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Chagas disease affects approximately 7 million people worldwide in Latin America and is a neglected tropical disease. Twenty to thirty percent of chronically infected patients develop chronic Chagas cardiomyopathy decades after acute infection. Identifying biomarkers of Chagas disease progression is necessary to develop better therapeutic and preventive strategies. Circulating microRNAs are increasingly reliable biomarkers of disease and therapeutic targets. To identify new circulating microRNAs for Chagas disease, we performed exploratory small RNA sequencing from the plasma of patients and performed de novo miRNA prediction, identifying potential new microRNAs. The levels of the new microRNAs temporarily named miR-Contig-1519 and miR-Contig-3244 and microRNAs that are biomarkers for nonchagasic cardiomyopathies, such as miR-148a-3p and miR-224-5p, were validated by quantitative reverse transcription. We found a specific circulating microRNA signature defined by low miR-Contig-3244, miR-Contig-1519, and miR-148a-3 levels but high miR-224-5p levels for patients with chronic Chagas disease. Finally, we predicted in silico that these altered circulating microRNAs could affect the expression of target genes involved in different cellular pathways and biological processes, which we will explore in the future.

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In the basic verbal task from Piaget, when a relation of the form if A > B and B > C is given, a logical inference A > C is expected. This process is called transitive inference (TI). The adapted version for animals involves the presentation of a simultaneous discrimination between stimuli pairs. In this way, when A+B-, B+C-, C+D-, D+E- is trained, a B>D preference is expected, assuming that if A>B>C>D>E, then B>D. This effect has been widely reported using several procedures and different species. In the current experiment TI was evaluated employing probabilistic reinforcement. Thus, for the positive stimuli a .7 probability was administered and for the negative stimuli a .3 probability was administered. Under this arrangement the relation A>B>C>D>E is still allowed, but TI becomes more difficult. Five pigeons (Columba Livia) were exposed to the mentioned arrangement. Only one pigeon reached the criterion in C+D- discrimination, whereas the remaining did not. Only the one who successfully solved C+D- was capable of learning TI, whereas the others were not. Additionally, it was found that correct response ratios did not predict BD performance. Consequently, probabilistic reinforcement disrupted TI, but some positional ordering was retained in the test. The results suggest that TI might be affected by associative strength but also by the positional ordering of the stimuli. The discussion addresses the two main accounts of TI: the associative account and the ordinal representation account.

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[RESUMEN]. Objetivo. Evaluar la factibilidad de monitorear la calidad de la utilización de medicamentos en instituciones sanitarias de países de la Región de las Américas mediante indicadores de prescripción racional. Métodos. Se realizó un estudio cuantitativo de utilización de medicamentos durante el período 2016-2018. Se desarrollaron y seleccionaron indicadores de prescripción racional de acuerdo a referencias internacionales y a la mejor evidencia disponible para: 1) antiinflamatorios: porcentaje de prescripción de ibuprofeno y/o naproxeno sobre prescripción total de antinflamatorios no esteroideos; 2) antidiabéticos orales: metformina como porcentaje de todos los antidiabéticos prescritos, metformina y/o sulfonilureas como porcentaje de todos los antidiabéticos prescritos; 3) insulinas: insulina cristalina y NPH como porcentaje del total de insulinas prescritas y 4) medicamentos antihipertensivos: porcentaje de inhibidores de la enzima convertidora de la angiotensina (IECA), antagonistas de los receptores de la angiotensina II (ARA-II) y diuréticos tiazídicos sobre el total de antihipertensivos prescritos. Se empleó la dosis diaria definida (DDD) por 1 000 habitantes y día (DHD) como medida del consumo por institución. Resultados. La prescripción de metformina con relación a todos los antidiabéticos fue menor al valor del indicador de referencia (27,9%-67,6% vs. 88%), mientras que la prescripción de metformina y/o una sulfonilurea fue comparable con dicho valor (80,9%-97,5% vs. 88%). Los valores de insulina NPH, cristalina y NPH/ cristalina con relación a las insulinas prescritas fueron variables frente al valor del indicador de referencia (37,1%-100% vs. 75%). La prescripción de ibuprofeno y naproxeno estuvo por debajo del valor del indicador (20%-50% vs. 80%). El porcentaje de IECA, ARA-II y tiazidas respecto a todos los antihipertensivos osciló entre 65,2%-77,2% vs 65%, acorde al valor del indicador propuesto. Conclusiones. Se demostró la factibilidad de aplicar los indicadores de prescripción racional seleccionados y construidos, que proporcionan información útil para analizar la calidad de la prescripción en las instituciones sanitarias de países de la Región y representan una herramienta útil para su monitoreo periódico.

