Multidisciplinary Treatment in Patients with Craniofacial, Neurocognitive, and Neuromuscular Disorders with Obstructive Sleep Apnea: A Systematic Review of the Literature.

Obstructive sleep apnea (OSA) is a respiratory disorder that has a high prevalence in patients with craniofacial, neurocognitive, and neuromuscular disorders. Currently, the treatments for this population are diverse and depend on the individual conditions of the patient and the severity of the case. However, there are no multidisciplinary dental treatment guidelines. The aim of the present study was to determine the multidisciplinary dental treatment alternatives in patients with craniofacial, neurocognitive, and neuromuscular disorders with a diagnosis of OSA through evidence-based medicine. A systematic review of the literature has been performed by searching scientific articles in the PubMed, Cochrane, Ovid, ScienceDirect and Scopus databases, through controlled and uncontrolled language. Articles were classified according to the level of evidence and grades of recommendation through the Scottish Intercollegiate Guidelines Network. A total of 19,439 references were identified, of which 15 articles met the predetermined requirements to be included in the investigation. The articles included for this systematic review showed that mandibular distraction osteogenesis and adenotonsilectomy are the first-choice therapies for craniofacial and neurocognitive disorders. However, for neuromuscular disorders, the findings reported were not enough to provide information about surgical or nonsurgical alternatives. Despite the reported high frequency of OSA in those children with craniofacial, neurocognitive, and neuromuscular disorders, the evidence on the surgical and nonsurgical therapeutic success for OSA in these patients is scarce. It is necessary to perform future studies to investigate successful therapies for OSA in children. [Pediatr Ann. 2024;53(2):e62-e69.].

Antitrypanosomal Chloronitrobenzamides.

Human African trypanosomiasis (HAT), a neglected tropical disease caused by Trypanosoma brucei gambiense (Tbg) or Trypanosoma brucei rhodesiense (Tbr), remains a significant public health concern with over 55 million people at risk of infection. Current treatments for HAT face the challenges of poor efficacy, drug resistance, and toxicity. This study presents the synthesis and evaluation of chloronitrobenzamides (CNBs) against Trypanosoma species, identifying previously reported compound 52 as a potent and selective orally bioavailable antitrypanosomal agent. 52 was well tolerated in vivo and demonstrated favorable oral pharmacokinetics, maintaining plasma concentrations surpassing the cellular EC50 for over 24 h and achieving peak brain concentrations exceeding 7 µM in rodents after single oral administration (50 mg/kg). Treatment with 52 significantly extended the lifespan of mice infected with Trypanosoma congolense and T. brucei rhodesiense. These results demonstrate that 52 is a strong antitrypanosomal lead with potential for developing treatments for both human and animal African trypanosomiasis.

Retrospective analysis of outcomes for pediatric acute lymphoblastic leukemia in South American centers.

Introduction: Acute lymphoblastic Leukemia (ALL) is the most common pediatric malignancy. While the survival rate for childhood ALL exceeds 90% in high-income countries, the estimated survival in low-and middle-income countries ranges from 22-79%, depending on the region and local resources. Methods: This study retrospectively reviewed demographic, biological, and clinical parameters of children under 18 years of age with newly diagnosed ALL presenting between 2013-2017 across five pediatric centers in 4 countries in South America. Survival analyses were estimated using the Kaplan-Meier method. Results: Across the five centers, 752 patients were analyzed (Bolivia [N=9], Ecuador [N=221], Paraguay [N=197], Peru [N=325]) and 92.1% (n=690) patients were diagnosed with B-cell and 7.5% (n= 56) with T-cell ALL. The median age was 5.5 years old (IQR 7.29). At diagnosis, 47.8% of patients were categorized as standard and 51.9% as high risk per their institutional regimen. Advanced diagnostics availability varied between modalities. MRD was evaluated in 69.1% of patients; molecular testing was available for ETV6-RUNX, BCR-ABL1, TCF3-PBX1, and KMT2A-rearranged ALL in 75-81% of patients; however, karyotyping and evaluation for iAMP21 were only performed in 42-61% of patients. Central nervous system (CNS) involvement was evaluated at diagnosis in 57.3% (n=429) patients; of these, 93.7% (n=402) were CNS 1, 1.6% (n=7) were CNS 2, 0.7% (n=11) were CNS3, 1.9% (n=8) had cranial nerve palsy, and 2.1% (n=9) results unavailable. Chemotherapy delays >2 weeks were reported in 56.0% (n=421) patients during treatment. Delays were attributed to infection in 63.2% (n=265), drug-related toxicities in 47.3% (n=198), and resource constraints, including lack of bed availability in 23.2% (n=97) of patients. The 3-year Abandonment-sensitive EFS and OS were 61.0±1.9% and 67.2±1.8%, respectively. The 3-year EFS and OS were 71.0±1.8% and 79.6±1.7%, respectively. Discussion: This work reveals opportunities to improve survival, including addressing severe infections, treatment interruptions, and modifications due to drug shortages. In 2018, healthcare professionals across South America established the Pediatric Oncology Latin America (POLA) group in collaboration with St. Jude Children's Research Hospital. POLA collaborators developed an evidence-based, consensus-derived, adapted treatment guideline, informed by preliminary results of this evaluation, to serve as the new standard of care for pediatric ALL in participating institutions.

Evaluation of factors leading to poor outcomes for pediatric acute lymphoblastic leukemia in Mexico: a multi-institutional report of 2,116 patients.

