Plant phenolics inhibit focal adhesion kinase and suppress host cell invasion by uropathogenic Escherichia coli.

Traditional folk treatments for the prevention and management of urinary tract infections (UTIs) and other infectious diseases often include plants and plant extracts that are rich in phenolic compounds. These have been ascribed a variety of activities, including inhibition of bacterial interactions with host cells. Here, we tested a panel of four well-studied phenolic compounds-caffeic acid phenethyl ester (CAPE), resveratrol, catechin, and epigallocatechin gallate-for the effects on host cell adherence and invasion by uropathogenic Escherichia coli (UPEC). These bacteria, which are the leading cause of UTIs, can bind and subsequently invade bladder epithelial cells via an actin-dependent process. Intracellular UPEC reservoirs within the bladder are often protected from antibiotics and host defenses and likely contribute to the development of chronic and recurrent infections. In cell culture-based assays, only resveratrol had a notable negative effect on UPEC adherence to bladder cells. However, both CAPE and resveratrol significantly inhibited UPEC entry into the host cells, coordinate with attenuated phosphorylation of the host actin regulator Focal Adhesion Kinase (FAK or PTK2) and marked increases in the numbers of focal adhesion structures. We further show that the intravesical delivery of resveratrol inhibits UPEC infiltration of the bladder mucosa in a murine UTI model and that resveratrol and CAPE can disrupt the ability of other invasive pathogens to enter host cells. Together, these results highlight the therapeutic potential of molecules like CAPE and resveratrol, which could be used to augment antibiotic treatments by restricting pathogen access to protective intracellular niches.IMPORTANCEUrinary tract infections (UTIs) are exceptionally common and increasingly difficult to treat due to the ongoing rise and spread of antibiotic-resistant pathogens. Furthermore, the primary cause of UTIs, uropathogenic Escherichia coli (UPEC), can avoid antibiotic exposure and many host defenses by invading the epithelial cells that line the bladder surface. Here, we identified two plant-derived phenolic compounds that disrupt activation of the host machinery needed for UPEC entry into bladder cells. One of these compounds, resveratrol, effectively inhibited UPEC invasion of the bladder mucosa in a mouse UTI model, and both phenolic compounds significantly reduced host cell entry by other invasive pathogens. These findings suggest that select phenolic compounds could be used to supplement existing antibacterial therapeutics by denying uropathogens shelter within host cells and tissues and help explain some of the benefits attributed to traditional plant-based medicines.

Ayuno intermitente y restricción calórica como tratamiento coadyuvante en enfermedad de Alzheimer y esclerosis múltiple / Intermittent Fasting and Caloric Restriction as an Adjunctive Treatment in Alzheimer's Disease and Multiple Sclerosis

Las enfermedades de Alzheimer y esclerosis múltiple son neurodegenerativas, con tratamientos complejos y de costos elevados, orientados a disminuir la progresión de la sintomatología. Sin embargo, a causa de la falta de terapias adecuadas y de los posibles efectos adversos ocasionados por tratamientos de primera línea, es necesario implementar mejores abordajes terapéuticos complementarios que no produzcan mayores efectos secundarios y mejoren la sintomatología de dichas patologías. La restricción calórica y el ayuno intermitente han demostrado ser estrategias novedosas y beneficiosas en enfermedades neurodegenerativas, a través de mecanismos inmunitarios, metabólicos y fisiológicos. Con el objetivo de determinar el uso del ayuno intermitente y la restricción calórica como tratamiento coadyuvante en esclerosis múltiple y enfermedad de Alzheimer, se realizó una revisión narrativa de artículos originales en revistas científicas, en idiomas inglés y español, de 2018 a 2022. El uso de la restricción calórica y ayuno intermitente han generado cambios positivos produciendo disminución de estados proinflamatorios, estrés oxidativo y envejecimiento. Se consideran abordajes que modulan la progresión de la enfermedad y mejoran la función cognitiva por vías de señalización de monofosfato de adenosina cinasa, factor de crecimiento similar a la insulina y la enzima sirtuina, generando un efecto neuroprotector.

