Preparation of von Hippel-Lindau (VHL) E3 ubiquitin ligase ligands exploiting constitutive hydroxyproline for benzylic amine protection.

The von Hippel-Lindau (VHL) protein serves as the substrate recognition subunit of the multi-subunit Cullin-2 RING E3 ubiquitin ligase (CRL2VHL), which regulates intracellular concentrations of hypoxia inducible factors (HIFs) through a ubiquitin proteasome system (UPS) cascade. Strategic recruitment of CRL2VHL by bi- or trifunctional targeted protein degraders (e.g., PROTACs®) offers the prospect of promoting aberrant polyubiquitination and ensuing proteasomal degradation of disease-related proteins. Non-peptidic, l-hydroxyproline-bearing VHL ligands such as VH032 (1) and its chiral benzylic amine analog Me-VH032 (2), are functional components of targeted protein degraders commonly employed for this purpose. Herein, we compare two approaches for the preparation of 1 and 2 primarily highlighting performance differences between Pd(OAc)2 and Pd-PEPPSI-IPr for the key C-H arylation of 4-methylthiazole. Results from this comparison prompted the development of a unified, five-step route for the preparation of either VH032 (1) or Me-VH032 (2) in multigram quantities, resulting in yields of 56% and 61% for 1 and 2, respectively. Application of N-Boc-l-4-hydroxyproline rather than N-tert-butoxycarbonyl to shield the benzylic amine during the coupling step enhances step economy. Additionally, we identified previously undisclosed minor byproducts generated during arylation steps along with observations from amine deprotection and amidation reaction steps that may prove helpful not only for the preparation of 1 and 2, but for other VHL recruiting ligands, as well.

Analyzing Preceding factors affecting behavioral intention on communicational artificial intelligence as an educational tool.

During the pandemic, artificial intelligence was employed and utilized by students around the globe. Students' conduct changed in a variety of ways when schooling returned to regular instruction. This study aimed to analyze the student's behavioral intention and actual academic use of communicational AI (CAI) as an educational tool. This study identified the variables by utilizing an integrated framework based on the Unified Theory of Acceptance and Use of Technology (UTAUT2) and self-determination theory. Through the use of an online survey and Structural Equation Modeling, data from 533 respondents were analyzed. The results showed that perceived relatedness has the most significant effect on the behavioral intention of students in using CAI as an educational tool, followed by perceived autonomy. It showed that students use CAI based on the objective and the possibility of increasing their productivity, rather than any other purpose in the education setting. Among the UTAUT2 domains, only facilitating conditions, habit, and performance expectancy provided a significant direct effect on behavioral intention and an indirect effect on actual academic use. Further implications were presented. Moreover, the methodology and framework of this study could be extended and applied to educational technology-related studies. Lastly, the outcome of this study may be considered in analyzing the behavioral intention of the students as the teaching-learning environment is still continuously expanding and developing.

Protocolo de enfermería para la valoración y manejo integral de las lesiones cutáneas asociadas a la humedad (LESCAH) / Nursing protocol for the assessment and comprehensive management of skin lesions associated with humidity (LESCAH)

Las lesiones cutáneas asociadas a la humedad (LESCAH) pueden ocasionar daños como quemaduras y heridas abiertas que complican la recuperación de los pacientes. Objetivo: desarrollar un protocolo de enfermería para la valoración y manejo integral de las LESCAH. Metodología: estudio cualitativo y descriptivo con revisión de la literatura para la creación de protocolo institucional tras encuesta de conocimientos del personal del Hospital Manuel Uribe Ángel. Resultado: 91,7% mujeres encuestadas, edad media de 35 años, 52,2% personal de hospitalización, mayor participación de auxiliares de enfermería (47,8%). Mejoría del reconocimiento de LESCAH en el 21,7% del personal. Conclusión: la vigilancia constante y la valoración rigurosa de enfermería es la mejor estrategia para la prevención de las lesiones cutáneas asociadas a la humedad en comparación con el manejo convencional.

Moisture-associated skin injuries (LESCAH) can cause damage such as burns and open wounds that complicate the recovery of patients. Objective: to develop a nursing protocol for the assessment and comprehensive management of LESCAH. Methodology: qualitative and descriptive with a review of the literature for the creation of an institutional protocol after a knowledge survey of the staff of the Manuel Uribe Ángel Hospital. Result: 91.7% women surveyed, mean age 35 years, 52.2% hospitalization staff, greater participation of nursing assistants (47.8%). Improvement in the recognition of LESCAH in 21.7% of the staff. Conclusion: constant vigilance and rigorous nursing testing is the best strategy for prevention of moisture-associated skin lesions compared to conventional management.