Background and aims: Pediatric acute lymphoblastic leukemia (ALL) survival rates in low- and middle-income countries are lower due to deficiencies in multilevel factors, including access to timely diagnosis, risk-stratified therapy, and comprehensive supportive care. This retrospective study aimed to analyze outcomes for pediatric ALL at 16 centers in Mexico. Methods: Patients <18 years of age with newly diagnosed B- and T-cell ALL treated between January 2011 and December 2019 were included. Clinical and biological characteristics and their association with outcomes were examined. Results: Overall, 2,116 patients with a median age of 6.3 years were included. B-cell immunophenotype was identified in 1,889 (89.3%) patients. The median white blood cells at diagnosis were 11.2.5 × 103/mm3. CNS-1 status was reported in 1,810 (85.5%), CNS-2 in 67 (3.2%), and CNS-3 in 61 (2.9%). A total of 1,488 patients (70.4%) were classified as high-risk at diagnosis. However, in 52.5% (991/1,889) of patients with B-cell ALL, the reported risk group did not match the calculated risk group allocation based on National Cancer Institute (NCI) criteria. Fluorescence in situ hybridization (FISH) and PCR tests were performed for 407 (19.2%) and 736 (34.8%) patients, respectively. Minimal residual disease (MRD) during induction was performed in 1,158 patients (54.7%). The median follow-up was 3.7 years. During induction, 191 patients died (9.1%), and 45 patients (2.1%) experienced induction failure. A total of 365 deaths (17.3%) occurred, including 174 deaths after remission. Six percent (176) of patients abandoned treatment. The 5-year event-free survival (EFS) was 58.9% ± 1.7% for B-cell ALL and 47.4% ± 5.9% for T-cell ALL, while the 5-year overall survival (OS) was 67.5% ± 1.6% for B-cell ALL and 54.3% ± 0.6% for T-cell ALL. The 5-year cumulative incidence of central nervous system (CNS) relapse was 5.5% ± 0.6%. For the whole cohort, significantly higher outcomes were seen for patients aged 1-10 years, with DNA index >0.9, with hyperdiploid ALL, and without substantial treatment modifications. In multivariable analyses, age and Day 15 MRD continued to have a significant effect on EFS. Conclusion: Outcomes in this multi-institutional cohort describe poor outcomes, influenced by incomplete and inconsistent risk stratification, early toxic death, high on-treatment mortality, and high CNS relapse rate. Adopting comprehensive risk-stratification strategies, evidence-informed de-intensification for favorable-risk patients and optimized supportive care could improve outcomes.

Effect of paediatric early warning systems (PEWS) implementation on clinical deterioration event mortality among children with cancer in resource-limited hospitals in Latin America: a prospective, multicentre cohort study.

BACKGROUND: Paediatric early warning systems (PEWS) aid in the early identification of clinical deterioration events in children admitted to hospital. We aimed to investigate the effect of PEWS implementation on mortality due to clinical deterioration in children with cancer in 32 resource-limited hospitals across Latin America. METHODS: Proyecto Escala de Valoración de Alerta Temprana (Proyecto EVAT) is a quality improvement collaborative to implement PEWS in hospitals providing childhood cancer care. In this prospective, multicentre cohort study, centres joining Proyecto EVAT and completing PEWS implementation between April 1, 2017, and May 31, 2021, prospectively tracked clinical deterioration events and monthly inpatient-days in children admitted to hospital with cancer. De-identified registry data reported between April 17, 2017, and Nov 30, 2021, from all hospitals were included in analyses; children with limitations on escalation of care were excluded. The primary outcome was clinical deterioration event mortality. Incidence rate ratios (IRRs) were used to compare clinical deterioration event mortality before and after PEWS implementation; multivariable analyses assessed the correlation between clinical deterioration event mortality and centre characteristics. FINDINGS: Between April 1, 2017, and May 31, 2021, 32 paediatric oncology centres from 11 countries in Latin America successfully implemented PEWS through Proyecto EVAT; these centres documented 2020 clinical deterioration events in 1651 patients over 556 400 inpatient-days. Overall clinical deterioration event mortality was 32·9% (664 of 2020 events). The median age of patients with clinical deterioration events was 8·5 years (IQR 3·9-13·2), and 1095 (54·2%) of 2020 clinical deterioration events were reported in male patients; data on race or ethnicity were not collected. Data were reported per centre for a median of 12 months (IQR 10-13) before PEWS implementation and 18 months (16-18) after PEWS implementation. The mortality rate due to a clinical deterioration event was 1·33 events per 1000 patient-days before PEWS implementation and 1·09 events per 1000 patient-days after PEWS implementation (IRR 0·82 [95% CI 0·69-0·97]; p=0·021). In the multivariable analysis of centre characteristics, higher clinical deterioration event mortality rates before PEWS implementation (IRR 1·32 [95% CI 1·22-1·43]; p<0·0001), being a teaching hospital (1·18 [1·09-1·27]; p<0·0001), not having a separate paediatric haematology-oncology unit (1·38 [1·21-1·57]; p<0·0001), and having fewer PEWS omissions (0·95 [0·92-0·99]; p=0·0091) were associated with a greater reduction in clinical deterioration event mortality after PEWS implementation; no association was found with country income level (IRR 0·86 [95% CI 0·68-1·09]; p=0·22) or clinical deterioration event rates before PEWS implementation (1·04 [0·97-1·12]; p=0·29). INTERPRETATION: PEWS implementation was associated with reduced clinical deterioration event mortality in paediatric patients with cancer across 32 resource-limited hospitals in Latin America. These data support the use of PEWS as an effective evidence-based intervention to reduce disparities in global survival for children with cancer. FUNDING: American Lebanese Syrian Associated Charities, US National Institutes of Health, and Conquer Cancer Foundation. TRANSLATIONS: For the Spanish and Portuguese translations of the abstract see Supplementary Materials section.

