeast species causing infections in susceptible hosts.

Divergent effects of RIP1 or RIP3 blockade in murine models of acute liver injury.

Necroptosis is a recently described Caspase 8-independent method of cell death that denotes organized cellular necrosis. The roles of RIP1 and RIP3 in mediating hepatocyte death from acute liver injury are incompletely defined. Effects of necroptosis blockade were studied by separately targeting RIP1 and RIP3 in diverse murine models of acute liver injury. Blockade of necroptosis had disparate effects on disease outcome depending on the precise etiology of liver injury and component of the necrosome targeted. In ConA-induced autoimmune hepatitis, RIP3 deletion was protective, whereas RIP1 inhibition exacerbated disease, accelerated animal death, and was associated with increased hepatocyte apoptosis. Conversely, in acetaminophen-mediated liver injury, blockade of either RIP1 or RIP3 was protective and was associated with lower NLRP3 inflammasome activation. Our work highlights the fact that diverse modes of acute liver injury have differing requirements for RIP1 and RIP3; moreover, within a single injury model, RIP1 and RIP3 blockade can have diametrically opposite effects on tissue damage, suggesting that interference with distinct components of the necrosome must be considered separately.

Activity of enzalutamide in men with metastatic castration-resistant prostate cancer is affected by prior treatment with abiraterone and/or docetaxel.

BACKGROUND: Enzalutamide and abiraterone are new androgen-axis disrupting treatments for metastatic castration-resistant prostate cancer (mCRPC). We examined the response and outcomes of enzalutamide-treated mCRPC patients in the real-world context of prior treatments of abiraterone and/or docetaxel. METHODS: We conducted a seven-institution retrospective study of mCRPC patients treated with enzalutamide between January 2009 and February 2014. We compared the baseline characteristics, PSA declines, PSA progression-free survival (PSA-PFS), duration on enzalutamide and overall survival (OS) across subgroups defined by prior abiraterone and/or docetaxel. RESULTS: Of 310 patients who received enzalutamide, 36 (12%) received neither prior abiraterone nor prior docetaxel, 79 (25%) received prior abiraterone, 30 (10%) received prior docetaxel and 165 (53%) received both prior abiraterone and prior docetaxel. Within these groups, respectively, ⩾30% PSA decline was achieved among 67, 28, 43 and 24% of patients; PSA-PFS was 5.5 (95% CI 4.2-9.1), 4.0 (3.2-4.8), 4.1 (2.9-5.4) and 2.8 (2.5-3.2) months; median duration of enzalutamide was 9.1 (7.3-not reached), 4.7 (3.7-7.7), 5.4 (3.8-8.4) and 3.9 (3.0-4.6) months. Median OS was reached only for the patients who received both prior abiraterone and docetaxel and was 12.2 months (95% CI 10.7-16.5). 12-month OS was 78% (59-100%), 64% (45-90%), 77% (61-97%) and 51% (41-62%). Of 70 patients who failed to achieve any PSA decline on prior abiraterone, 19 (27%) achieved ⩾30% PSA decline with subsequent enzalutamide. CONCLUSIONS: The activity of enzalutamide is blunted after abiraterone, after docetaxel, and still more after both, suggesting subsets of overlapping and distinct mechanisms of resistance.

IRF5rs2004640 single nucleotide polymorphism is associated with susceptibility to rheumatoid arthritis in South Indian Tamils.

Polymorphism of interferon regulatory factor 5 (IRF5), a latent transcription factor gene has been associated with various auto-immune diseases. Our aim was to study the IRF5rs2004640 gene polymorphism and its association with disease susceptibility, disease phenotype and treatment response in South Indian Tamil patients with rheumatoid arthritis (RA).The study was conducted on 217 RA patients fulfilling the American College of Rheumatology (ACR) 2010 criteria and 482 healthy controls (HCs) without family history of autoimmune disease. The IRF5rs2004640 genotyping was performed using a TaqMan 5' allelic discrimination assay. We found that the IRF5rs2004640T allele [P < 0.0001, odds ratio (OR) 3.25, 95% confidence interval (CI) 2.55-4.12] and TT genotype (P < 0.0001, OR 4.60, 95% CI 3.23-6.57) were significantly more frequent in RA patients as compared with HCs. No association was found between IRF5rs2004640 polymorphism, clinical manifestations, autoantibody profile and treatment response. IRF5rs2004640 T (mutant) allele may be a susceptibility factor conferring risk for RA in South Indian Tamils, whereas G allele (wild type) may be protective.

