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The Rutaceae family is one of the most studied plant families due to the large number of alkaloids isolated from them with outstanding biological properties, among them the quinoline-based alkaloids Graveoline 1 and Dubamine 2. The most common methods for the synthesis of alkaloids 1 and 2 and their derivatives involves cycloaddition reactions or metal-catalyzed coupling processes but with some limitations in scope and functionalization of the quinoline moiety. As a continuation of our current studies on the synthesis and chemical transformation of 2-aminochalcones, we are reporting here an efficient metal-free approach for the total synthesis of alkaloids 1 and 2 along with their analogues with structural diversity, through a two-step sequence involving intramolecular cyclization, oxidation/aromatization, N-methylation and oxidative C-C bond processes, starting from dihydroquinolin-4-ones as common precursors for the construction of the structures of both classes of alkaloids.

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BACKGROUND: Obesity is a known risk factor for developing endometrial cancer. However, the association of obesity with endometrial cancer (EC) outcomes has not been clearly established. This study examined how outcomes in women with early stage EC vary with body composition measured via computed tomography (CT). METHODS: In this retrospective study, patients diagnosed with EC international Federation of Gynecology and Obstetrics stages I-III and available CT scans were included. Automatica software was used to assess the areas of visceral adipose tissue, subcutaneous adipose tissue (SAT), and intermuscular adipose tissue (IMAT) and skeletal muscle area. RESULTS: Of 293 patient charts assessed, 199 met eligibility criteria. Median body mass index (BMI) was 32.8 kg/m2 (interquartile range [IQ] = 26.8-38.9); 61.8% had histologic subtype endometrioid carcinoma. Adjusted for age, international Federation of Gynecology and Obstetrics stage, and histologic subtype, a BMI of at least 30 vs less than 30 kg/m2 was associated with lower endometrial cancer-specific survival (ECSS) (hazard ratio [HR] = 2.32, 95% confidence interval [CI] = 1.27 to 4.25) and overall survival (OS) (HR = 2.7, 95% CI = 1.35 to 5.39). Higher IMAT 75th vs 25th percentile and SAT of at least 225.6 vs less than 225.6 cm2 were associated with lower ECSS (HR = 1.53, 95% CI = 1.1 to 2.13, and HR = 2.57, 95% CI = 1.13 to 5.88) and OS (HR = 1.50, 95% CI = 1.11 to 2.02, and HR = 2.46, 95% CI = 1.2 to 5.01), respectively. The association of visceral adipose tissue (75th vs 25th percentile) with ECSS and OS was not statistically significant (HR = 1.42, 95% CI = 0.91 to 2.22, and HR = 1.24, 95% CI = 0.81 to 1.89). CONCLUSION: Higher BMI, IMAT, and SAT were associated with higher mortality from EC and lower OS. A better understanding of the mechanisms underlying these relationships could inform strategies to improve patient outcomes.

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Uveal melanomas are rare tumors arising from melanocytes that reside in the eye. Despite surgical or radiation treatment, approximately 50% of patients with uveal melanoma will progress to metastatic disease, most often to the liver. Cell-free DNA (cfDNA) sequencing is a promising technology due to the minimally invasive sample collection and ability to infer multiple aspects of tumor response. We analyzed 46 serial cfDNA samples from 11 patients with uveal melanoma over a 1-year period following enucleation or brachytherapy (n = ∼4/patient) using targeted panel, shallow whole genome, and cell-free methylated DNA immunoprecipitation sequencing. We found detection of relapse was highly variable using independent analyses (P = 0.06-0.46), whereas a logistic regression model integrating all cfDNA profiles significantly improved relapse detection (P = 0.02), with greatest power derived from fragmentomic profiles. This work provides support for the use of integrated analyses to improve the sensitivity of circulating tumor DNA detection using multi-modal cfDNA sequencing. Significance: Here, we demonstrate integrated, longitudinal cfDNA sequencing using multi-omic approaches is more effective than unimodal analysis. This approach supports the use of frequent blood testing using comprehensive genomic, fragmentomic, and epigenomic techniques.