Treatment-related mortality in children with cancer in low-income and middle-income countries: a systematic review and meta-analysis.

BACKGROUND: Approximately 90% of children with cancer live in low-income and middle-income countries (LMICs), where 5-year survival is lower than 20%. Treatment-related mortality in high-income countries is approximately 3-5%; however, in LMICs, treatment-related mortality has been reported in up to 45% of children with cancer. This study aimed to systematically explore the burden of treatment-related mortality in children with cancer in LMICs and to explore the association between country income level and treatment-related mortality. METHODS: For this systematic review and meta-analysis we identified articles published between Jan 1, 2010, and June 22, 2021, describing treatment-related mortality in paediatric patients (aged 0-21 years) with cancer in LMICs. We searched PubMed, Trip, Web of Science, Embase, and the WHO Global Metric Index databases. The search was limited to full-text articles and excluded case reports (<10 patients) and haematopoietic stem-cell transplantation recipients. Two reviewers independently screened studies for eligibility, extracted data from included publications, and evaluated data quality. Random and mixed-effects models were used to estimate treatment-related mortality burden and trends. The Cochran-Q statistic was used to assess heterogeneity between studies. This study is registered on PROSPERO (CRD42021264849). FINDINGS: Of 13 269 identified abstracts, 501 studies representing 68 351 paediatric patients with cancer were included. The treatment-related mortality estimate was 6·82% (95% CI 5·99-7·64), accounting for 30·9% of overall mortality (4437 of 14 358 deaths). Treatment-related mortality was inversely related to country income. Treatment-related mortality was 14·19% (95% CI 9·65-18·73) in low-income countries, 9·21% (7·93-10·49) in lower-middle-income countries, and 4·47% (3·42-5·53) in upper-middle-income countries (Cochran-Q 42·39, p<0·0001). In upper-middle-income countries, the incidence of treatment-related mortality decreased over time (slope -0·002, p=0·0028); however, outcomes remained unchanged in low-income (p=0·21) and lower-middle-income countries (p=0·16). INTERPRETATION: Approximately one in 15 children receiving cancer treatment in LMICs die from treatment-related complications. Although treatment-related mortality has decreased in upper-middle-income countries over time, it remains unchanged in LMICs. There is an urgent need for targeted supportive care interventions to reduce global disparities in childhood cancer survival. FUNDING: American Lebanese Syrian Associated Charities and National Cancer Institute.

Model for regional collaboration: Successful strategy to implement a pediatric early warning system in 36 pediatric oncology centers in Latin America.

BACKGROUND: Pediatric early warning systems (PEWS) aid in the early identification of deterioration in hospitalized children with cancer; however, they are under-used in resource-limited settings. The authors use the knowledge-to-action framework to describe the implementation strategy for Proyecto Escala de Valoracion de Alerta Temprana (EVAT), a multicenter quality-improvement collaborative, to scale-up PEWS in pediatric oncology centers in Latin America. METHODS: Proyecto EVAT mentored participating centers through an adaptable implementation strategy to: (1) monitor clinical deterioration in children with cancer, (2) contextually adapt PEWS, (3) assess barriers to using PEWS, (4) pilot and implement PEWS, (5) monitor the use of PEWS, (6) evaluate outcomes, and (7) sustain PEWS. The implementation outcomes assessed included the quality of PEWS use, the time required for implementation, and global program impact. RESULTS: From April 2017 to October 2021, 36 diverse Proyecto EVAT hospitals from 13 countries in Latin America collectively managing more than 4100 annual new pediatric cancer diagnoses successfully implemented PEWS. The time to complete all program phases varied among centers, averaging 7 months (range, 3-13 months) from PEWS pilot to implementation completion. All centers ultimately implemented PEWS and maintained high-quality PEWS use for up to 18 months after implementation. Across the 36 centers, more than 11,100 clinicians were trained in PEWS, and more than 41,000 pediatric hospital admissions had PEWS used in their care. CONCLUSIONS: Evidence-based interventions like PEWS can be successfully scaled-up regionally basis using a systematic approach that includes a collaborative network, an adaptable implementation strategy, and regional mentorship. Lessons learned can guide future programs to promote the widespread adoption of effective interventions and reduce global disparities in childhood cancer outcomes. LAY SUMMARY: Pediatric early warning systems (PEWS) are clinical tools used to identify deterioration in hospitalized children with cancer; however, implementation challenges limit their use in resource-limited settings. Proyecto EVAT is a multicenter quality-improvement collaborative to implement PEWS in 36 pediatric oncology centers in Latin America. This is the first multicenter, multinational study reporting a successful implementation strategy (Proyecto EVAT) to regionally scale-up PEWS. The lessons learned from Proyecto EVAT can inform future programs to promote the adoption of clinical interventions to globally improve childhood cancer outcomes.

Clinical and organizational risk factors for mortality during deterioration events among pediatric oncology patients in Latin America: A multicenter prospective cohort.