Obesity and the obesity paradox in patients with severe COVID-19 / Obesidad y paradoja de la obesidad en pacientes con COVID-19 severo: Resultados de dos cohortes prospectivas

Objective: To test the presence of the obesity paradox in two cohorts of patients hospitalized for COVID-19. Design: Two multicenter prospective cohorts. Setting: Three fourth level institutions. Patients: Adults hospitalized in the general ward for confirmed COVID-19 in the three institutions and those admitted to one of the 9 critical care units of one of the institutions. Interventions: None. Main variables of interest: Categorized weight and its relationship with admission to the ICU in hospitalized patients and death in the ICU. Result: Of 402 hospitalized patients, 30.1% were obese. Of these, 36.1% were admitted to the ICU vs. 27.1% of non-obese patients. Of the 302 ICU patients, 46.4% were obese. Of these, mortality was 45.0% vs. 52.5% for non-obese. The requirement to transfer hospitalized patients to the ICU admission get a HR of 1.47 (95%CI 0.87–2.51, p = 0.154) in the multivariate analysis. In intensive care patients, an HR of 0.99 (95%CI: 0.92–1.07, p = 0.806) was obtained to the association of obesity with mortality. Conclusions: The present study does not demonstrate an association between obesity and risk of inpatient transfer to intensive care or death of intensive care patients due to COVID-19 therefore, the presence of an obesity paradox is not confirmed. (AU)

Objetivo: Comprobar la presencia la paradoja de la obesidad en dos cohortes de pacientes hospitalizados por COVID-19. Diseño: Dos cohortes prospectivas multicéntricas. Ámbito: Tres instituciones de cuarto nivel. Pacientes: Adultos hospitalizados en pabellón general por COVID-19 confirmado en las tres instituciones y aquellos internados en alguna de las 9 unidades de cuidado crítico de una de las instituciones. Intervenciones: Ninguna. Variables de interés principales: El peso categorizado y su relación con el ingreso a UCI en hospitalizados y de muerte en UCI. Resultado: Entre 402 hospitalizados 30.1% fueron obesos, de los que 36.1% ingresaron a UCI vs. 27.1% en los no obesos. De los 302 pacientes en UCI, el 46.4% fueron obesos, entre ellos la mortalidad fue de 45.0% vs. 52.5% en los no obesos. En hospitalizados el análisis multivariado obtuvo HR de 1.47 (IC95% 0.87–2.51, p = 0.154) para traslado a UCI. En UCI se obtuvo un OR de 0.99 (IC95%: 0.92–1.07, p = 0.806) para la muerte. Conclusiones: El presente estudio no demuestran una asociación entre la obesidad y el riesgo de traslados a cuidados intensivos en pacientes hospitalizados ni con la muerte en pacientes en cuidados intensivos por COVID-19 por lo que no se confirma la presencia de una paradoja de la obesidad. (AU)

Evaluating Rural Health Disparities in Colombia: Identifying Barriers and Strategies to Advancing Refugee Health.

Health disparities within rural communities, notably those affecting migrant and refugee populations, are well-documented. Refugees often grapple with high disease burdens and mortality rates due to limited access to primary healthcare and their vulnerable socio-economic and political situations. This issue is particularly acute in the rural areas around Medellin, Colombia, where the refugee influx exacerbates the existing public health challenges. Studies highlight a substantial gap between community needs and public health policies, resulting in inadequate healthcare access. Our study, utilizing the Delphi technique, aimed to identify common barriers and strategies to enhance rural healthcare for refugees. Through consensus-building with community leaders, we identified six primary barriers to healthcare access and five barriers to healthcare quality. Community leaders endorsed five strategies to address the access barriers and eight strategies to improve healthcare quality. This research provides valuable insights for optimizing resource allocation and designing effective support programs for these vulnerable populations.

How can residents protect and promote pollinators? The diffusion of residential pollinator-friendly gardening.

Urbanization and land use change are leading causes of declines in pollinator abundance and diversity. However, researchers in different regions of the world have found that some pollinators can thrive in urban landscapes, depending on land use practices, environmental conditions, and species traits. Residential landscapes constitute a significant portion of urban green space and thus, residents' adoption of landscape practices to promote pollinators can play a central role in addressing the global pollinator challenge. Yet, although residents' willingness and intention appear strong, adoption of pollinator-friendly gardening remains low. The present study - guided by the Diffusion of Innovations theory - aimed to build empirical understanding by surveying 1598 [State] residents on their experiences and perceptions related to pollinator-friendly gardening to determine the most salient barriers and opportunities to engagement. Key findings suggest making the practice more widely observable and reducing perceived complexity in learning to do the practice are critical to promoting adoption. This demonstrates, in practical terms, that: (1) targeted efforts to build residents' actionable knowledge about pollinator-friendly gardening may significantly reduce uncertainty and boost the likelihood of adoption; and (2) examples of active pollinator gardens need to be more widely showcased and popularized (e.g., through experiential or virtual demonstrations). We also found most residents living in homeowner associations (HOAs) believed HOA policies on pollinator-friendly gardening were restrictive or the residents were unsure whether they are allowed to practice pollinator-friendly gardening. Given these perceptions strongly associated with residents' low intent to engage in pollinator-friendly gardening, a major opportunity exists to diffuse the practice and increase adoption by working with HOAs and community leaders to become promoters of - rather than barriers to - pollinator-friendly gardening.

