A research definition and framework for acute paediatric critical illness across resource-variable settings: a modified Delphi consensus.

The true global burden of paediatric critical illness remains unknown. Studies on children with life-threatening conditions are hindered by the absence of a common definition for acute paediatric critical illness (DEFCRIT) that outlines components and attributes of critical illness and does not depend on local capacity to provide critical care. We present an evidence-informed consensus definition and framework for acute paediatric critical illness. DEFCRIT was developed following a scoping review of 29 studies and key concepts identified by an interdisciplinary, international core expert panel (n=24). A modified Delphi process was then done with a panel of multidisciplinary health-care global experts (n=109) until consensus was reached on eight essential attributes and 28 statements as the basis of DEFCRIT. Consensus was reached in two Delphi rounds with an expert retention rate of 89%. The final consensus definition for acute paediatric critical illness is: an infant, child, or adolescent with an illness, injury, or post-operative state that increases the risk for or results in acute physiological instability (abnormal physiological parameters or vital organ dysfunction or failure) or a clinical support requirement (such as frequent or continuous monitoring or time-sensitive interventions) to prevent further deterioration or death. The proposed definition and framework provide the conceptual clarity needed for a unified approach for global research across resource-variable settings. Future work will centre on validating DEFCRIT and determining high priority measures and guidelines for data collection and analysis that will promote its use in research.

CritCom: assessment of quality of interdisciplinary communication around deterioration in pediatric oncologic patients.

Background: High-quality clinical care requires excellent interdisciplinary communication, especially during emergencies, and no tools exist to evaluate communication in critical care. We describe the development of a pragmatic tool focusing on interdisciplinary communication during patient deterioration (CritCom). Methods: The preliminary CritCom tool was developed after a literature review and consultation with a multidisciplinary panel of global experts in communication, pediatric oncology, and critical care to review the domains and establish content validity iteratively. Face and linguistic validity were established through cognitive interviews, translation, and linguistic synthesis. We conducted a pilot study among an international group of clinicians to establish reliability and usability. Results: After reviewing 105 potential survey items, we identified 52 items across seven domains. These were refined through cognitive interviews with 36 clinicians from 15 countries. CritCom was piloted with 433 clinicians (58% nurses, 36% physicians, and 6% other) from 42 hospitals in 22 countries. Psychometric testing guided the refinement of the items for the final tool. CritCom comprised six domains with five items each (30 total). The final tool has excellent reliability (Cronbach's alpha 0.81-0.86), usability (93% agree or strongly agree that the tool is easy to use), and similar performance between English and Spanish tools. Confirmatory factor analysis was used to establish the final 6-domain structure. Conclusions: CritCom is a reliable and pragmatic bilingual tool to assess the quality of interdisciplinary communication around patient deterioration for children in diverse resource levels globally. Critcom results can be used to design and evaluate interventions to improve team communication.

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.

A new measure for multi-professional medical team communication: design and methodology for multilingual measurement development.

Background: As implementation science in global health continues to evolve, there is a need for valid and reliable measures that consider diverse linguistic and cultural contexts. A standardized, reproducible process for multilingual measure development may improve accessibility and validity by participants in global health settings. To address this need, we propose a rigorous methodology for multilingual measurement development. We use the example of a novel measure of multi-professional team communication quality, a determinant of implementation efforts. Methods: The development and translation of this novel bilingual measure is comprised of seven steps. In this paper, we describe a measure developed in English and Spanish, however, this approach is not language specific. Participants are engaged throughout the process: first, an interprofessional panel of experts and second, through cognitive interviewing for measure refinement. The steps of measure development included: (1) literature review to identify previous measures of team communication; (2) development of an initial measure by the expert panel; (3) cognitive interviewing in a phased approach with the first language (English); (4): formal, forward-backward translation process with attention to colloquialisms and regional differences in languages; (5) cognitive interviewing repeated in the second language (Spanish); (6) language synthesis to refine both instruments and unify feedback; and (7) final review of the refined measure by the expert panel. Results: A draft measure to assess quality of multi-professional team communication was developed in Spanish and English, consisting of 52 questions in 7 domains. This measure is now ready for psychometric testing. Conclusions: This seven-step, rigorous process of multilingual measure development can be used in a variety of linguistic and resource settings. This method ensures development of valid and reliable tools to collect data from a wide range of participants, including those who have historically been excluded due to language barriers. Use of this method will increase both rigor and accessibility of measurement in implementation science and advance equity in research and practice.

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.