[ABSTRACT]. Objective. Evaluate the feasibility of monitoring the quality of use of medicines in health institutions in countries of the Region of the Americas by means of rational prescription indicators. Methodology. A quantitative study of the use of medicines was conducted during the period 2016-2018. Rational prescription indicators were developed and selected in accordance with international reference values and the best available evidence for: 1) anti-inflammatory drugs: prescription of ibuprofen and/or naproxen as a percentage of all prescribed non-steroidal anti-inflammatory drugs; 2) oral antidiabetics: metformin as a percentage of all prescribed antidiabetics, and metformin and/or sulfonylureas as a percentage of all prescribed antidiabetics; 3) insulins: crystalline insulin and NPH as a percentage of total prescribed insulins; and 4) antihypertensive drugs: angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs-II), and thiazide diuretics as a percentage of all prescribed antihypertensives. The defined daily dose (DDD) per 1 000 inhabitants was used as a measure of consumption per institution. Results. Prescription of metformin as a percentage of all antidiabetics was lower than the value of the reference indicator (27.9%-67.6% vs. 88%), while the prescription of metformin and/or a sulfonylurea was comparable with that value (80.9%-97.5% vs. 88%). The values of NPH, crystalline, and NPH/crystalline insulin in relation to all prescribed insulins were variable with respect to the reference indicator (37.1%-100% vs. 75%). Prescription of ibuprofen and naproxen was below the value of the indicator (20%-50% vs. 80%). The percentage of ACE inhibitors, ARBs, and thiazides with respect to all antihypertensives ranged from 65.2%-77.2% to 65%, consistent with the value of the proposed indicator. Conclusions. The feasibility of applying the selected and constructed indicators of rational prescription was demonstrated. These indicators provide useful information for analyzing the quality of prescription in health institutions in countries in the Region and are a useful tool for periodically monitoring it.

[RESUMO]. Objetivo. Avaliar a viabilidade de monitorar a qualidade do uso de medicamentos em instituições de saúde em países da Região das Américas por meio de indicadores de prescrição racional. Métodos. Foi realizado um estudo quantitativo do uso de medicamentos durante o período 2016-2018. Indicadores de prescrição racional foram desenvolvidos e selecionados de acordo com referências internacionais e as melhores evidências disponíveis para: 1) anti-inflamatórios: prescrições de ibuprofeno e/ou naproxeno como porcentagem da prescrição total de anti-inflamatórios não esteroidais; 2) antidiabéticos orais: prescrições de metformina como porcentagem de todos os antidiabéticos prescritos, metformina e/ou sulfonilureias como porcentagem de todos os antidiabéticos prescritos; 3) insulinas: insulina cristalina e NPH como porcentagem do total de insulinas prescritas; e 4) anti-hipertensivos: porcentagem de inibidores da enzima de conversão da angiotensina (IECA), antagonistas do receptor da angiotensina II (BRA) e diuréticos tiazídicos sobre o total de anti-hipertensivos prescritos. A dose diária definida (DDD) por 1 000 habitantes por dia (DHD) foi usada como medida de consumo por instituição. Resultados. A prescrição de metformina em relação a todos os antidiabéticos foi inferior ao valor do indicador de referência (27,9%-67,6% x 88%), enquanto a prescrição de metformina e/ou uma sulfonilureia foi comparável ao valor de referência (80,9%-97,5% x 88%). As porcentagens de prescrição de insulina NPH, cristalina e NPH/cristalina em relação a todas as insulinas prescritas foram variáveis em relação ao valor de referência (37,1%-100% x 75%). A prescrição de ibuprofeno e naproxeno foi inferior ao valor de referência (20%-50% x 80%). A porcentagem de IECA, BRA e tiazídicos em relação a todos os anti-hipertensivos variou entre 65,2% e 77,2%, compatível com o valor do indicador proposto (65%). Conclusões. Demonstrou-se a viabilidade de aplicação dos indicadores de prescrição racional aqui selecionados e construídos, os quais fornecem informações úteis para analisar a qualidade da prescrição nas instituições de saúde dos países da Região e representam uma ferramenta útil para seu monitoramento periódico.