A mixed methods study assessing the adoption potential of a saliva-based malaria rapid test in the Democratic Republic of Congo.

BACKGROUND: The reliance on blood for thin and thick blood smear microscopy-using a relatively invasive procedure has presented challenges to the use of reliable diagnostic tests in non-clinical settings at the point-of-need (PON). To improve the capacity of non-blood-based rapid diagnostic tests to confirm subclinical infections, and thereby identify and quantify the human reservoir at the PON, a cross-sectoral collaboration between university researchers and commercial partners produced an innovative, non-invasive saliva-based RDT capable of identifying novel, non-hrp2/3 parasite biomarkers. While this new saliva-based malaria asymptomatic and asexual rapid test (SMAART-1) shows increased detection sensitivity and precision potential by identifying a new P. falciparum protein marker (PSSP17), appraising its utility in the field-particularly with respect to its adoption potential with children and adults in high risk, endemic regions-is necessary to warrant its continued development. METHODS: The purpose of this study was to assess the acceptability and adoption potential of the SMAART-1 at select PON sites in the Kinshasa Province. Teachers, community health workers, nurses, and laboratory technicians participated in data collection at three distinct community sites in Kinshasa Province, Democratic Republic of the Congo. Three data collection methods were utilized in this mixed methods study to provide an overarching acceptability evaluation of the SMAART-1 at PON field sites: observation checklists of SMAART-1 implementation, focus group discussions, and surveys with local health care practitioners-particularly teachers and community health workers. RESULTS: Findings indicate participants were interested in and supportive of the SMAART-1 protocol, with approximately 99% of the participants surveyed indicating that they either "agreed" or "strongly agreed" with the statement that they "would use the saliva-based malaria asymptomatic rapid test as part of a community malaria detection and treatment programme." Data also suggest that the protocol was broadly appealing for its testing sensitivity and ease of use. CONCLUSIONS: The SMAART-1 protocol's clinically reliable results demonstrate a promising new level of sensitivity and precision for detecting parasite biomarkers. This study's mixed-methods assessment of the protocol's utility and adoption potential in the field, with a target user audience, advances its development and points to opportunities to formalize and expand evaluation efforts.

Application of the pulmonary embolism rule-out criteria (PERC rule) and age-adjusted D-Dimer in patients undergoing computed tomography pulmonary angiography for diagnosis of pulmonary embolism.

Background: Diagnosis of pulmonary embolism (PE) constitutes a challenge for practitioners. Current practice involves use of pre-test probability prediction rules. Several strategies to optimize this process have been explored. Objectives: To explore whether application of the pulmonary embolism rule-out criteria (PERC rule) and age-adjusted D-dimer (DD) would have reduced the number of computed tomography pulmonary angiography (CTPA) examinations performed in patients with suspected PE. Methods: A retrospective cross-sectional study of adult patients taken for CTPA under suspicion of PE in 2018 and 2020. The PERC rule and age-adjusted DD were applied. The number of cases without indications for imaging studies was estimated and the operational characteristics for diagnosis of PE were calculated. Results: 302 patients were included. PE was diagnosed in 29.8%. Only 27.2% of 'not probable' cases according to the Wells criteria had D-dimer assays. Age adjustment would have reduced tomography use by 11.1%, with an AUC of 0.5. The PERC rule would have reduced use by 7%, with an AUC of 0.72. Conclusions: Application of age-adjusted D-dimer and the PERC rule to patients taken for CTPA because of suspected PE seems to reduce the number of indications for the procedure.

Contexto: O diagnóstico de embolia pulmonar (EP) representa um desafio para o profissional. A prática atual envolve o uso de modelos de previsão de probabilidade pré-teste e, para otimizar esse processo, várias estratégias têm sido exploradas. Objetivos: Investigar se a aplicação dos critérios de exclusão de EP (pulmonary embolism rule-out criteria, PERC) e do D-dímero (DD) ajustado para idade diminui o número de angiografias computadorizadas (ATCs) pulmonares realizadas em pacientes com suspeita de EP. Métodos: Estudo transversal retrospectivo com pacientes adultos submetidos a ATC pulmonar com suspeita de EP em 2018 e 2020. Foram aplicados os critérios PERC e o DD ajustado para idade. Foi estimado o número de casos não indicados para exames de imagem, e foram calculadas as características operacionais para o diagnóstico de EP. Resultados: Foram incluídos 302 pacientes, dos quais 29,8% apresentaram diagnóstico de EP. Apenas 27,2% dos casos não prováveis ​​de acordo com os critérios de Wells apresentaram DD; o ajuste implicou em uma diminuição de ACTs de 11,1%, com área sob a curva de 0,5. Os critérios PERC diminuiriam em 7%, com área sob a curva de 0,72. Conclusões: A aplicação do DD ajustado para idade e dos critérios PERC em pacientes submetidos a ATC pulmonar por suspeita de EP parece diminuir a indicação para tais exames.