BACKGROUND: Hospitalized pediatric hematology-oncology (PHO) patients have frequent clinical deterioration events (CDE) requiring intensive care unit (ICU) admission, particularly in resource-limited settings. The objective of this study was to describe CDEs in hospitalized PHO patients in Latin America and to identify event-level and center-level risk factors for mortality. METHODS: In 2017, the authors implemented a prospective registry of CDEs, defined as unplanned transfers to a higher level of care, use of ICU-level interventions on the floor, or nonpalliative floor deaths, in 16 PHO centers in 10 countries. PHO hospital admissions and hospital inpatient days were also reported. This study analyzes the first year of registry data (June 2017 to May 2018). RESULTS: Among 16 centers, 553 CDEs were reported in PHO patients during 11,536 admissions and 119,414 inpatient days (4.63 per 1000 inpatient days). Event mortality was 29% (1.33 per 1000 inpatient days) but ranged widely across centers (11%-79% or 0.36-5.80 per 1000 inpatient days). Significant risk factors for event mortality included requiring any ICU-level intervention on the floor and not being transferred to a higher level of care. Events with organ dysfunction, a higher severity of illness, and a requirement for ICU intervention had higher mortality. In center-level analysis, hospitals with a higher volume of PHO patients, less floor use of ICU intervention, lower severity of illness on transfer, and lower rates of floor cardiopulmonary arrest had lower event mortality. CONCLUSIONS: Hospitalized PHO patients who experience CDEs in resource-limited settings frequently require floor-based ICU interventions and have high mortality. Modifiable hospital practices around the escalation of care for these high-risk patients may contribute to poor outcomes. Earlier recognition of critical illness and timely ICU transfer may improve survival in hospitalized children with cancer.

Abnormal Vital Signs Predict Critical Deterioration in Hospitalized Pediatric Hematology-Oncology and Post-hematopoietic Cell Transplant Patients.

Introduction: Hospitalized pediatric hematology-oncology and post-hematopoietic cell transplant (HCT) patients have frequent deterioration requiring Pediatric Intensive Care Unit (PICU) care. Critical deterioration (CD), defined as unplanned PICU transfer requiring life-sustaining interventions within 12 h, is a pragmatic metric to evaluate emergency response systems (ERS) in pediatrics, however, it has not been investigated in these patients. The goal of this study was to evaluate if CD is an appropriate metric to assess effectiveness of ERS in pediatric hematology-oncology and post-HCT patients and if it is preceded by an actionable period of vital sign changes. Methods: A retrospective review of all unplanned PICU transfers and floor cardiopulmonary arrests in a dedicated pediatric hematology-oncology hospital between August 2014 and July 2016. Vital signs and physical exam findings 48 h prior to events were converted to Pediatric Early Warning System-Like Scores (PEWS-LS) using cardiovascular, respiratory, and neurologic criteria. Results: There were 220 deterioration events, with 107 (48.6%) meeting criteria for CD, representing a rate of 2.98 per 1,000-inpatient-days. Using the first event per hospitalization (n = 184), patients with CD had higher mortality (17.4 vs. 7.6%, p = 0.045), fewer median ICU-free-days (21 vs. 24, p = 0.011), ventilator-free-days (25 vs. 28, p < 0.001), and vasoactive-free-days (27 vs. 28, p < 0.001). Using vital sign data 48 h prior to deterioration events, those with CD had higher PEWS-LS on PICU admission (p < 0.001), spent more time with elevated PEWS-LS prior to PICU transfer (p = 0.008 to 0.023) and had a longer time from first abnormal PEWS-LS (p = 0.007 to 0.043). Significant difference between the two groups was observed as early as 4 h prior to the event (p = 0.047). Conclusion: Hospitalized pediatric hematology-oncology and post-HCT patients have frequent deterioration resulting in a high mortality. In these patients, CD is over 13 times more common than floor cardiopulmonary arrests and associated with higher mortality and fewer event-free days, making it a useful metric in these patients. CD is preceded by a long duration of abnormal vital signs, making it potentially preventable through earlier recognition.

El curso Básico en Educación Médica. Experiencias de la Facultad de Ciencias Médicas "General Calixto García" / Basic Course in Medical Education. Experiences in Calisto Garcia Medical School

Introducción: La preparación como docentes de los profesionales de la salud es una necesidad a la que la universidad médica cubana ha dado su atención y prioridad como respuesta al encargo social de la formación de sus recursos humanos, dado la correspondencia entre la preparación científica de los docentes en el área de las ciencias de la educación con la pertinencia, calidad y eficiencia de la enseñanza. A este fin ha contribuido el desarrollo del Curso Básico en Educación Médica en la Facultad de Ciencias Médicas "General Calixto García". Objetivo: Caracterizar el desarrollo del Curso Básico en Educación Médica en la Facultad de Ciencias Médicas "General Calixto García" en el periodo de 2014-2017, y las experiencias acumuladas para su continuo perfeccionamiento. Métodos: Se realizó un estudio descriptivo de las 6 últimas ediciones comprendidas en el período 2012-2017, considerándose las variables de: programa de estudio, categoría docente de los participantes al iniciar el curso, satisfacción con su desarrollo y resultados de la promoción docente. Para las indagaciones empíricas se aplicaron dos encuestas a los cursistas y la técnica de PNI como parte de la valoración general del curso. Resultados: Se obtuvo que se capacitaron un total de 313 profesionales de la salud vinculados a las actividades docentes, de ellos un 40 percent no tenían categoría docente, el 1 percent eran Instructores, y el 1 9 percent con categoría de Asistente, todos inmersos en el proceso de obtención o promoción de categorización docente. La valoración general del curso fue muy satisfactoria, destacándose como opiniones positivas la calidad y preparación de los profesores del claustro, satisfacción sobre los temas y contenidos tratados y la aplicación a su práctica docente, la amplia bibliografía ofrecida, así como el intercambio producido en los trabajos grupales. Conclusiones: El Curso Básico en Educación Médica facilita a los profesores sin preparación docente, apropiarse de herramientas fundamentales que les permitan aplicar los fundamentos científicos y pedagógicos en los procesos de formación de profesionales en Ciencias de la Salud y ha sido muy bien valorado por los cursistas y otros actores del proceso. Los criterios obtenidos contribuirán a su continuo perfeccionamiento en función de lograr transformación de los profesionales de la salud vinculados con las ciencias de la educación(AU)