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1. INTRODUCCIÓN El desprendimiento de retina es un problema visual grave que puede ocurrir a cualquier edad, aunque suele darse en individuos de edad media o en personas de la tercera edad. La incidencia es relativamente baja considerando que las estima-ciones varían según zonas geográficas; y, se han reportado datos de entre 6,3 y 17,9 por 100 000 habitantes. Otras características im-portantes a considerar son la degeneración en encaje de 45,75% y la miopía de 47,28% que influyen en la presentación del desprendi-miento de retina. Al mismo tiempo que la edad, los cambios vítreos retinianos y la presencia de pseudofaquia1,2. Además, de los factores oculares relacionados también influyen, el seguimiento inadecuado de los factores de riesgo y el difícil acceso a médicos especialistas que se traduce en retraso en el diagnóstico certero y tratamiento tardío que implica deterioro del pronóstico visual cuando el área macular está incluida en el área desprendida con pobres resultados en adultos jóvenes y en edad productiva.El tratamiento evitará el deterioro o pérdida irreversible de la visión. El pronóstico con tratamiento quirúrgico es bueno si el des-prendimiento no incluye a la mácula.

1. INTRODUCTIONRetinal Detachment is a serious visual problem that can occur at any age, although it usually occurs in middle-aged or elderly in-dividuals. The incidence is relatively low considering that estimates vary ac-cording to geographical areas; and, data have been reported be-tween 6,3 and 17,9 per 100 000 inhabitants. Other important cha-racteristics to consider are socket degeneration of 45,75% and myopia of 47,28% that influence the presentation of retinal deta-chment, as well as age, vitreoretinal changes and the presence of pseudophakia1,2.In addition to the related ocular factors, inadequate follow-up of risk factors and difficult access to medical specialists also play a role, resulting in delayed accurate diagnosis and late treatment that implies deterioration of the visual prognosis when the macular area is included in the detached area with poor results in young adults and those of productive age.Treatment will prevent irreversible deterioration or loss of vision. The prognosis with surgical treatment is good if the detachment does not include the macula.

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Epileptiform syndromes are represented by a variety of clinical scenarios. In this context, dacrystic seizures (DS) are characterized by paroxysmal episodes of stereotyped crying and are considered a rare ictal phenomenon. Their neuroanatomical and pathophysiological findings tend to be nonspecific, and to date, there is no consensus on their treatment. Additionally, most of the existing case reports describe that the patients who suffer from them are usually refractory to conventional care. Also, most of the existing literature is approached from a neurological practice perspective; however, there's evidence of patients with these paroxysms that occasionally end up in the hands of psychiatric services due to the uniqueness of their symptoms. However, there is very little information about this phenomenon due to its rarity. For this reason, this manuscript presents the case of a middle-aged man with these seizures who initially attended a psychiatric emergency service and subsequently received neuropsychiatric management and follow-up.

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Introducción: la desnutrición crónica en menores de 5 años se define como el retraso en el crecimiento, resultado de recurrentes carencias nutricionales, asociadas con pobreza, de salud y nutrición materna. El objetivo fue identificar la prevalencia de desnutrición crónica y factores asociados en menores de 5 años de la comunidad indígena awá, atendidos en la ips Unidad del Pueblo Indígena Awá (unipa) de Barbacoas (Nariño, Colombia) durante 2019. Materiales y métodos: estudio de corte transversal con enfoque analítico. Se incluyeron 527 niños menores de 5 años de la comunidad awá acudientes al programa de crecimiento y desarrollo de la ipsunipa. Se evaluó como desenlace la desnutrición crónica y, como factores asociados, características sociodemográficas, nutricionales y otras del estado de salud. Se consideró un valor de p menor al 5 % cuando se utilizó chi cuadrado, test exacto de Fisher y U de Mann-Whitney para determinar asociación estadística; además, se ajustó la relación a través de un modelo de regresión logística múltiple. Resultados: el 17.6 % de los niños pre-sentó desnutrición crónica. Se encontró asociación estadística con ser hijo de madre adolescente (p = 0.006), esquema de vacunación incompleto (p = 0.012), la edad (p = 0.017) y el peso al nacer (p = 0.017). Conclusión: en menores de 5 años de la comunidad awála frecuencia de desnutrición crónica está por encima de la media para esta población en general en Colombia. Es importante priorizar la búsqueda activa de desnutrición crónica en niños cuyas madres son adolescentes, niños con bajo peso al nacer y vacunación incompleta