Obesity and the obesity paradox in patients with severe COVID-19.

OBJECTIVE: To test the presence of the obesity paradox in two cohorts of patients hospitalized for COVID-19. DESIGN: Two multicenter prospective cohorts. SETTING: Three fourth level institutions. PATIENTS: Adults hospitalized in the general ward for confirmed COVID-19 in the three institutions and those admitted to one of the 9 critical care units of one of the institutions. INTERVENTIONS: None. MAIN VARIABLES OF INTEREST: Categorized weight and its relationship with admission to the ICU in hospitalized patients and death in the ICU. RESULT: Of 402 hospitalized patients, 30.1% were obese. Of these, 36.1% were admitted to the ICU vs. 27.1% of non-obese patients. Of the 302 ICU patients, 46.4% were obese. Of these, mortality was 45.0% vs. 52.5% for non-obese. The requirement to transfer hospitalized patients to the ICU admission get a HR of 1.47 (95%CI 0.87-2.51, p = 0.154) in the multivariate analysis. In intensive care patients, an HR of 0.99 (95%CI: 0.92-1.07, p = 0.806) was obtained to the association of obesity with mortality. CONCLUSIONS: The present study does not demonstrate an association between obesity and risk of inpatient transfer to intensive care or death of intensive care patients due to COVID-19 therefore, the presence of an obesity paradox is not confirmed.

Evidence of two mitochondrial lineages and genetic variability in forensically important Lucilia eximia (Diptera: Calliphoridae) in Colombia.

Lucilia eximia (Wiedemann, 1819) (Diptera: Calliphoridae) is a blowfly with medical and forensic importance that shows genetic and color variation, however, these variations have not justified the description of new species. But in forensic entomology an accurate identification of species and subpopulations is crucial. We explored the genetic variation of L. eximia from eight localities, in five natural regions in Colombia using two mitochondrial fragments, including the standard locus for insect identification COI and the Cytb-tRNA-Ser-ND1 region. We found significant differentiation at COI and Cytb-tRNA-Ser-ND1 level, characterizing two lineages and revealing a deep and significant genetic split. High values of FST and genetic distances supported the two lineages. The origin of the divergence of L. eximia remains to discover. Examining whether the lineages have diverse ecological and biological behaviors could be a significant impact on the use of L. eximia in forensic and medical science. Our results could have relevant implications for the use of post-mortem interval estimation based on insect evidence, as well as our sequences improve the database used in DNA-based methods for identifying forensically important flies.

Application of the pulmonary embolism rule-out criteria (PERC rule) and age-adjusted D-Dimer in patients undergoing computed tomography pulmonary angiography for diagnosis of pulmonary embolism / Aplicação dos critérios PERC e do D-Dímero ajustado para idade em pacientes submetidos a angiotomografia pulmonar para o diagnóstico de embolia pulmonar

Abstract Background Diagnosis of pulmonary embolism (PE) constitutes a challenge for practitioners. Current practice involves use of pre-test probability prediction rules. Several strategies to optimize this process have been explored. Objectives To explore whether application of the pulmonary embolism rule-out criteria (PERC rule) and age-adjusted D-dimer (DD) would have reduced the number of computed tomography pulmonary angiography (CTPA) examinations performed in patients with suspected PE. Methods A retrospective cross-sectional study of adult patients taken for CTPA under suspicion of PE in 2018 and 2020. The PERC rule and age-adjusted DD were applied. The number of cases without indications for imaging studies was estimated and the operational characteristics for diagnosis of PE were calculated. Results 302 patients were included. PE was diagnosed in 29.8%. Only 27.2% of 'not probable' cases according to the Wells criteria had D-dimer assays. Age adjustment would have reduced tomography use by 11.1%, with an AUC of 0.5. The PERC rule would have reduced use by 7%, with an AUC of 0.72. Conclusions Application of age-adjusted D-dimer and the PERC rule to patients taken for CTPA because of suspected PE seems to reduce the number of indications for the procedure.