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Chagas disease principally affects Latin-American people, but it currently has worldwide distribution due to migration. Death among those with Chagas disease can occur suddenly and without warning, even in those who may not have evidence of clinical or structural cardiac disease and who are younger than 60 years old. HCN4 channels, one of the principal elements responsible for pacemaker currents, are associated with cardiac fetal reprogramming and supraventricular and ventricular arrhythmias, but their role in chagasic arrhythmias is not clear. We found that a single-dose administration of ivabradine, which blocks HCN4, caused QTc and QRS enlargement and an increase in P-wave amplitude and was associated with ventricular and supraventricular arrhythmias in mice challenged with isoproterenol, a chronotropic/ionotropic positive agent. Continuous treatment with ivabradine did not alter the QTc interval, but P-wave morphology was deeply modified, generating supraventricular arrhythmias. In addition, we found that repolarization parameters improved with ivabradine treatment. These effects could have been caused by the high HCN4 expression observed in auricular and ventricular tissue in infected mice. Thus, we suggest, for the first time, that molecular remodeling by overexpression of HCN4 channels may be related to supraventricular arrhythmias in acute Chagas disease, causing ivabradine over-response. Thus, ivabradine treatment should be administered with caution, while HCN4 overexpression may be an indicator of heart failure and/or sudden death risk.

RESUMO

In Chagas disease (ChD) caused by Trypanosoma cruzi, new biomarkers to predict chronic cardiac pathology are urgently needed. Previous studies in chagasic patients with mild symptomatology showed that antibodies against the immunodominant R3 epitope of sCha, a fragment of the human basic helix-loop-helix transcription factor like 5, correlated with cardiac pathology. To validate sCha as a biomarker and to understand the origin of anti-sCha antibodies, we conducted a multicenter study with several cohorts of chagasic patients with severe cardiac symptomatology. We found that levels of antibodies against sCha discriminated the high risk of sudden death, indicating they could be useful for ChD prognosis. We investigated the origin of the antibodies and performed an alanine scan of the R3 epitope. We identified a minimal epitope MRQLD, and a BLAST search retrieved several T. cruzi antigens. Five of the hits had known or putative functions, of which phosphonopyruvate decarboxylase showed the highest cross-reactivity with sCha, confirming the role of molecular mimicry in the development of anti-sCha antibodies. Altogether, we demonstrate that the development of antibodies against sCha, which originated by molecular mimicry with T. cruzi antigens, could discriminate electrocardiographic alterations associated with a high risk of sudden death.

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We tested whether maternal energy supplementation during the last third of gestation improves birth weight, neonatal wellbeing, and mother-young bonding. Thirty-six pregnant French Alpine goats were randomly allocated among three nutritional treatments for the last third of pregnancy: (i) Control, fed alfalfa (T-0; n = 12); (ii) alfalfa + 150 g/head daily energy concentrate (T-150; n = 12); (iii) alfalfa + 300 g/head daily energy concentrate (T-300; n = 12). At birth, we collected progeny data on birth weight, birth type, sex, rectal temperature, heart rate, respiratory rate, time to standing, time to udder connection, and time to first feeding. For the dams, we collected data on the duration of labor, time to clean the progeny, and time to allow first suckling. At birth, body weight, rectal temperature, heart rate, and the respiratory rate did not differ among treatments (p > 0.05). In the dams, labor duration was not affected by the treatments (p > 0.05). The T-150 dams were faster to clean the newborn and allow first suckling (p < 0.05). The T-150 progeny were faster to stand and the T-300 progeny were faster to connect to the udder (p < 0.05). We conclude that energy supplementation of the dam during the last third of gestation does not affect the birth weight of the progeny, but enhances the mother-young bonding.