Introduction: The health professionals' training as further professors is a necessity to which the Cuban medical university has given attention and priority as a response to the social mission of training its human resources, given the correspondence between scientific preparation of professors in the field of ​​educational sciences with the relevance, quality and efficiency of teaching. The development of the Basic Course in Medical Education has contributed to this aim in General Calixto García Medical School. Objective: To characterize the development of the Basic Course in Medical Education in General Calixto García Medical School, in the period 2014-2017, and the accumulated experiences for its continuous improvement. Methods: A descriptive study was carried out of the last sex editions within the period 2012-2017, considering the variables study program, teaching category of the participants at the beginning of the course, satisfaction with their development, and outcomes of the teaching promotion. For the empirical investigations, two surveys were applied to the course students. The PNI technique was applied as part of the general assessment of the course. Results: It was obtained that a total of 313 health professionals associated to the teaching activities were trained, of which 40 percent did not have a teaching category, 1 percent were Instructors, and 1 percent had the category of Assistant, all immersed in the process of obtaining or promoting teaching categorization. The general evaluation of the course was very satisfactory, highlighting with positive opinions the quality and preparation of the faculty, the satisfaction with the topics and contents treated and their application to their teaching practice, the wide bibliography offered, as well as the exchange produced in the group work. Conclusions: The Basic Course in Medical Education facilitates professors without teaching training the appropriation of fundamental tools that allow them to apply the scientific and pedagogical foundations in the training processes of professionals in Health Sciences and has been highly valued by the students and other actors in the process. The criteria obtained will contribute to its continuous improvement, in order to achieve the transformation of health professionals associated with education sciences(AU)

Discovery of novel, orally bioavailable, antileishmanial compounds using phenotypic screening.

Leishmaniasis is a parasitic infection that afflicts approximately 12 million people worldwide. There are several limitations to the approved drug therapies for leishmaniasis, including moderate to severe toxicity, growing drug resistance, and the need for extended dosing. Moreover, miltefosine is currently the only orally available drug therapy for this infection. We addressed the pressing need for new therapies by pursuing a two-step phenotypic screen to discover novel, potent, and orally bioavailable antileishmanials. First, we conducted a high-throughput screen (HTS) of roughly 600,000 small molecules for growth inhibition against the promastigote form of the parasite life cycle using the nucleic acid binding dye SYBR Green I. This screen identified approximately 2,700 compounds that inhibited growth by over 65% at a single point concentration of 10 µM. We next used this 2700 compound focused library to identify compounds that were highly potent against the disease-causing intra-macrophage amastigote form and exhibited limited toxicity toward the host macrophages. This two-step screening strategy uncovered nine unique chemical scaffolds within our collection, including two previously described antileishmanials. We further profiled two of the novel compounds for in vitro absorption, distribution, metabolism, excretion, and in vivo pharmacokinetics. Both compounds proved orally bioavailable, affording plasma exposures above the half-maximal effective concentration (EC50) concentration for at least 12 hours. Both compounds were efficacious when administered orally in a murine model of cutaneous leishmaniasis. One of the two compounds exerted potent activity against trypanosomes, which are kinetoplastid parasites related to Leishmania species. Therefore, this compound could help control multiple parasitic diseases. The promising pharmacokinetic profile and significant in vivo efficacy observed from our HTS hits highlight the utility of our two-step phenotypic screening strategy and strongly suggest that medicinal chemistry optimization of these newly identified scaffolds will lead to promising candidates for an orally available anti-parasitic drug.

Identificación de problemas y propuesta de acciones en el contexto de la educación técnico- profesional en enfermería / Identification of problems and proposal of actions in the context of technical-professional education in nursing

Se realizó un estudio descriptivo destinado a identificar aquellos problemas que inciden en el proceso docente educativo en el contexto de la Educación Técnico- Profesional en Enfermería (ETP) en la Facultad de Ciencias Médicas "Gral. Calixto García". Además, se elaboró una propuesta de acciones que pudieran formar parte de un proyecto de intervención para el mejoramiento de los que se consideran más importantes. Para la realización de este, se revisó el pensamiento estratégico de Fidel Castro sobre la formación de capital humano en salud. Se requirió de la colaboración del colectivo de profesores del departamento docente de Enfermería de la Facultad de Ciencias Medicas "Gral. Calixto García" integrado por 33 profesores de la plantilla facultad todos con categoría docente; de ellos, 10 participaron en el ejercicio. Durante la realización del trabajo se aplicaron técnicas de dirección cualitativa y cuantitativa. Los resultados de la aplicación denotan cómo los tres problemas considerados de manera global como los de mayor importancia. En primer lugar, la descentralización del proceso formativo hacia las diferentes facultades sin la creación de la estructura necesaria, al recibir una puntuación total de 60 puntos y un puntaje promedio de 6.0. En segundo lugar, la masividad sin calidad en el ingreso al recibir una puntuación total de 58 puntos y un puntaje promedio de 5,8. En tercer lugar, los profesores de los Centros de Educación Superior (CES) no preparados metodológicamente para la enseñanza media y media superior al recibir una puntuación total de 55 puntos y un puntaje promedio de 5,5. La prioridad fue para el segundo problema, al recibir una puntuación total de 76 puntos y un puntaje promedio de 7,6(AU)