Introduction: Chronic malnutrition in children under 5 years old is defined as stunting due to recurrent nutritional deficiencies associated with poverty, maternal health, and nutrition. This study aimed to iden-tify the prevalence of chronic malnutrition and associated factors in children under 5 years old from the indigenous Awá community, at Barbacoas, Nariño in 2019. Materials and methods: A cross-sectional study was conducted, which included 527 children under 5 years old from the Awá community who attended a health institution for growth and development program. Chronic malnutrition was evaluated as an outcome, whereas sociodemographic, nutritional and other health characteristics as associated factors. Chi-square, Fisher's exact, and Mann­Whitney's U test were used to determine statistical association. Additionally, the relationship was adjusted through a multiple logistic regression model. Results: Chronic malnutrition was found in 17.6% of children. The statistical association was found in children of the ado-lescent mother, incomplete vaccination schedule, and age and birth weight. Conclusion: In children under 5 years old in the Awá community, the frequency of chronic malnutrition is above the average for the general population in Colombia. Prioritizing the active search for chronic malnutrition in children whose mothers are adolescents and those with low birth weight and incomplete vaccination is important

Introdução: a desnutrição crônica em crianças menores de cinco anos é definida como retardo de crescimento como resultado de deficiências nutricionais recorrentes associadas à pobreza, saúde materna e nutrição. O objetivo é identificar a prevalência de desnutrição crônica e fatores associados em crianças menores de 5 anos da comunidade indígena Awá, atendidas na Unidade ips do Povo Indígena Awá (unipa) de Barbacoas, Nariño durante 2019. Materiais e métodos: estudo transversal de abordagem analítica. Foram incluídas 527 crianças menores de 5 anos da comunidade Awá que participaram do programa de crescimento e desen-volvimento da ipsunipa. A desnutrição crônica foi avaliada como desfecho e as características sociodemo-gráficas, nutricionais e outras características de saúde como fatores associados. Um valor de p inferior a 5% foi considerado quando o qui-quadrado, o teste exato de Fisher e o U de Mann Whitney foram usados para determinar a associação estatística, além disso, a relação foi ajustada por meio de um modelo de regressão logística múltipla. Resultados: 17,6% das crianças apresentavam desnutrição crônica. Associação estatística foi encontrada com os fatores ser filho de mãe adolescente (valor p: 0,006), esquema vacinal incompleto (valor p: 0,012), idade (valor p: 0,017) e peso ao nascer (valor p: 0,017). Conclusão: em crianças menores de 5 anos da comunidade Awá, a frequência de desnutrição crônica está acima da média geral para esta popu-lação na Colômbia. É importante priorizar a busca ativa da desnutrição crônica em crianças cujas mães são adolescentes, em crianças com baixo peso ao nascer e com esquema de vacinação incompleto