Resumo Contexto O diagnóstico de embolia pulmonar (EP) representa um desafio para o profissional. A prática atual envolve o uso de modelos de previsão de probabilidade pré-teste e, para otimizar esse processo, várias estratégias têm sido exploradas. Objetivos Investigar se a aplicação dos critérios de exclusão de EP (pulmonary embolism rule-out criteria, PERC) e do D-dímero (DD) ajustado para idade diminui o número de angiografias computadorizadas (ATCs) pulmonares realizadas em pacientes com suspeita de EP. Métodos Estudo transversal retrospectivo com pacientes adultos submetidos a ATC pulmonar com suspeita de EP em 2018 e 2020. Foram aplicados os critérios PERC e o DD ajustado para idade. Foi estimado o número de casos não indicados para exames de imagem, e foram calculadas as características operacionais para o diagnóstico de EP. Resultados Foram incluídos 302 pacientes, dos quais 29,8% apresentaram diagnóstico de EP. Apenas 27,2% dos casos não prováveis ​​de acordo com os critérios de Wells apresentaram DD; o ajuste implicou em uma diminuição de ACTs de 11,1%, com área sob a curva de 0,5. Os critérios PERC diminuiriam em 7%, com área sob a curva de 0,72. Conclusões A aplicação do DD ajustado para idade e dos critérios PERC em pacientes submetidos a ATC pulmonar por suspeita de EP parece diminuir a indicação para tais exames.

Profilaxis para sangrado gastrointestinal en pacientes del servicio de medicina interna de un hospital universitario / Gastrointestinal bleeding prophylaxis in internal medicine patients of a univeristy hospital

Introducción: Los medicamentos antiulcerosos son utilizados frecuentemente en pacientes hospitalizados, sin embargo, a menudo este uso no está indicado. Objetivo: Describir la frecuencia de prescripción e indicación de medicamentos para prevenir el sangrado gastrointestinal en pacientes hospitalizados. Materiales y métodos: Estudio de corte trasversal, descriptivo, prospectivo del servicio de Medicina Interna de la Sociedad de Cirugía de Bogotá- Hospital de San José de Bogotá, Colombia. Se excluyeron pacientes con diagnóstico de sangrado gastrointestinal o antecedente de alergia a los medicamentos antiulcerosos. Se recolectaron datos demográficos, así como fármacos prescritos. Se determinó si la indicación del fármaco era adecuada y se identificó el tipo de error de prescripción. Resultados: Se incluyeron 179 pacientes, 102 (57%) mujeres. Promedio de edad de 61,3 años (±20,2). El principal diagnóstico de ingreso fue enfermedad infecciosa 76 (42,4%). Del total de pacientes, 165 (92,17%) recibieron medicamento para prevención del sangrado gastrointestinal. La indicación fue adecuada en 75 pacientes (41,89%). El error más frecuente fue el uso en pacientes de bajo riesgo de sangrado, 101 (97,1%). Conclusión: Un alto porcentaje de los pacientes recibió medicación para la prevención del sangrado gastrointestinal. En aproximadamente la mitad de estos no estaba indicada.

Introduction: Anti-ulcer medications are frequently used in hospitalized patients, yet their use is not usually indicated. Objective: To describe the frequency of prescription and indication of medications to prevent gastrointestinal bleeding in hospitalized patients. Materials and methods: A cross-sectional, descriptive, prospective study was carried out in the Internal Medicine service of the Surgery Society of Bogota-San Jose Hospital of Bogota (Colombia). Excluded patients were those with either a gastrointestinal bleeding diagnosis or a history of allergy to anti-ulcer medications. Demographic data and information regarding prescribed medications were collected. It was determined whether the medicine indication was adequate and the type of prescription error was identified. Results: 179 patients were included in the study, 57% (102) of which were women. The average age was 61.3 (±20.2) years old. Infectious disease was the main admission diagnosis (76; 42.4%). A 92.17% (165) of the total number of patients received medications to prevent gastrointestinal bleeding. This indication was adequate for 75 (41.89%) patients. The most frequent error was their use in bleeding low-risk patients (101; 97.1%). Conclusion: A high percentage of patients received medication to prevent gastrointestinal bleeding. However, in about half of these patients it was not indicated.

Early warning scores to identify the risk of clinical worsening or death in patients hospitalized for COVID-19

Background: identifying patients at risk for negative outcomes is key for performing a timely triage and adapting the care intensity for patients with COVID-19. Early warning scores are rules that alert to the risk of adverse outcomes during hospitalization. We sought to validate the modified NEWS, NEWS-2 and COVID-19 Severity Index (CSI). Methods: a prospective observational multicenter study of patients hospitalized for CO VID-19 at three quaternary care hospitals in Bogotá, Colombia, between April and November 2020. The operating characteristics and areas under the ROC curve were calculated. Results: 711 patients were included, in whom the AUC for death was 0.68, 0.58 and 0.68, and for ICU admission was 0.61, 0.63 and 0.66 for mNEWS, NEWS-2 and CSI, respectively. The CSI had the greatest sensitivity for ICU admission or death (87.6 and 90.0%) and NEWS-2 had the greatest specificity (76.8 and 75.5%). Conclusions: the three early warning scores had a low to moderate performance in pre dicting ICU admission or death in patients hospitalized for COVID-19. (Acta Med Colomb 2022; 47. DOI:https://doi.org/10.36104/amc.2022.2225).