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OBJECTIVE: Evaluate the feasibility of monitoring the quality of use of medicines in health institutions in countries of the Region of the Americas by means of rational prescription indicators. METHODOLOGY: A quantitative study of the use of medicines was conducted during the period 2016-2018. Rational prescription indicators were developed and selected in accordance with international reference values and the best available evidence for: 1) anti-inflammatory drugs: prescription of ibuprofen and/or naproxen as a percentage of all prescribed non-steroidal anti-inflammatory drugs; 2) oral antidiabetics: metformin as a percentage of all prescribed antidiabetics, and metformin and/or sulfonylureas as a percentage of all prescribed antidiabetics; 3) insulins: crystalline insulin and NPH as a percentage of total prescribed insulins; and 4) antihypertensive drugs: angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs-II), and thiazide diuretics as a percentage of all prescribed antihypertensives. The defined daily dose (DDD) per 1 000 inhabitants was used as a measure of consumption per institution. RESULTS: Prescription of metformin as a percentage of all antidiabetics was lower than the value of the reference indicator (27.9%-67.6% vs. 88%), while the prescription of metformin and/or a sulfonylurea was comparable with that value (80.9%-97.5% vs. 88%). The values of NPH, crystalline, and NPH/crystalline insulin in relation to all prescribed insulins were variable with respect to the reference indicator (37.1%-100% vs. 75%). Prescription of ibuprofen and naproxen was below the value of the indicator (20%-50% vs. 80%). The percentage of ACE inhibitors, ARBs, and thiazides with respect to all antihypertensives ranged from 65.2%-77.2% to 65%, consistent with the value of the proposed indicator. CONCLUSIONS: The feasibility of applying the selected and constructed indicators of rational prescription was demonstrated. These indicators provide useful information for analyzing the quality of prescription in health institutions in countries in the Region and are a useful tool for periodically monitoring it.

OBJETIVO: Avaliar a viabilidade de monitorar a qualidade do uso de medicamentos em instituições de saúde em países da Região das Américas por meio de indicadores de prescrição racional. MÉTODOS: Foi realizado um estudo quantitativo do uso de medicamentos durante o período 2016-2018. Indicadores de prescrição racional foram desenvolvidos e selecionados de acordo com referências internacionais e as melhores evidências disponíveis para: 1) anti-inflamatórios: prescrições de ibuprofeno e/ou naproxeno como porcentagem da prescrição total de anti-inflamatórios não esteroidais; 2) antidiabéticos orais: prescrições de metformina como porcentagem de todos os antidiabéticos prescritos, metformina e/ou sulfonilureias como porcentagem de todos os antidiabéticos prescritos; 3) insulinas: insulina cristalina e NPH como porcentagem do total de insulinas prescritas; e 4) anti-hipertensivos: porcentagem de inibidores da enzima de conversão da angiotensina (IECA), antagonistas do receptor da angiotensina II (BRA) e diuréticos tiazídicos sobre o total de anti-hipertensivos prescritos. A dose diária definida (DDD) por 1 000 habitantes por dia (DHD) foi usada como medida de consumo por instituição. RESULTADOS: A prescrição de metformina em relação a todos os antidiabéticos foi inferior ao valor do indicador de referência (27,9%-67,6% x 88%), enquanto a prescrição de metformina e/ou uma sulfonilureia foi comparável ao valor de referência (80,9%-97,5% x 88%). As porcentagens de prescrição de insulina NPH, cristalina e NPH/cristalina em relação a todas as insulinas prescritas foram variáveis em relação ao valor de referência (37,1%-100% x 75%). A prescrição de ibuprofeno e naproxeno foi inferior ao valor de referência (20%-50% x 80%). A porcentagem de IECA, BRA e tiazídicos em relação a todos os anti-hipertensivos variou entre 65,2% e 77,2%, compatível com o valor do indicador proposto (65%). CONCLUSÕES: Demonstrou-se a viabilidade de aplicação dos indicadores de prescrição racional aqui selecionados e construídos, os quais fornecem informações úteis para analisar a qualidade da prescrição nas instituições de saúde dos países da Região e representam uma ferramenta útil para seu monitoramento periódico.