Alzheimer's disease and multiple sclerosis are neurodegenerative disorders with expensive and complex treatments aimed at reducing the progression of symptoms. However, due to the lack of adequate therapies and the possible adverse effects caused by first-line treatments, it's necessary to implement better complementary therapeutic approaches that do not produce major side effects and improve symptoms. Caloric restriction and intermittent fasting have been shown to be novel and beneficial strategies in neurodegenerative diseases, through immune, metabolic, and physiological mechanisms. To determine the use of intermittent fasting and caloric restriction as a new treatment in multiple sclerosis and Alzheimer's disease, a narrative review of original articles in both national and international scientific journals, in English and Spanish languages with no greater obsolescence than five years. The use of caloric restriction and intermittent fasting have generated positive changes, producing a decrease in pro-inflammatory states, oxidative stress, and aging. Approaches that modulate disease progression and improve cognitive function of adenosine monophosphate kinase, insulin-like growth factor, and sirtuin enzyme pathways are considered, generating a neuroprotective effect.

Plant Phenolics Inhibit Focal Adhesion Kinase and Suppress Host Cell Invasion by Uropathogenic Escherichia coli.

Traditional folk treatments for the prevention and management of urinary tract infections (UTIs) and other infectious diseases often include plants and plant extracts that are rich in phenolic and polyphenolic compounds. These have been ascribed a variety of activities, including inhibition of bacterial interactions with host cells. Here we tested a panel of four well-studied phenolic compounds - caffeic acid phenethyl ester (CAPE), resveratrol, catechin, and epigallocatechin gallate - for effects on host cell adherence and invasion by uropathogenic Escherichia coli (UPEC). These bacteria, which are the leading cause of UTIs, can bind and subsequently invade bladder epithelial cells via an actin-dependent process. Intracellular UPEC reservoirs within the bladder are often protected from antibiotics and host defenses, and likely contribute to the development of chronic and recurrent infections. Using cell culture-based assays, we found that only resveratrol had a notable negative effect on UPEC adherence to bladder cells. However, both CAPE and resveratrol significantly inhibited UPEC entry into the host cells, coordinate with attenuated phosphorylation of the host actin regulator Focal Adhesion Kinase (FAK, or PTK2) and marked increases in the numbers of focal adhesion structures. We further show that the intravesical delivery of resveratrol inhibits UPEC infiltration of the bladder mucosa in a murine UTI model, and that resveratrol and CAPE can disrupt the ability of other invasive pathogens to enter host cells. Together, these results highlight the therapeutic potential of molecules like CAPE and resveratrol, which could be used to augment antibiotic treatments by restricting pathogen access to protective intracellular niches.

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.

Stages of change: Strategies to promote use of a Pediatric Early Warning System in resource-limited pediatric oncology centers.

BACKGROUND: Pediatric Early Warning Systems (PEWS) assist early detection of clinical deterioration in hospitalized children with cancer. Relevant to successful PEWS implementation, the "stages of change" model characterizes stakeholder support for PEWS based on willingness and effort to adopt the new practice. METHODS: At five resource-limited pediatric oncology centers in Latin America, semi-structured interviews were conducted with 71 hospital staff involved in PEWS implementation. Purposive sampling was used to select centers requiring variable time to complete PEWS implementation, with low-barrier centers (3-4 months) and high-barrier centers (10-11 months). Interviews were conducted in Spanish, professionally transcribed, and translated into English. Thematic content analysis explored "stage of change" with constant comparative analysis across stakeholder types and study sites. RESULTS: Participants identified six interventions (training, incentives, participation, evidence, persuasion, and modeling) and two policies (environmental planning and mandates) as effective strategies used by implementation leaders to promote stakeholder progression through stages of change. Key approaches involved presentation of evidence demonstrating PEWS effectiveness, persuasion and incentives addressing specific stakeholder interests, enthusiastic individuals serving as models for others, and policies enforced by hospital directors facilitating habitual PEWS use. Effective engagement targeted hospital directors during early implementation phases to provide programmatic legitimacy for clinical staff. CONCLUSION: This study identifies strategies to promote adoption and maintained use of PEWS, highlighting the importance of tailoring implementation strategies to the motivations of each stakeholder type. These findings can guide efforts to implement PEWS and other evidence-based practices that improve childhood cancer outcomes in resource-limited hospitals.