A descriptive study to identify those problems that affect the educational process in the context of the Technical and Vocational Education in Nursing (ETP) at the Faculty of Medical Sciences "Gral. Calixto García ". In addition to developing a proposal for actions that could be part of an intervention project to improve those considered most important. To achieve the same strategic thinking of Fidel Castro on the formation of human capital. It required the collaboration of the group of teachers of Department of Nursing, composed of 33 teachers of all faculty staff with teaching category. Ten of them participated in the exercise. During the performance of work qualitative and quantitative management techniques were applied. The results of the application denoted as the three problems considered globally as the most important, first decentralization of the training process to the different faculties without the creation of the necessary structure to receive a total score of 60 points and an average score 6.0, second massiveness without quality income to receive a total score of 58 points and an average score of 5.8 and thirdly teachers of the Centers for Higher Education (CES) not prepared methodologically for secondary education and than average receive a total score of 55 points and an average score of 5.5. The priority was for the second problem receiving a total score of 76 points and an average score of 7.6(AU)

Estrategia pedagógica para elevar la formación vocacional y orientación profesional de los estudiantes de Enfermería en la Facultad "Gral. Calixto García", 2013-2014 / Pedagogical strategy for increasing vocational formation and professional orientation in Nursing students from "General Calixto García School", 2013-2014

INTRODUCCIÓN: el trabajo de formación vocacional y orientación profesional es un derecho y un beneficio al que todos los estudiantes deben tener acceso y con la calidad requerida durante su formación precedente al ingreso a una carrera universitaria o de formación técnica, aun así llegan a las instituciones de estudios superiores con desconocimiento de la carrera elegida. OBJETIVOS: diseñar una estrategia pedagógica para elevar la formación vocacional y orientación profesional de los estudiantes de nuevo ingreso a la Educación técnica y profesional en la especialidad de Enfermería, con nivel de noveno grado, en la Facultad de Ciencias Médicas "General Calixto García" en el curso 2013 - 2014. MÉTODOS: el universo estuvo constituido por 249 estudiantes que se forman en los municipios de Centro Habana y Habana del Este. Se seleccionó una muestra de un 20 % de manera intencional, al elegirse dos brigadas de estudiantes de los Municipios de Centro Habana y La Habana del Este. Los métodos y procedimientos utilizados tuvieron un enfoque cuanticualitativo, se aplicaron encuestas a estudiantes y profesores, se revisó documentación que aporta el diagnóstico psicopedagógico que se realiza a los estudiantes de nuevo ingreso en esta Facultad y finalmente se realizó la triangulación metodológica, que permitió la información necesaria para elaborar la estrategia, la cual fue validada por un grupo de expertos. RESULTADOS: los estudiantes denotan que solo el 58 % recibieron información sobre la especialidad de enfermería en la enseñanza precedente, de ellos el 46,4 % la valoró entre regular y mala, y que ésta proviene en su mayoría de sus profesores de secundaria básica y no de especialistas de Enfermería. El diagnóstico psicopedagógico denotó dificultades en el funcionamiento familiar, la motivación hacia la especialidad y las técnicas de estudio. CONCLUSIONES: se presenta la estrategia pedagógica estructurada en tres ciclos con las acciones, objetivos, responsables, participantes e indicadores de evaluación, la misma fue sometida a criterios de especialistas para su validación.

INTRODUCTION: The work of vocational formation and professional orientation is a right and a benefit all the students should have access to with the required quality during its training before starting the university or another technical training, but they start ignorant of the chosen major. OBJECTIVE: To design a pedagogic strategy to increase the vocational formation and professional orientation of the newly admitted students for the technical and professional education in the specialty of Nursing, with ninth grade schooling and to General Calixto García School of Medical Sciences, in the academic year 2013 - 2014. METHODS: The target group was made up by 249 students who receive their training in Centro Havana and La Habana del Este Municipalities. A 20 % sample was intentionally chosen, when two school brigades of students from the aforementioned municipalities were chosen. The methods and procedures used had an approach both qualitative and quantitative, surveys were conducted on students and professors, the documentation providing the psycho-pedagogical diagnostic of the students newly admitted to this School was revised, and finally the results' methodological triangulation was carried out, which showed the necessary information to elaborate the strategy, which was validated by a group of experts. RESULTS: The students denote that only 58 % received information about the Nursing specialty in their previous school level, 46.4 % of them evaluated that information from fair to bad, as coming mostly from their junior high school teachers and not Nursing specialists. The psycho-pedagogical diagnosis denoted difficulties in the functioning of the family, the motivation towards the specialty and the study techniques. CONCLUSIONS: The pedagogic strategy is presented as structured in three stages, with the actions, objectives, responsible stakeholders, participants and evaluation indicators, the same was subjected to specialists' criteria for its validation.