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[This corrects the article DOI: 10.3389/fpsyg.2018.01791.].

RESUMO

Transitive inference (TI) has been studied in humans and several animals such as rats, pigeons and fishes. Using different methods for training premises it has been shown that a non-trained relation between stimuli can be stablished, so that if A > B > C > D > E, then B > D. Despite the widely reported cases of TI, the specific mechanisms underlying this phenomenon remain under discussion. In the present experiment pigeons were trained in a TI procedure with four premises. After being exposed to all premises, the pigeons showed a consistent preference for B over D during the test. After overtraining C+D- alone, B was still preferred over D. However, the expected pattern of training performance (referred to as serial position effect) was distorted, whereas TI remained unaltered. The results are discussed regarding value transfer and reinforcement contingencies as possible mechanisms. We conclude that reinforcement contingencies can affect training performance without altering TI.

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Non-steroidal anti-inflammatories (NSAIDs) are among the most commonly used drugs in clinical practice. They block cyclooxygenases (COX) enzymes, but the degree of inhibition of COX-1 and COX-2 varies between them. In general, NSAIDs are classified in selective COX-2 or coxibs and non-selective or traditional NSAIDs. Both the analgesic and antiinflammatory effects, as well as the cardiovascular adverse effects, depend on the COX-2 inhibition. This paper reviews the available evidence of the increased risk of thrombotic events for both coxibs and traditional NSAID. The prothrombotic effect could be due to the inhibition of endothelial COX-2, with a decrease in production of prostacyclin and a relative increase in platelet thromboxane levels. Coxibs and diclofenac 150 mg/day seem to increase the risk of major vascular events by more than a third. Ibuprofen 2400 mg/day could slightly increase the risk of coronary events. Naproxen 1000 mg/day apparently does not increase the risk of vascular events. Besides ibuprofen and naproxen have the potential to decrease the cardioprotective effect of low doses of aspirin. Naproxen (= 1000 mg/day) and low doses of ibuprofen (= 1200 mg/day) are considered to have the most favorable thrombotic cardiovascular safety profiles of all NSAIDs. Therapeutic decisions should be based on an assessment of a person's individual risk factors, using the safest NSAIDs, at the lowest effective doses, for the shortest duration necessary to control symptoms, restricting their use in patients with increased cardiovascular risk.

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Los antiinflamatorios no esteroideos (AINEs) se encuentran entre los fármacos más utilizados en la práctica clínica. Actúan mediante el bloqueo de las enzimas ciclooxigenasas (COX), pero el grado de inhibición de COX-1 y COX-2 varía entre ellos. Se ha generalizado la clasificación entre COX-2 selectivos o coxibs, y los no selectivos o AINEs tradicionales. Tanto los efectos analgésico y antiinflamatorio como los efectos adversos cardiovasculares dependen de la inhibición de COX-2. Este trabajo revisa las evidencias disponibles del aumento del riesgo de eventos trombóticos tanto para los coxibs como para los AINEs tradicionales. El efecto protrombótico podría deberse a la inhibición de la COX-2 endotelial, con disminución de la prostaciclina y un incremento relativo de los niveles del tromboxano plaquetario. Los coxibs y el diclofenac, 150 mg/día, aumentarían el riesgo de eventos vasculares mayores en más de un tercio. El ibuprofeno 2400 mg/día aumentaría levemente el riesgo de eventos coronarios. El naproxeno 1000 mg/día no incrementaría el riesgo de eventos vasculares. Además, el ibuprofeno y el naproxeno tienen el potencial del disminuir el efecto cardioprotector de bajas dosis de aspirina. El naproxeno (≤ 1000 mg/día) y el ibuprofeno a bajas dosis (≤ 1200 mg/día) deberían considerarse los AINEs con el mejor perfil de seguridad cardiovascular. Las decisiones terapéuticas deben basarse en una adecuada evaluación del riesgo del paciente, utilizando los AINEs más seguros, a las menores dosis efectivas, por el menor tiempo posible que permita el control de los síntomas, restringiendo su utilización en enfermos con aumento del riesgo cardiovascular.