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.

Impact of hospital characteristics on implementation of a Pediatric Early Warning System in resource-limited cancer hospitals.

Background: Pediatric Early Warning Systems (PEWS) aid in identification of deterioration in hospitalized children with cancer but are underutilized in resource-limited settings. Proyecto EVAT is a multicenter quality improvement (QI) collaborative in Latin America to implement PEWS. This study investigates the relationship between hospital characteristics and time required for PEWS implementation. Methods: This convergent mixed-methods study included 23 Proyecto EVAT childhood cancer centers; 5 hospitals representing quick and slow implementers were selected for qualitative analysis. Semi-structured interviews were conducted with 71 stakeholders involved in PEWS implementation. Interviews were recorded, transcribed and translated to English, then coded using a priori and novel codes. Thematic content analysis explored the impact of hospital characteristics and QI experience on time required for PEWS implementation and was supplemented by quantitative analysis exploring the relationship between hospital characteristics and implementation time. Results: In both quantitative and qualitative analysis, material and human resources to support PEWS significantly impacted time to implementation. Lack of resources produced various obstacles that extended time necessary for centers to achieve successful implementation. Hospital characteristics, such as funding structure and type, influenced PEWS implementation time by determining their resource-availability. Prior hospital or implementation leader experience with QI, however, helped facilitate implementation by assisting implementers predict and overcome resource-related challenges. Conclusions: Hospital characteristics impact time required to implement PEWS in resource-limited childhood cancer centers; however, prior QI experience helps anticipate and adapt to resource challenges and more quickly implement PEWS. QI training should be a component of strategies to scale-up use of evidence-based interventions like PEWS in resource-limited settings.

The COVID-19 Pandemic's impact on sustainability and expansion of a Pediatric Early Warning System in resource-limited hospitals.

BACKGROUND: The COVID-19 pandemic impacted healthcare delivery worldwide, including pediatric cancer care, with a disproportionate effect in resource-limited settings. This study evaluates its impact on existing quality improvement (QI) programs. METHODS: We conducted 71 semi-structured interviews of key stakeholders at five resource-limited pediatric oncology centers participating in a collaborative to implement Pediatric Early Warning System (PEWS). Interviews were conducted virtually using a structured interview guide, recorded, transcribed, and translated into English. Two coders developed a codebook of a priori and inductive codes and independently coded all transcripts, achieving a kappa of 0.8-0.9. Thematic analysis explored the impact of the pandemic on PEWS. RESULTS: All hospitals reported limitations in material resources, reduction in staffing, and impacts on patient care due to the pandemic. However, the impact on PEWS varied across centers. Identified factors that promoted or limited ongoing PEWS use included the availability of material resources needed for PEWS, staff turnover, PEWS training for staff, and the willingness of staff and hospital leaders to prioritize PEWS. Consequently, some hospitals were able to sustain PEWS; others halted or reduced PEWS use to prioritize other work. Similarly, the pandemic delayed plans at all hospitals to expand PEWS to other units. Several participants were hopeful for future expansion of PEWS post-pandemic. CONCLUSION: The COVID-19 pandemic created challenges for sustainability and scale of PEWS, an ongoing QI program, in these resource-limited pediatric oncology centers. Several factors mitigated these challenges and promoted ongoing PEWS use. These results can guide strategies to sustain effective QI interventions during future health crises.

MSH-5: malignant knee tumors timely detection index.