Estrategia pedagógica para elevar la formación vocacional y orientación profesional de los estudiantes de Enfermería en la Facultad "Gral. Calixto García", 2013-2014 / Estrategia pedagógica para elevar la formación vocacional y orientación profesional de los estudiantes de Enfermería en la Facultad "Gral. Calixto García", 2013-2014 / Pedagogical strategy for increasing vocational formation and professional orientation in Nursing students from "General Calixto García School", 2013-2014 / Pedagogical strategy for increasing vocational formation and professional orientation in Nursing students from "General Calixto García School", 2013-2014

Introducción: el trabajo de formación vocacional y orientación profesional es un derecho y un beneficio al que todos los estudiantes deben tener acceso y con la calidad requerida durante su formación precedente al ingreso a una carrera universitaria o de formación técnica, aun así llegan a las instituciones de estudios superiores con desconocimiento de la carrera elegida.Objetivos: diseñar una estrategia pedagógica para elevar la formación vocacional y orientación profesional de los estudiantes de nuevo ingreso a la Educación técnica y profesional en la especialidad de Enfermería, con nivel de noveno grado, en la Facultad de Ciencias Médicas "General Calixto García" en el curso 2013 - 2014.Métodos: el universo estuvo constituido por 249 estudiantes que se forman en los municipios de Centro Habana y Habana del Este. Se seleccionó una muestra de un 20 por ciento de manera intencional, al elegirse dos brigadas de estudiantes de los Municipios de Centro Habana y La Habana del Este. Los métodos y procedimientos utilizados tuvieron un enfoque cuanticualitativo, se aplicaron encuestas a estudiantes y profesores, se revisó documentación que aporta el diagnóstico psicopedagógico que se realiza a los estudiantes de nuevo ingreso en esta Facultad y finalmente se realizó la triangulación metodológica, que permitió la información necesaria para elaborar la estrategia, la cual fue validada por un grupo de expertos.Resultados: los estudiantes denotan que solo el 58 por ciento recibieron información sobre la especialidad de enfermería en la enseñanza precedente, de ellos el 46,4 por ciento la valoró entre regular y mala, y que ésta proviene en su mayoría de sus profesores de secundaria básica y no de especialistas de Enfermería. El diagnóstico psicopedagógico denotó dificultades en el funcionamiento familiar, la motivación hacia la especialidad y las técnicas de estudio...

Introducción: el trabajo de formación vocacional y orientación profesional es un derecho y un beneficio al que todos los estudiantes deben tener acceso y con la calidad requerida durante su formación precedente al ingreso a una carrera universitaria o de formación técnica, aun así llegan a las instituciones de estudios superiores con desconocimiento de la carrera elegida.Objetivos: diseñar una estrategia pedagógica para elevar la formación vocacional y orientación profesional de los estudiantes de nuevo ingreso a la Educación técnica y profesional en la especialidad de Enfermería, con nivel de noveno grado, en la Facultad de Ciencias Médicas "General Calixto García" en el curso 2013 - 2014.Métodos: el universo estuvo constituido por 249 estudiantes que se forman en los municipios de Centro Habana y Habana del Este. Se seleccionó una muestra de un 20 por ciento de manera intencional, al elegirse dos brigadas de estudiantes de los Municipios de Centro Habana y La Habana del Este. Los métodos y procedimientos utilizados tuvieron un enfoque cuanticualitativo, se aplicaron encuestas a estudiantes y profesores, se revisó documentación que aporta el diagnóstico psicopedagógico que se realiza a los estudiantes de nuevo ingreso en esta Facultad y finalmente se realizó la triangulación metodológica, que permitió la información necesaria para elaborar la estrategia, la cual fue validada por un grupo de expertos.Resultados: los estudiantes denotan que solo el 58 por ciento recibieron información sobre la especialidad de enfermería en la enseñanza precedente, de ellos el 46,4 por ciento la valoró entre regular y mala, y que ésta proviene en su mayoría de sus profesores de secundaria básica y no de especialistas de Enfermería. El diagnóstico psicopedagógico denotó dificultades en el funcionamiento familiar, la motivación hacia la especialidad y las técnicas de estudio...

Introduction: The work of vocational formation and professional orientation is a right and a benefit all the students should have access to with the required quality during its training before starting the university or another technical training, but they start ignorant of the chosen major.Objective: To design a pedagogic strategy to increase the vocational formation and professional orientation of the newly admitted students for the technical and professional education in the specialty of Nursing, with ninth grade schooling and to General Calixto García School of Medical Sciences, in the academic year 2013 - 2014.Methods: The target group was made up by 249 students who receive their training in Centro Havana and La Habana del Este Municipalities. A 20 percent sample was intentionally chosen, when two school brigades of students from the aforementioned municipalities were chosen. The methods and procedures used had an approach both qualitative and quantitative, surveys were conducted on students and professors, the documentation providing the psycho-pedagogical diagnostic of the students newly admitted to this School was revised, and finally the results' methodological triangulation was carried out, which showed the necessary information to elaborate the strategy, which was validated by a group of experts.Results: The students denote that only 58 percent received information about the Nursing specialty in their previous school level, 46.4 percent of them evaluated that information from fair to bad, as coming mostly from their junior high school teachers and not Nursing specialists. The psycho-pedagogical diagnosis denoted difficulties in the functioning of the family, the motivation towards the specialty and the study techniques...

Introduction: The work of vocational formation and professional orientation is a right and a benefit all the students should have access to with the required quality during its training before starting the university or another technical training, but they start ignorant of the chosen major.Objective: To design a pedagogic strategy to increase the vocational formation and professional orientation of the newly admitted students for the technical and professional education in the specialty of Nursing, with ninth grade schooling and to General Calixto García School of Medical Sciences, in the academic year 2013 - 2014.Methods: The target group was made up by 249 students who receive their training in Centro Havana and La Habana del Este Municipalities. A 20 percent sample was intentionally chosen, when two school brigades of students from the aforementioned municipalities were chosen. The methods and procedures used had an approach both qualitative and quantitative, surveys were conducted on students and professors, the documentation providing the psycho-pedagogical diagnostic of the students newly admitted to this School was revised, and finally the results' methodological triangulation was carried out, which showed the necessary information to elaborate the strategy, which was validated by a group of experts.Results: The students denote that only 58 percent received information about the Nursing specialty in their previous school level, 46.4 percent of them evaluated that information from fair to bad, as coming mostly from their junior high school teachers and not Nursing specialists. The psycho-pedagogical diagnosis denoted difficulties in the functioning of the family, the motivation towards the specialty and the study techniques...