Immunoglobulin-like transcripts 6 (ILT6) polymorphism influences the anti-Ro60/52 autoantibody status in South Indian SLE patients.

INTRODUCTION: Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder with complex etiology. Loss of immune tolerance against self-antigens results in activation of the immune system to produce autoantibodies, which in turn contribute to the clinical manifestations of the disease. Immune cells harbor a plethora of regulatory receptors. Immunoglobulin-like transcripts (ILTs) exhibit both immune activation and inhibitory properties. Genetic defects in genes encoding these receptors may predispose to development of autoimmune diseases secondary to loss of their function. The aim of our study was to analyze the presence or absence of the 6.7 kb segment in the ILT6 gene and its association with susceptibility to SLE and its different manifestations. METHOD: A total of 188 SLE patients and 192 age-, sex similar-, ethnicity-matched controls were recruited. They were genotyped to test the presence or absence of the 6.7 kb segment of the ILT6 gene by polymerase chain reaction. RESULTS: The mutant allele lacking the 6.7 kb gene segment had an equal frequency in patients as well as controls (20% and 18%, respectively). The mutant allele was not associated with SLE or its clinical manifestations. However, the mutant allele was associated with the presence of anti-Ro60 (p = 0.0005, OR 3.5, 95% CI 1.8-7.1) and anti-Ro52 (p = 0.0027, OR 2.99, 95% CI 1.5-6.06) autoantibodies. CONCLUSION: ILT6 deletion polymorphism does not appear to be a lupus susceptibility gene in South Indian Tamils, but may behave as a genetic modifier of autoantibody phenotype by influencing the production of anti-Ro60 and anti-Ro52 autoantibodies and thus indirectly contribute to autoimmune responses in SLE.

The CTLA4 +49 A/G (rs231775) polymorphism influences susceptibility to SLE in South Indian Tamils.

Systemic lupus erythematosus (SLE) is a prototype autoimmune disease with complex etiology. Loss of immune tolerance and synthesis of autoantibodies against nuclear antigens contributes to the disease. Genetic aberrations disrupting the functions of immune regulatory receptors may facilitate the development of autoimmune diseases. Cytotoxic T-lymphocyte antigen 4 (CTLA4) is an inhibitory receptor for T cells and this study was carried out to analyze the influence of CTLA4 +49A/G (rs231775) polymorphism on susceptibility to SLE in ethnic Tamils. Three hundred SLE patients and 460 age and sex similar, ethnicity-matched controls were screened for the +49 A/G polymorphism by real time polymerase chain reaction (PCR). The wild allele (A) frequency in controls and cases was 63% and 47%, respectively. The presence of heterozygous (AG) and homozygous mutant (GG) genotype was associated with a significant risk to develop SLE (P = 0.0001, OR-2.29, 95% confidence interval (CI), 1.6-3.3) and (P = 0.0001, OR-4.3, 95% CI, 2.8-6.99). The frequency of mutant allele (G) in patients was also significantly associated with SLE (P = 0.0001, OR-1.9, 95% CI, 1.5-2.4). However, this polymorphism did not influence the clinical or serological phenotypes in our study. Therefore the CTLA4 +49 A/G polymorphism is a potential genetic risk factor for lupus susceptibility in South Indian Tamils, but does not appear to influence either the clinical or serological phenotype.

Deriving benefit of early detection from biomarker-based prognostic models.

Many prognostic models for cancer use biomarkers that have utility in early detection. For example, in prostate cancer, models predicting disease-specific survival use serum prostate-specific antigen levels. These models typically show that higher marker levels are associated with poorer prognosis. Consequently, they are often interpreted as indicating that detecting disease at a lower threshold of the biomarker is likely to generate a survival benefit. However, lowering the threshold of the biomarker is tantamount to early detection. For survival benefit to not be simply an artifact of starting the survival clock earlier, we must account for the lead time of early detection. It is not known whether the existing prognostic models imply a survival benefit under early detection once lead time has been accounted for. In this article, we investigate survival benefit implied by prognostic models where the predictor(s) of disease-specific survival are age and/or biomarker level at disease detection. We show that the benefit depends on the rate of biomarker change, the lead time, and the biomarker level at the original date of diagnosis as well as on the parameters of the prognostic model. Even if the prognostic model indicates that lowering the threshold of the biomarker is associated with longer disease-specific survival, this does not necessarily imply that early detection will confer an extension of life expectancy.