Non-steroidal anti-inflammatories (NSAIDs) are among the most commonly used drugs in clinical practice. They block cyclooxygenases (COX) enzymes, but the degree of inhibition of COX-1 and COX-2 varies between them. In general, NSAIDs are classified in selective COX-2 or coxibs and non-selective or traditional NSAIDs. Both the analgesic and anti-inflammatory effects, as well as the cardiovascular adverse effects, depend on the COX-2 inhibition. This paper reviews the available evidence of the increased risk of thrombotic events for both coxibs and traditional NSAID. The prothrombotic effect could be due to the inhibition of endothelial COX-2, with a decrease in production of prostacyclin and a relative increase in platelet thromboxane levels. Coxibs and diclofenac 150 mg/day seem to increase the risk of major vascular events by more than a third. Ibuprofen 2400 mg/day could slightly increase the risk of coronary events. Naproxen 1000 mg/day apparently does not increase the risk of vascular events. Besides ibuprofen and naproxen have the potential to decrease the cardioprotective effect of low doses of aspirin. Naproxen (≤ 1000 mg/day) and low doses of ibuprofen (≤ 1200 mg/day) are considered to have the most favorable thrombotic cardiovascular safety profiles of all NSAIDs. Therapeutic decisions should be based on an assessment of a person´s individual risk factors, using the safest NSAIDs, at the lowest effective doses, for the shortest duration necessary to control symptoms, restricting their use in patients with increased cardiovascular risk.

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RESUMEN: Introducción: El síndrome de burnout genera impacto negativo en la actuación profesional, la seguridad del paciente y la vida del residente. Esta problemática ha tomado vigencia en las residencias argentinas; sin embargo, no se han evaluado medidas efectivas para prevenir su aparición. Objetivo: Evaluar la prevalencia del síndrome de burnout antes y después de la implementación del descanso postguardia en médicos residentes de cardiología. Material y métodos: Estudio analítico, prospectivo. Se implementó el cuestionario de Maslach en residentes de cardiología de una institución de la Ciudad de Buenos Aires, antes y después de la implementación de un período de descanso de 24 horas (DPG) luego de una guardia de 24h. Resultados: La encuesta fue respondida por 42 residentes (2014: 19; 2015: 23). Hubo una tendencia a menor prevalencia de burnout en el grupo con DPG (26,1% vs. 47,4% p = 0,152) y mejores resultados en la escala de despersonalización (19 11-21 vs. 10 [1-17] p = 0,023). Presentaron menor agotamiento y despersonalización las mujeres y los mudados a Buenos Aires. Conclusiones: La implementación del DPG se asoció a la reducción de la escala de despersonalización, principalmente en mujeres. Se remarca la importancia de crear estrategias de prevención que mejoren las condiciones de trabajo y la calidad de vida del residente.

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The ambiguous-cue task is composed of two-choice simultaneous discriminations involving three stimuli: positive (P), ambiguous (A), and negative (N). Two different trial types are presented: PA and NA. The ambiguous cue (A) served as an S- in PA trials, but as an S+ in NA trials. When using this procedure, it is typical to observe a less accurate performance in PA trials than in NA trials. This is called the ambiguous-cue effect. Recently, it was reported in starlings that the ambiguous-cue effect decreases when the stimuli are presented on an angled (120°) panel. The hypothesis is that the angled panel facilitates that the two cues from each discrimination are perceived as a compound, precluding value transfer via a second-order conditioning mechanism. In this experiment, we used pigeons and a flat panel. Nevertheless, our data were quite similar to the previous data in starlings. We conclude that the form of the panel cannot explain the ambiguous-cue effect. Several alternatives to be explored in future experiments are suggested. The riddle of the ambiguous-cue problem still remains unsolved.

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