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PURPOSE: Anti-programmed cell death protein 1 (PD1)±anti-cytotoxic T-lymphocyte associated protein 4 (CTLA4) immune checkpoint inhibitors (ICIs) are standard therapeutic options for metastatic melanoma. We assessed whether biologic subtype according to primary tumor type or genomic subtype can function as predictive biomarkers for anti-PD1±anti-CTLA4 ICI in patients with advanced melanoma. METHODS: We performed a single-center retrospective cohort analysis of patients who received anti-PD1±anti-CTLA4 ICI for advanced melanoma between 2012 and 2019. Primary tumor type, BRAF and NRAS mutation status, and other covariates were abstracted from chart review. Log-rank tests and multivariable Cox regression models were used to assess differences in clinical progression-free (cPFS) and overall survival (OS). RESULTS: We identified 230 patients who received 249 lines of anti-PD1±anti-CTLA4 ICI for unresectable or metastatic disease. Of these patients, 74% were cutaneous, 11% mucosal, 8% unknown primary and 7% acral. BRAF and NRAS mutations were identified in 35% and 28% of patients, respectively. In multivariable analyses of the entire cohort, acral or mucosal primary tumor type, >3 metastatic sites, elevated LDH were predictive of shorter cPFS and OS. Combination ICI therapy was associated with longer cPFS (HR 0.57, 95% CI 0.38 to 0.86, p=0.007) and OS (HR 0.42, 95% CI 0.28 to 0.65, p<0.001). Combination ICI was significantly associated with longer OS in unknown primary and mucosal melanoma. There was a non-significant trend toward longer OS with anti-PD1+anti-CTLA4 in cutaneous melanoma, but not in acral melanoma. In multivariable analyses, combination ICI was associated with longer OS in NRAS (HR 0.24, 95% CI 0.10 to 0.62, p=0.003, n=69) and BRAF V600E/K (HR 0.47, 95% CI 0.24 to 0.90, p=0.024, n=86) mutant melanoma but not BRAF/NRAS wild-type (n=94) melanoma. CONCLUSIONS: In our cohort, primary melanoma tumor type and genomic subtype were independent predictive markers of cPFS and OS for patients with metastatic melanoma receiving anti-PD1 ICI. Primary tumor type and genomic subtype-including NRAS-should be further evaluated in prospective clinical trials to determine their value as predictive markers. Biologic subtypes may facilitate clinical decision-making when recommending combination ICI treatment (anti-PD1±anti-CTLA4) versus anti-PD1 alone for patients with metastatic melanoma.

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Immune checkpoint inhibitor (ICI)-induced insulin-dependent diabetes mellitus (IDDM) is a rare but potentially fatal immune-related adverse event (irAE). In this multicentre retrospective cohort study, we describe the characteristics of ICI-induced IDDM in patients treated across five Canadian cancer centres, as well as their tumor response rates and survival. In 34 patients identified, 25 (74%) were male and 19 (56%) had melanoma. All patients received anti-programed death 1 (anti-PD1) or anti-programmed death ligand-1 (anti-PD-L1)-based therapy. From ICI initiation, median time to onset of IDDM was 2.4 months (95% CI 1.1-3.6). Patients treated with anti-PD1/PD-L1 in combination with an anti-cytotoxic T lymphocyte antigen 4 antibody developed IDDM earlier compared with patients on monotherapy (1.4 vs. 3.9 months, p = 0.05). Diabetic ketoacidosis occurred in 21 (62%) patients. Amongst 30 patients evaluable for response, 10 (33%) had a complete response and another 10 (33%) had a partial response. Median overall survival was not reached (95% CI NE; median follow-up 31.7 months). All patients remained insulin-dependent at the end of follow-up. We observed that ICI-induced IDDM is an irreversible irAE and may be associated with a high response rate and prolonged survival.

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OBJECTIVE: The aim of this study was shown clinical characteristics and follow-up of patients with atrioventricular reentrant tachycardia (AVRT) who underwent radiofrequency catheter ablation (RCA) therapy. MATERIAL AND METHODS: From April 1992 to December 1995, 413 patients with AVRT underwent RCA therapy. RESULTS: Two hundred thirty four men (57%) and one hundred seventy nine women (43%) aged 31.3 +/- 16.3 years were studied. 437 single accessory pathways were found; 24 had multiple accessory pathways. Ablation therapy was successful in 381 accessory pathways. During follow-up of 7 years, AVRT recurred in 51 patients (13%) and in 80% this occurred within the first 3 months after the procedure. 56 patients underwent a second RCA therapy with success in 35 patients (83.5); two reoccurred (5.7%); 365 accessory pathways (83.5) remained without evidence of preexcitation AVRT. CONCLUSIONS: During follow-up, these patients with successful ablation therapy remained without symptoms. In patients who underwent a second RCA therapy, atrioventricular reentrant mechanism was always present.