BACKGROUND: Bone neoplasms are usually misdiagnosed causing a delay in their treatment. Bone neoplasms are usually confused with tendinitis, 31% of the cases corresponds to osteosarcomas and in 21% to Ewing's sarcomas. OBJECTIVE: To create a clinical-radiographic instrument of high diagnostic suspicion of knee bone neoplasms to prevent a delay in diagnosis. METHOD: A clinimetric study (sensitivity, consistency and validity) was performed in the bone tumor service, Hospital de Ortopedia de la Unidad Médica de Alta Especialidad Dr. Victorio de la Fuente Narváez, Instituto Mexicano del Seguro Social, in México City. RESULTS: Characteristics of 153 patients were collected. For the sensitivity phase, 3 domains (signs, symptoms, and radiology) and 12 items were included. Consistency was evaluated with ICC (0.944), 95%CI (0.865-0.977), p < 0.001 and a-Cronbach (0.863). Index obtained a sensitivity of 0.80 and a specificity of 0.882 were obtained. The positive predictive value of the test was 66.6% and the negative predictive value was 93.75%. The positive likelihood ratio was 6.8 and the negative likelihood ratio was 0.2. Validity was evaluated using r-Pearson (0.894; p < 0.001). CONCLUSIONS: A high suspicion clinical-radiographic index was designed to detect malignant knee tumors with adequate sensitivity, specificity, appearance, content, criteria, and construct validity.

ANTECEDENTES: Los tumores óseos suelen ser subdiagnosticados, provocando un retraso en su tratamiento. El diagnóstico erróneo más frecuente es tendinitis, en el cual el 31% corresponden a osteosarcomas y el 21% a sarcomas de Ewing. OBJETIVO: Crear un instrumento clínico-radiográfico de alta sospecha diagnóstica de tumores óseos de rodilla. MÉTODO: Se realizó un estudio clinimétrico (sensibilidad, consistencia y validez) en el servicio de tumores óseos del Hospital de Ortopedia de la Unidad Médica de Alta Especialidad Dr. Victorio de la Fuente Narváez, Instituto Mexicano del Seguro Social, en Ciudad de México. RESULTADOS: El índice se realizó tomando las características de 153 pacientes. Para la fase de sensibilidad se incluyeron tres dominios (signos, síntomas y radiología) y 12 ítems. La consistencia se evaluó con coeficiente de correlación intraclase (0.944), intervalo de confianza del 95% (0.865-0.977), p < 0.001 y α de Cronbach (0.863). Se obtuvo una sensibilidad del instrumento de 0.80 y una especificidad de 0.882. El valor predictivo positivo de la prueba fue del 66.6% y el valor predictivo negativo fue de 93.75%. La razón de verosimilitud positiva fue de 6.8 y la razón de verosimilitud negativa fue de 0.2. La validez se evaluó mediante r-Pearson (0.894; p < 0.001). CONCLUSIONES: Se diseñó un índice clínico-radiográfico de alta sospecha para detectar tumores malignos de rodilla con adecuada sensibilidad, especificidad y validez de apariencia, de contenido, de criterio y de constructo.

Prospective assessment of risk biomarkers of sinusoidal obstruction syndrome after hematopoietic cell transplantation.

BACKGROUNDCurrently, no laboratory tests exist to stratify for the risk of developing sinusoidal obstruction syndrome (SOS), an early endothelial complication after hematopoietic cell transplantation (HCT). Risk biomarkers of SOS have not been verified in a prospective cohort accounting for differences between practices across institutions. Herein, we aimed to define risk groups for SOS occurrence using 3 proteins: L-ficolin, hyaluronic acid (HA), and stimulation 2 (ST2). METHODSBetween 2017 and 2021, we prospectively accrued 80 pediatric patients across 4 US centers. Biomarkers were tested by ELISA blind to patient groupings and associated with SOS incidence on day 35 after HCT, and overall survival (OS) on day 100 after HCT. Cutpoints were identified using retrospective cohorts and applied to the prospective cohort.RESULTSCombination of the 3 biomarkers measured on day 3 after HCT in the prospective cohort provided 80% (95% CI 55%-100%) sensitivity and 73% (95% CI 62%-83%) specificity for risk of SOS occurrence. Patients with low L-ficolin were 9 times (95% CI 3-32) more likely to develop SOS, while patients with high HA and ST2 were 6.5 (95% CI 1.9-22.0) and 5.5 (95% CI 2.3-13.1) times more likely to develop SOS. These 3 markers also predicted worse day 100 OS - L-ficolin: HR, 10.0 (95% CI 2.2-45.1), P = 0.0002; HA: HR, 4.1 (95% CI 1.0-16.4), P = 0.031; and ST2: HR, 3.9 (95% CI 0.9-16.4), P = 0.04.CONCLUSIONL-ficolin, HA, and ST2 levels measured as early as 3 days after HCT improved risk stratification for SOS occurrence and OS and may guide risk-adapted preemptive therapy.TRIAL REGISTRATIONClinicalTrials.gov NCT03132337.FUNDINGNIH.