Associations of obesity with triglycerides and C-reactive protein are attenuated in adults with high red blood cell eicosapentaenoic and docosahexaenoic acids.

BACKGROUND: N-3 fatty acids are associated with favorable, and obesity with unfavorable, concentrations of chronic disease risk biomarkers. OBJECTIVE: We examined whether high eicosapentaenoic (EPA) and docosahexaenoic (DHA) acid intakes, measured as percentages of total red blood cell (RBC) fatty acids, modify associations of obesity with chronic disease risk biomarkers. METHODS: In a cross-sectional study of 330 Yup'ik Eskimos, generalized additive models (GAM) and linear and quadratic regression models were used to examine associations of BMI with biomarkers across RBC EPA and DHA categories. RESULTS: Median (5th-95th percentile) RBC EPA and DHA were 2.6% (0.5-5.9%) and 7.3% (3.3-8.9%), respectively. In regression models, associations of BMI with triglycerides, glucose, insulin, C-reactive protein (CRP) and leptin differed significantly by RBC EPA and DHA. The GAM confirmed regression results for triglycerides and CRP: at low RBC EPA and RBC DHA, the predicted increases in triglycerides and CRP concentrations associated with a BMI increase from 25 to 35 were 99.5±45.3 mg/dl (106%) and 137.8±71.0 mg/dl (156%), respectively, for triglycerides and 1.2±0.7 mg/l (61%) and 0.8±1.0 mg/l (35%), respectively, for CRP. At high RBC EPA and RBC DHA, these predicted increases were 13.9±8.1 mg/dl (23%) and 12.0±12.3 mg/dl (18%), respectively, for triglycerides and 0.5±0.5 mg/l (50%) and -0.5±0.6 mg/l (-34%), respectively, for CRP. CONCLUSIONS: In this population, high RBC EPA and DHA were associated with attenuated dyslipidemia and low-grade systemic inflammation among overweight and obese persons. This may help inform recommendations for n-3 fatty acid intakes in the reduction of obesity-related disease risk.

Haematological effects of multimicronutrient supplementation in non-pregnant Gambian women.

BACKGROUND/OBJECTIVES: The use of multimicronutrient (MMN) supplementation to reduce the burden of anaemia in non-pregnant women of reproductive age has been little studied, particularly in Africa. The objective of the study was to evaluate haematological outcomes in non-pregnant, rural Gambian women of reproductive age, receiving daily MMN supplements for 1 year. SUBJECTS/METHODS: The study in 293 women aged from 17 to 45 years old was nested within a double-blind, randomized placebo-controlled trial of periconceptional MMN supplementation [ISRCTN 13687662], using the United Nations International Multiple Micronutrient Preparation (UNIMMAP), received daily for 1 year or until conception. Red cell parameters and free erythrocyte protoporphyrin concentration were measured at baseline and after 12 months in those women who did not conceive. RESULTS: Anaemic women (haemoglobin concentration <12 g per 100 ml) were more likely to be older and in economic deficit at baseline. Mean change in haemoglobin concentration was +0.6+/-1.4 g per 100 ml in the intervention arm and -0.2+/-1.2 g per 100 ml in the placebo arm (P<0.001). After supplementation with MMN, the relative risk of anaemia (<12 g per 100 ml) was 0.59 (0.46, 0.76) compared with placebo. Anaemic subjects at baseline showed an increase in mean haemoglobin from 10.6 g per 100 ml to 11.8 g/l (P<0.001) after MMN supplementation. CONCLUSIONS: MMN supplementation should be considered as a strategy for improving the micronutrient and haematological status of non-pregnant women of reproductive age.

Multiple foreign bodies in a neonate.

We report a rare instance of nine foreign bodies in a neonate that included a coin, safety pin, screw, cotton piece, polythene piece, and four glass pieces. Of these, six foreign bodies were removed by esophagoscopy and endoscopy, two glass pieces were passed in feces and one could not be removed. The child died 5 days after admission.