Malnutrición por exceso en niños de 5 a 10 años y su asociación con el estado nutricional pre y gestacional, lactancia materna y patología materna

La malnutrición por exceso es un problema de salud pública relevante, con origen multifactorial y factores asociados como el estado nutricional pregestacional (ENP), durante y post gestación, ganancia excesiva de peso (EGP) gestacional y duración de la lactancia materna. El objetivo del estudio fue evaluar la malnutrición por exceso en niños de 5 a 10 años y su asociación con el estado nutricional pre y gestacional, lactancia materna exclusiva (LME) y patologías maternas. Se realizó un estudio con 213 niños y niñas estudiantes de 5 a 10 años. Los datos biosociodemográficos se obtuvieron mediante entrevistas con las madres y datos maternos previos y el embarazo con el carné de control. El estimó estado nutricional se estimó con z-score del peso para la talla e IMC/E, según sexo. Para los análisis estadísticos se usó el software STATA 15.0. El 56% de los estudiantes tuvo malnutrición por exceso. Un 53,1% de las madres presentó malnutrición por exceso previo al embarazo que aumentó a 74,6% post gestación. El 71,4% de los niños tuvo una LME ≥6 meses. Se relacionó estadísticamente la edad materna ≥35 años (p= 0,044) y la malnutrición por exceso pregestacional (p= 0,014). La edad materna ≥35 años aumentó el riesgo de malnutrición por exceso casi dos veces (OR= 1,78; IC: 1,029-3,046), al igual que el ENP (OR= 2,11; IC: 1,193-3,693) y en patologías maternas (OR= 1,41; IC: 1, 073-2,694). En conclusión, los niños preescolares de 5 a 10 años con factores de edad materna ≥35, ENP y patologías maternas tuvieron entre 1,4 y 2,11 veces más riesgo de presentar malnutrición por exceso comparado con aquellos niños sin estos factores.

Overnutrition is a relevant public health problem with a multifactorial origin. Associated factors include maternal nutritional status before, during, and after gestation, excessive gestational weight gain, and breastfeeding duration. The objective of the study was to evaluate the association between overnutrition in children aged 5-10 years and pre- and gestational nutritional status, exclusive breastfeeding, and maternal pathologies. The study consisted of 213 schoolchildren aged 5-10 years. Bio-socio-demographic data were obtained through interviews with mothers, previous maternal data and pregnancy follow-up records. Nutritional status was measured using weight-for-height and BMI z-score by age and sex. The STATA 15.0 software was used for statistical analysis. A total of 56% of the schoolchildren had overnutrition. Meanwhile, 53.1% of the mothers demonstrated pre-pregnancy overnutrition, which increased to 74.6% post-pregnancy. It was found that 71.4% of schoolchildren had experienced exclusive breastfeeding ≥6 months. Maternal age ≥35 years (p= 0.044) and pre-gestational nutritional status (p= 0.014) were statistically related. Maternal age ≥35 years increased overnutrition by almost two-fold (OR= 1.78; IC: 1.029-3.046), as did pre-gestational nutritional status (OR= 2.11; IC: 1.193-3.693) and maternal pathologies (OR= 1.41; IC: 1.073-2.694). In conclusion, schoolchildren aged 5-10 years with mothers ≥35 years of age, who had overnutrition in the pre-gestational period, and a pathology were 1.4 to 2.44 times more at risk of developing overnutrition than children without these factors.

Infusion of HIV-1 Nef-expressing astrocytes into the rat hippocampus induces enteropathy and interstitial pneumonitis and increases blood-brain-barrier permeability.

Even though HIV-1 replication can be suppressed by combination antiretroviral therapy (cART) inflammatory processes still occur, contributing to comorbidities. Comorbidities are attributed to variety of factors, including HIV-1 mediated inflammation. Several HIV-1 proteins mediate central nervous system (CNS) inflammation, including Nef. Nef is an early HIV-1 protein, toxic to neurons and glia and is sufficient to cause learning impairment similar to some deficits observed in HIV-1 associated neurocognitive disorders. To determine whether hippocampal Nef expression by astrocytes contributes to comorbidities, specifically peripheral inflammation, we infused Sprague Dawley rats with GFP- (control) or Nef-transfected astrocytes into the right hippocampus. Brain, lung, and ileum were collected postmortem for the measurement of inflammatory markers. Increased blood-brain-barrier permeability and serum IL-1ß levels were detected in the Nef-treated rats. The lungs of Nef-treated rats demonstrated leukocyte infiltration, macrophage upregulation, and enhanced vascular permeability. Ileal tissue showed reactive follicular lymphoid hyperplasia, increased permeability and macrophage infiltration. The intracerebroventricular application of IL-1 receptor antagonist reduced infiltration of immune cells into ileum and lung, indicating the important role of IL-1ß in mediating the spread of inflammation from the brain to other tissues. This suggests that localized expression of a single viral protein, HIV-1 Nef, can contribute to a broader inflammatory response by upregulation of IL-1ß. Further, these results suggest that Nef contributes to the chronic inflammation seen in HIV patients, even in those whose viremia is controlled by cART.