Asociación entre las características radiográficas y los tumores óseos de rodilla.

BACKGROUND: Bone neoplasms require an adequate clinical-radiographic evaluation for their diagnosis. Plain radiographs are the usual method to establish the diagnosis and evaluate differential diagnoses in the study of bone tumor pathology. OBJECTIVE: To recognize the frequency of radiographic characteristics and associate them with bone tumor pathology. METHOD: Radiographic data were collected from 132 patients with tumor pathology confirmed by biopsy from bone tumors service of the Traumatology and Orthopedics Hospital Unidades Médicas de Alta Especialidad Dr. Victorio de la Fuente Narváez, Instituto Mexicano del Seguro Social, Ciudad de México, during 2019. RESULTS: 132 patients were registered. The most frequent benign tumor was osteochondroma (27.3%), and malignant was osteosarcoma (9.8%). Active lytic lesions (odds ratio [OR]: 6.9; 95% confidence interval [95% CI]: 2.83-16.85) or aggressive (OR: 26.85; 95% CI: 3.21-224) were associated with giant cells tumors. Poorly differentiated intraosseous blast lesions of bone lineage (OR: 36.15; 95% CI: 4.4-295.5) were associated with osteosarcoma. The periosteal reaction (OR: 36.15; 95% CI: 4.4-295.5), the moth-eaten or permeative pattern (OR: 11.75; 95% CI: 1.26-109) and the central location of the lesion (OR: 3.03; 95% CI: 1.37-6.69) were associated with malignant tumor lesions. CONCLUSIONS: Poorly defined intraosseous blast lesions of bone lineage, periosteal reaction, and moth-eaten or permeative pattern of destruction are associated with malignant lesions.

ANTECEDENTES: Los tumores óseos requieren una adecuada evaluación clínico-radiográfica para su diagnóstico. Las radiografías simples son el método incruento usual para establecer el diagnóstico y evaluar diagnósticos diferenciales en el estudio de la patología tumoral ósea. OBJETIVO: Reconocer la frecuencia de las características radiográficas y asociarlas con patología tumoral ósea. MÉTODO: Se recolectaron datos radiográficos de 132 pacientes con patología tumoral confirmada mediante biopsia del servicio de tumores óseos del Hospital de Traumatología y Ortopedia Unidades Médicas de Alta Especialidad Dr. Victorio de la Fuente Narváez, Instituto Mexicano del Seguro Social, en Ciudad de México, durante el año 2019. RESULTADOS: Integraron la muestra 132 pacientes. El tumor benigno más frecuente fue el osteocondroma (27.3%), y el maligno, el osteosarcoma (9.8%). Las lesiones líticas activas (odds ratio [OR]: 6.9; intervalo de confianza del 95% [IC95%]: 2.83-16.85) o agresivas (OR: 26.85; IC95%: 3.21-224) se asociaron a tumor de células gigantes. Las lesiones blásticas de estirpe ósea mal diferenciadas intraóseas (OR: 36.15; IC95%: 4.4-295.5) se asociaron a osteosarcoma. La reacción perióstica (OR: 36.15; IC95%: 4.4-295.5), el patrón apolillado o permeativo (OR: 11.75; IC95%: 1.26-109) y la ubicación central (OR: 3.03; IC95%: 1.37-6.69) se asociaron a lesiones tumorales malignas. CONCLUSIONES: Las lesiones blásticas de estirpe ósea mal definidas intraóseas, la reacción perióstica y el patrón de destrucción apolillado o permeativo se asocian a lesiones malignas.