Antecedentes: la identificación de los pacientes con riesgo de desenlaces negativos es clave para realizar un triage oportuno y adecuar la intensidad de los cuidados en los pacientes con COVID-19. Las puntuaciones de alerta temprana son reglas para advertir el riesgo de desenlaces adversos durante la hospitalización. Buscamos validar el NEWS modificado, NEWS-2 y COVID-19 Severity Index. Metodología: estudio observacional, prospectivo, multicéntrico con pacientes hospitalizados por COVID-19 en tres hospitales de cuarto nivel en Bogotá (Colombia), entre abril y noviembre de 2020. Se calcularon las características operativas y áreas bajo la curva ROC. Resultados: se contó con 711 pacientes entre los cuales el AUC para muerte fue 0.68, 0.58 y 0.68, y para ingreso a UCI de 0.61, 0.63 y 0.66 para NEWSm, NEWS-2 y CSI respectivamente. El CSI alcanzó la mayor sensibilidad para ingreso a UCI o muerte (87.6 y 90.0%) y la mayor especificidad fue el NEWS-2 (76.8 y 75.5%). Conclusiones: las tres puntuaciones de alerta temprana mostraron un desempeño bajo a moderado para la predicción del ingreso a UCI o muerte en pacientes hospitalizados por COVID-19. (Acta Med Colomb 2022; 47. DOI:https://doi.org/10.36104/amc.2022.2225).

Cediranib in Combination with Olaparib in Patients without a Germline BRCA1/2 Mutation and with Recurrent Platinum-Resistant Ovarian Cancer: Phase IIb CONCERTO Trial.

PURPOSE: The efficacy, safety, and tolerability of cediranib plus olaparib (cedi/ola) were investigated in patients with nongermline-BRCA-mutated (non-gBRCAm) platinum-resistant recurrent ovarian cancer. PATIENTS AND METHODS: PARP inhibitor-naïve women aged ≥18 years with platinum-resistant non-gBRCAm ovarian cancer, ECOG performance status of 0-2, and ≥3 prior lines of therapy received cediranib 30 mg once daily plus olaparib 200 mg twice daily in this single-arm, multicenter, phase IIb trial. The primary endpoint was objective response rate (ORR) by independent central review (ICR) using RECIST 1.1. Progression-free survival (PFS), overall survival (OS), and safety and tolerability were also examined. RESULTS: Sixty patients received cedi/ola, all of whom had confirmed non-gBRCAm status. Patients had received a median of four lines of chemotherapy; most (88.3%) had received prior bevacizumab. ORR by ICR was 15.3%, median PFS was 5.1 months, and median OS was 13.2 months. Forty-four (73.3%) patients reported a grade ≥3 adverse event (AE), with one patient experiencing a grade 5 AE (sepsis), considered unrelated to the study treatment. Dose interruptions, reductions, and discontinuations due to AEs occurred in 55.0%, 18.3%, and 18.3% of patients, respectively. Patients with high global loss of heterozygosity (gLOH) had ORR of 26.7% [4/15; 95% confidence interval (CI), 7.8-55.1], while ORR was 12.5% (4/32; 95% CI, 3.5-29.0) in the low gLOH group. CONCLUSIONS: Clinical activity was shown for the cedi/ola combination in heavily pretreated, non-gBRCAm, platinum-resistant patients with ovarian cancer despite failing to meet the target ORR of 20%, highlighting a need for further biomarker studies.

Pembrolizumab activity in patients with Fanconi anemia repair pathway competent and deficient tumors.