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Objetivo: se analizan los resultados clínicos y el seguimiento a largo plazo de los pacientes que fueron sometidos a ablación endocárdica mediante radiofrecuencia para el tratamiento de la taquicardia paroxística supraventricular por vía accesoria atrioventricular. Material y métodos: se incluyeron 413 pacientes a quienes se les realizó ablación con radiofrecuencia de vías accesorias atrioventricular de abril de 1992 a diciembre de 1995. Resultados: de los 413 pacientes seleccionados, 234 (57%) eran hombres y 179 (43%) eran mujeres, con edad promedio de 31.3 ± 16.3 años (límites 2 a 69 años). Se localizó un total de 437 vías accesorias atrioventriculares, 389 (93)% eran únicas y en 24 enfermos estuvieron presentes dos vías accesorias. La ablación tuvo éxito inmediato en 381 vías atrioventriculares (87%), durante el seguimiento promedio de siete años, se observó recurrencia de 51 vías atrioventriculares (13%), de estas 41 (80%) recurrieron en los primeros tres meses. A cincuenta y seis pacientes se les realizó una segunda sesión de ablación, con éxito de 35 (62.5%) y nueva recurrencia en 2 (5.7%). Son 365 vías accesorias (83.5) que permanecen sin recurrencia de taquicardia o preexcitación. Conclusiones: durante el seguimiento, los efectos de la ablación exitosa con RF se preservan en el tiempo. La taquicardia identificada en recurrencia siempre correspondió al mecanismo de reentrada a través de la vía accesoria.

Objective: the aim of this study was shown clinical characteristics and follow-up of patients with atrioventricular reentrant tachycardia (AVRT) who underwent radiofrequency catheter ablation (RCA) therapy. Material and Methods: from April 1992 to December 1995, 413 patients with AVRT underwent RCA therapy. Results: two hundred thirty four men (57%) and one hundred seventy nine women (43%) aged 31.3 ± 16-3 years were studied. 437 single accessory pathways were found; 24 had multiple accessory pathways. Ablation therapy was successful in 381 accessory pathways. During follow-up of 7 years, AVRT recurred in 51 patients (13%) and in 80% this occurred within the first 3 months after the procedure. 56 patients underwent a second RCA therapy with success in 35 patients (83.5); two reoccurred (5.7%); 365 accessory pathways (83.5) remained without evidence of preexcitation AVRT. Conclusions: during follow-up, these patients with successful ablation therapy remained without symptoms. In patients who underwent a second RCA therapy, atrioventricular reentrant mechanism was always present.

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Se efectuó el estudio prospectivo de las modificaciones del tiempo de relajación isométrica ventricular izquierda (TRIVI), en un modelo experimental de reperfusión miocárdica (RM), en 19 perrros. Estos se estudiaron con tórax abierto, en asistencia ventilatoria mecánica y monitoreo hemodinámico. Se colocó un catéter intracoronario en el tercio medio de la arteria descendente anterior (DA) para el registro directo de su presión. Se ligó la DA diatalmente a la primera diagonal durante 15 minutos y posteriormente se desligó. Se registraron ECO2D y Doppler pulsado con aproximaciones epicárdicas, en condiciones basales, a los 5 y 15 min de isquemia, a los 5, 15, 30 y 60 min de RM. Se analizaron la movilidad del septum interventricular (SIV) y sus cambios de grosor en sístole (S) y diástole (D). Se midió el TRIVI en todos los períodos mencionados. Para el estudio estadístico, se utilizó la T de Student. No hubo cambios significativos en el grosor S o D del septum interventricular. El TRIVI aumentó al comparar el registro basal con los minutos 5 y 15 de isquemia (p < 0.0001) y hubo regresión del mismo con la RM (p< 0.05). La isquemia miocárdica aguda prolonga el TRIVI. En este modelo, con la RM el TRIVI regresa a la normalidad. La medición del TRIVI puede ser utilizada coomo criterio de reperfusión.

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