Condición post-quirúrgica relacionada al cumplimiento del protocolo de procedimientos de exodoncia en unidades comunitarias de salud familiar, SIBASI centro octubre 2013-enero 2014 / Post-surgical condition related to compliance with the protocol of extraction procedures in community family health units, SIBASI center October 2013-January 2014

Objetivo: Evaluar el cumplimiento del protocolo de procedimientos de exodoncia y su relación en la evolución de la condición post-quirúrgica en Unidades Comunitarias de Salud Familiar del SIBASI CENTRO. Metodología: Es una investigación de tipo descriptiva asociativa, en la que se observó la aplicación del protocolo de exodoncia simple; y su relación con las condiciones post operatorias que pueda presentar el paciente. La población fue de 88 pacientes de 20-59 años; durante el periodo octubre 2013-enero 2014. Para recolectar datos se utilizaron dos guías de observación una dirigida al cumplimiento en gran medida, buena medida y en escasa medida del protocolo de exodoncia y la segunda guía a la condición post-quirúrgica del paciente en buen estado y mal estado. Como prueba estadística se utilizó el Chi Cuadrado para determinar la relación de las variables. Resultados: El 71.6% de las exodoncias se realizaron bajo un cumplimiento del protocolo de exodoncia en gran medida, 28.4% bajo un cumplimiento del protocolo de exodoncia en buena medida. En relación a la condición postquirúrgica de 88 pacientes que asistieron a la realización de tratamientos de exodoncias a 25 se les aplicó un protocolo en buena medida, 10 presentaron una condición post-quirúrgica en mal estado y 15 pacientes llegaron en buen estado; a 63 pacientes que se les ejecutó un protocolo de exodoncia en gran medida, 18 llegaron en mal estado y 45 en buen estado. Conclusiones: Ningún odontólogo ejecutó el protocolo de exodoncia en escasa medida. Determinando que el riesgo de tener una condición postquirúrgica en mal estado es 1.42 veces más en los que recibieron un protocolo en buena medida (regular), que el que lo recibió en gran medida, siendo este último a quien se le aplicó entre un 90 a 100 % el protocolo vigente en el Ministerio de Salud. Por lo que estos resultados indican que, no solamente aplicar en gran medida el protocolo de exodoncia simple basta para tener una buena condición post-quirúrgica. Ya que este podría depender de otros factores.

Objective: To evaluate the compliance of the procedures of dental extraction protocol and its relationship with evolution of post-surgical condition in Family Health Community Centers of SIBASI Centro. Methodology: This is a descriptive-associative investigation, in which studies the application of the of the simple dental extraction protocol; and its relationship with the post-surgical condition presented by patient. The sample of this investigation was conformed by 88 patients from 20 to 59 years old; during the period from October, 2013 to January, 2014. To collect the data there were used two observation format documents, one of these led to determine great extent, large extent and small extent of dental extraction protocol accomplishment and the second instrument guide led to check the post-surgical condition of the patient in good condition and bad condition. It was used the Chi-squared to determinethe connection of the variables. Results: 71.6% of the dental extraction were executed under the compliance of the dental extraction protocol in great extent, 28.4% was executed under compliance of the dental extraction protocol in large extent. In relation to the post-surgical condition of the 88 patients who attended to be treated with simple dental extraction, to 25 of them was applied a protocol in large extent, 10 of them presented a bad post-surgical condition and 15 a good condition; to 63 patient whose was applied a dental extraction protocol in great extent, 18 presented bad condition and 45 a good condition. Conclusions: Not dentist executed the dental extraction protocol in small extent. Having established that the risk of suffering bad post-surgical condition is 1.4 times more in those who were treated with a protocol in large extent, in comparison to those who was applied between 90 to 100% of Ministerio de Salud's current protocol. In addition data were obtained (p>0.05) does not confirm that a patient who was exposed to a proper implementation of the dental extraction protocol will have impact in the post- surgical condition in good or bad condition, for the ultimate result could depend on other factors not included in this study

Discovery of Dinaciclib (SCH 727965): A Potent and Selective Inhibitor of Cyclin-Dependent Kinases.

Inhibition of cyclin-dependent kinases (CDKs) has emerged as an attractive strategy for the development of novel oncology therapeutics. Herein is described the utilization of an in vivo screening approach with integrated efficacy and tolerability parameters to identify candidate CDK inhibitors with a suitable balance of activity and tolerability. This approach has resulted in the identification of SCH 727965, a potent and selective CDK inhibitor that is currently undergoing clinical evaluation.

Pyrazolo[1,5-a]pyrimidines as orally available inhibitors of cyclin-dependent kinase 2.

Properly substituted pyrazolo[1,5-a]pyrimidines are potent and selective CDK2 inhibitors. Compound 15j is orally available and showed efficacy in a mouse A2780 xenograft model.