BACKGROUND: Given the observed antitumor activity of immune-checkpoint-inhibitors in patients with mismatch-repair deficient (MSI-H) tumors, we hypothesized that deficiency in homologous-recombination-repair (HRR) can also influence susceptibility. METHODS: Patients with disease progression on standard of care and for whom pembrolizumab had no FDA approved indication received pembrolizumab. Patients with MSI-H tumors were excluded. Objectives included immune-related objective response rate (iORR), progression-free survival (PFS) and 20-weeks-PFS. Pembrolizumab was given every 3 weeks and scans performed every six. We evaluated a triple-stain (FANCD2foci/DAPI/Ki67) functional assay of the Fanconi Anemia (FA) pathway: FATSI, in treated patients' archived tumors. The two-stage sample size of 20/39 patients evaluated an expected iORR≥20% in the whole population vs. the null hypothesis of an iORR≤5%, based on an assumed iORR≥40% in patients with functional FA deficiency, and < 10% in patients with intact HRR. An expansion cohort of MSI stable endometrial cancer (MS-EC) followed. Exploratory stool microbiome analyses in selected patients were performed. RESULTS: Fifty-two patients (45F,7M;50-evaluable) were enrolled. For the 39 in the two-stage cohort, response evaluation showed 2CR,5PR,11SD,21PD (iORR-18%). FATSI tumor analyses showed 29 competent (+) and 10 deficient (-). 2PR,9SD,17PD,1NE occurred among the FATSI+ (iORR-7%) and 2CR,3PR,2SD,3PD among the FATSI(-) patients (iORR-50%). mPFS and 20w-PFS were 43 days and 21% in FATSI+, versus 202 days and 70% in FATSI(-) patients. One PR occurred in the MS-EC expansion cohort. CONCLUSIONS: Pembrolizumab has meaningful antitumor activity in malignancies with no current FDA approved indications and FA functional deficiency. The results support further evaluation of FATSI as a discriminatory biomarker for population-selected studies.

Experimental and theoretical study of the mechanism and rate constants of the sequential 5-exo-trig spirocyclization involving vinyl, aryl and N-alkoxyaminyl radicals.

In this research the sequential generation and cyclization of N-alkoxyaminyl radicals to produce 1-azaspiro[4.4]nonane, a prominent scaffold in organic and medicinal chemistry, was studied. Competition experiments in benzene at 80 °C with brominated oxime ethers using Bu3SnH as chain transfer and AIBN as the initiator generated vinyl or aryl radicals which were captured by oxime ethers, allowing approximate 5-exo-trig cyclization constants at 4.6 × 108 s-1 and 9.9 × 108 s-1 respectively to be established. Similar results were obtained by kinetic studies using the transition state theory (TST) from ab initio calculations with density functional theory (DFT) using the M06-2X, B3LYP, mPW1PW91 and TPSSh functionals in combination with the 6-311+G(d, p) basis set. Additionally, it was found that the 5-exo-trig cyclization of the N-alkoxyaminyl radical onto CC double bonds is a reversible process whose constants were determined to be in the range of 6.2 × 100 s-1 and 3.5 × 106 s-1 at 80 °C, depending on the nature of the substituents. The calculation of the radical stabilization energy (RSE) shows that the N-alkoxyaminyl radical is a very stable species and its reactivity in the addition on alkenes is governed by its nucleophilic character and the stability of the carbon-centered radical formed after cyclization. The reduction constant of the N-alkoxyaminyl radical with Bu3SnH in the gas phase at 80 °C was also estimated to be 3.4 × 100 M-1 s-1 through computational calculations. This information facilitates the rational planning of cascades and other methodologies applied to the construction of carbocyclic and aza-heterocyclic compounds.

Echocardiographic 60-day mortality markers in patients hospitalized in intensive care for COVID-19.

BACKGROUND: Coronavirus disease COVID-19 produces a predominantly pulmonary affection, being cardiac involvement an important component of the multiorganic dysfunction. At the moment there are few reports about the behavior of echocardiographic images in the patients who have the severe forms of the disease. OBJECTIVE: Identify the echocardiographic prognostic markers for death within 60 days in patients hospitalized in intensive care. METHODS: A single-center prospective cohort was made with patients hospitalized in intensive care for COVID-19 confirmed via polymerase chain reaction who got an echocardiogram between May and October 2020. A Cox multivariate model was plotted reporting the HR and confidence intervals with their respective p values for clinical and echocardiographic variables. RESULTS: Out of the 326 patients included, 153 patients got an echocardiogram performed on average 6.8 days after admission. The average age was 60.7, 47 patients (30.7%) were females and 67 (44.7%) registered positive troponin. 91 patients (59.5%) died. The univariate analysis identified TAPSE, LVEF, pulmonary artery systolic pressure, acute cor pulmonale, right ventricle diastolic dysfunction, and right ventricular dilatation as variables associated with mortality. The multivariate model identified that the acute cor pulmonale with HR= 4.05 (CI 95% 1.09 - 15.02, p 0.037), the right ventricular dilatation with HR= 3.33 (CI 95% 1.29 - 8.61, p 0.013), and LVEF with HR= 0.94 (CI 95% 0.89 - 0.99, p 0.020) were associated with mortality within 60 days. CONCLUSIONS: In patients hospitalized in the intensive care unit for COVID-19, the LVEF, acute cor pulmonale and right ventricular dilatation are prognostic echocardiographic markers associated with death within 60 days.

Evaluating connections between personal well-being and adoption of landscape best management practices: An audience segmentation study.