Pentacyclic nitrofurans that rapidly kill nifurtimox-resistant trypanosomes.

OBJECTIVES: In response to reports of Trypanosoma brucei resistance to the nitroaromatic drug nifurtimox, we evaluated the potential of antituberculosis nitrofuran isoxazolines as inhibitors of trypanosome growth. METHODS: The susceptibility of T. brucei brucei was assessed in vitro. The lowest effective concentration to inhibit growth (EC90) against drug-susceptible and -resistant parasites, time-kill kinetics, reversibility of inhibition and propensity for P-glycoprotein-mediated exclusion from the blood-brain barrier were determined. RESULTS: Nitrofuran isoxazolines were potent inhibitors of T. brucei brucei proliferation at nanomolar concentrations, with pentacyclic nitrofurans being 100-fold more potent than nifurtimox. Activity was sustained against nifurtimox-resistant parasites, suggesting the possibility of a unique mechanism of activation and potential for use in the treatment of drug-resistant infections. Exposure of parasites to the maximum concentrations of Compound 15 achieved in vivo with oral dosing yielded >2 logs of irreversible killing in <4 h, indicating rapid trypanocidal activity. CONCLUSIONS: Pentacyclic nitrofuran isoxazolines warrant further development for the treatment of drug-susceptible and nifurtimox-resistant trypanosome infections.

Evaluation of histone deacetylase inhibitors (HDACi) as therapeutic leads for human African trypanosomiasis (HAT).

Two of the histone deacetylases, TbDAC1 and TbDAC3, have been reported to be essential genes in trypanosomes. Therefore, we tested the activity of a panel of human histone deacetylase inhibitors (HDACi) for their ability to block proliferation of Trypanosoma brucei brucei. Among the HDACi's, the hydroxamic acid derivatives panobinostat and belinostat exhibited potency that appeared to make them viable candidates for development due to their reported pharmacokinetic characteristics. However, cellular pharmacodynamic analysis demonstrated that these drugs were unable to kill cultured parasites at exposures seen in patients at their tolerated doses and additionally failed to show any synergistic effects in combination with pentamidine, suramin, melarsoprol, or nifurtimox. Analysis of the potency of the entire HDACi panel revealed no correlations between potency against any human HDAC isoform and inhibition of T. brucei proliferation, suggesting that the trypanosome histone deacetylases possess a unique specificity. These studies confirmed that HDAC inhibitors have potential as leads against human African trypanosomiasis but that none of the current clinical candidates can be directly repurposed. Therefore, development of HDACi's with appropriate specificity and potency may be a viable route to a new class of anti-trypanosomal drugs.

(+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium.

Drug discovery for malaria has been transformed in the last 5 years by the discovery of many new lead compounds identified by phenotypic screening. The process of developing these compounds as drug leads and studying the cellular responses they induce is revealing new targets that regulate key processes in the Plasmodium parasites that cause malaria. We disclose herein that the clinical candidate (+)-SJ733 acts upon one of these targets, ATP4. ATP4 is thought to be a cation-transporting ATPase responsible for maintaining low intracellular Na(+) levels in the parasite. Treatment of parasitized erythrocytes with (+)-SJ733 in vitro caused a rapid perturbation of Na(+) homeostasis in the parasite. This perturbation was followed by profound physical changes in the infected cells, including increased membrane rigidity and externalization of phosphatidylserine, consistent with eryptosis (erythrocyte suicide) or senescence. These changes are proposed to underpin the rapid (+)-SJ733-induced clearance of parasites seen in vivo. Plasmodium falciparum ATPase 4 (pfatp4) mutations that confer resistance to (+)-SJ733 carry a high fitness cost. The speed with which (+)-SJ733 kills parasites and the high fitness cost associated with resistance-conferring mutations appear to slow and suppress the selection of highly drug-resistant mutants in vivo. Together, our data suggest that inhibitors of PfATP4 have highly attractive features for fast-acting antimalarials to be used in the global eradication campaign.

Synthesis and evaluation of methylsulfonylnitrobenzamides (MSNBAs) as inhibitors of the thyroid hormone receptor-coactivator interaction.

We previously identified the methylsulfonylnitrobenzoates (MSNBs) that block the interaction of the thyroid hormone receptor with its obligate transcriptional coactivators and prevent thyroid hormone signaling. As part of our lead optimization work we demonstrated that sulfonylnitrophenylthiazoles (SNPTs), which replace the ester linkage of MSNBs with a thiazole, also inhibited coactivator binding to TR. Here we report that replacement of the ester with an amide (methylsulfonylnitrobenzamides, MSNBA) also provides active TR antagonists.

Decarbonylative approach to the synthesis of enamides from amino acids: stereoselective synthesis of the (Z)-aminovinyl-D-cysteine unit of mersacidin.

The Pd- and Ni-promoted decarbonylation of amino acid thioesters proceeds smoothly to yield enamides. The synthesis of the (S)-(Z)-AviMeCys subunit of mersacidin, an MRSA-active lantibiotic, via this approach, is described.

Synthesis of the AviMeCys-containing D-ring of mersacidin.

A chemical synthesis of the D-ring of mersacidin is reported. The synthetic route relied upon development of a method for late-stage introduction of an unusual S-[(Z)-2-aminovinyl]-(3S)-3-methyl-D-cysteine (AviMeCys) functional group via an oxidative decarbonylation/decarboxylation reaction.