Integrated pest management and outdoor water conservation comprise key practices encouraged by nonformal educators who work with the public to address significant issues related to water quality and availability. Disconnects among diverse audiences and educational programs pose challenges in achieving the goals of these types of programs. To discern a potential nonformal educational programming strategy, we conducted audience segmentation research incorporating residential environmental landscape best management practices and compared resulting subgroups' characteristics. We explored this paradigm through the context of Extension education and used a nationally-distributed electronic survey instrument to measure well-being and landscape management perceptions and practices in the United States. We collected 2601 complete survey responses and employed cluster analysis to divide the respondents into homogenous subgroups, followed by analysis of variance and chi-square analyses to identify differences among the subgroups. The group that indicated the highest level of engagement with water conservation and IPM practices also had significantly higher well-being, demonstrating the potential to align IPM education with more commonly promoted conservation practices. Membership in the highest IPM and water conservation group was related to several socio-demographic characteristics, including age, homeownership, and homeowners' association membership. This group was also most likely to engage with educational programs. Understanding these indicators of engagement in landscape best management practices and nonformal education, along with higher well-being, may be useful in determining target audiences and potential engagement with nonformal education programs.

Factors influencing job satisfaction among dentists during the new normal of the COVID-19 pandemic in Indonesia: A structural equation modeling approach.

BACKGROUND: Dentistry is one of the highest risk occupations that face COVID-19, especially in countries that are severely affected by the pandemic, such as Indonesia. OBJECTIVE: The purpose of the study was to determine factors influencing job satisfaction among dentists during the new normal of COVID-19 pandemic in Indonesia by utilizing the Structural Equation Modeling (SEM) approach. METHODS: A total of 310 Indonesian dentists voluntary completed an online questionnaire, which contained 58 questions. Several latent variables such as perceived severity of COVID-19, staff cooperation and management commitment, personal protective equipment, job stress, working hours, income, and overall job satisfaction were analyzed simultaneously. RESULTS: SEM revealed perceived severity of COVID-19 had significant effects on job stress (ß:0.394, p = 0.025) and the utilization of personal protective equipment (ß:0.757, p = 0.001). Subsequently, job stress (ß:-0.286, p = 0.001), working hours (ß:0.278, p = 0.018), income (ß:0.273, p = 0.003), personal protective equipment (ß:0.145, p = 0.038), and staff cooperation & management commitment (ß:0.091, p = 0.002) were found to have significant effects on overall job satisfaction. In addition, management & staff cooperation was found to have a significant association with job stress reduction (ß:-0.319, p = 0.003) which subsequently led to higher satisfaction. CONCLUSIONS: The current study is one of the first that analyzed job satisfaction among dentists in Indonesia during the global COVID-19 pandemic. The integrated latent variables can be applied and extended to evaluate job satisfaction among dentists during the COVID-19 pandemic in other countries. Finally, this study contributed as a theoretical foundation for policymakers to enhance the job satisfaction of dentists during the COVID-19 pandemic.

The Evaluation of Preference and Perceived Quality of Health Communication Icons Associated with COVID-19 Prevention Measures.

Icons have been widely utilized to describe and promote COVID-19 prevention measures. The purpose of this study was to analyze the preference and subjective design features of 133 existing icons associated with COVID-19 prevention measures published by the health and medical organizations of different countries. The 133 icons represent nineteen different function names, such as "Wash Hands" and "Wear Face Mask". A total of 57 participants were recruited to perform two different tests: ranking test and subjective rating test. The ranking test was conducted to elicit the preference ranking of seven icon designs representing each function name. It was followed by a subjective rating test using 13 semantic scales on the two most preferred icons to analyze their perceived quality. Spearmen correlation was applied to derive the possible correlations between users' rankings and the semantic scales, and Friedman's test was also performed to determine the true difference between ranking in terms of each semantic scale to provide a fully meaningful interpretation of the data. Generally, findings from the current study showed that the image presented in the icon is the key point that affects the icons' perceived quality. Interestingly, Spearman's correlation analysis between preference ranking and semantic scales showed that vague-clear, weak-strong, incompatible-compatible, and ineffective-effective were the four strongest semantic scales that highly correlated with the preference ranking. Considering the significant relationships between the semantic distances and the functions, images depicted in an icon should be realistic and as close as possible to its respected function to cater to users' preferences. In addition, the results of Spearman's correlation and Friedman's test also inferred that compatibility and clarity of icon elements are the main factors determining a particular icon's preferability. This study is the first comprehensive study to evaluate the icons associated with the COVID-19 prevention measures. The findings of this study can be utilized as the basis for redesigning icons, particularly for icons related to COVID-19 prevention measures. Furthermore, the approach can also be applied and extended for evaluating other medical icons.