Development and pilot testing of PROACTIVE: A pediatric onco-critical care capacity and quality assessment tool for resource-limited settings.

BACKGROUND: Nearly 90% children with cancer reside in low- and middle-income countries, which face multiple challenges delivering high-quality pediatric onco-critical care (POCC). We recently identified POCC quality and capacity indicators for PROACTIVE (PediatRic Oncology cApaCity assessment Tool for IntensiVe carE), a tool that evaluates strengths and limitations in POCC services. This study describes pilot testing of PROACTIVE, development of center-specific reports, and identification of common POCC challenges. METHODS: The original 119 consensus-derived PROACTIVE indicators were converted into 182 questions divided between 2 electronic surveys for intensivists and oncologists managing critically ill pediatric cancer patients. Alpha-testing was conducted to confirm face-validity with four pediatric intensivists. Eleven centers representing diverse geographic regions, income levels, and POCC services conducted beta-testing to evaluate usability, feasibility, and applicability of PROACTIVE. Centers' responses were scored and indicators with mean scores ≤75% in availability/performance were classified as common POCC challenges. RESULTS: Alpha-testing ensured face-validity and beta-testing demonstrated feasibility and usability of PROACTIVE (October 2020-June 2021). Twenty-two surveys (response rate 99.4%) were used to develop center-specific reports. Adjustments to PROACTIVE were made based on focus group feedback and surveys, resulting in 200 questions. Aggregated data across centers identified common POCC challenges: (1) lack of pediatric intensivists, (2) absence of abstinence and withdrawal symptoms monitoring, (3) shortage of supportive care resources, and (4) limited POCC training for physicians and nurses. CONCLUSIONS: PROACTIVE is a feasible and contextually appropriate tool to help clinicians and organizations identify challenges in POCC services across a wide range of resource-levels. Widespread use of PROACTIVE can help prioritize and develop tailored interventions to strengthen POCC services and outcomes globally.

Multilevel impacts of a pediatric early warning system in resource-limited pediatric oncology hospitals.

Background: Pediatric Early Warning Systems (PEWS) reduce clinical deterioration, improve interdisciplinary communication, and provide cost savings; however, little is known about how these impacts are achieved or related. This study evaluates the multi-level impacts of PEWS in resource-limited pediatric oncology centers. Methods: We conducted 71 semi-structured interviews including physicians (45%), nurses (45%), and administrators (10%) from 5 resource-limited pediatric oncology centers in 4 Latin American countries. Interviews were conducted in Spanish, transcribed, and translated into English. A code book was developed using a priori and inductively derived codes. Transcripts were independently coded by 2 coders, achieving a kappa of 0.8-0.9. Thematic content analysis explored perceived impacts of PEWS at the level of the patient, clinician, healthcare team, and institution. Results: PEWS improved the quality of attention for patients, reducing morbidity and mortality. Clinicians felt more knowledgeable, confident, and empowered providing patient care, resulting in greater job satisfaction. PEWS affected team dynamics by improving interdisciplinary (ward and intensive care unit) and interprofessional (physicians and nurses) relationships and communication. This ultimately led to institutional culture change with emphasis on patient safety, collaboration with other centers, and receipt of institutional awards. Together, these impacts led to hospital-wide support of ongoing PEWS use. Conclusions: In resource-limited hospitals, PEWS use results in multi-level positive impacts on patients, clinicians, teams, and institutions, creating a feedback loop that further supports ongoing PEWS use. These findings can guide advocacy for PEWS to various stakeholders, improve PEWS effectiveness, and inform assessment of other interventions to improve childhood cancer outcomes.

Ucl fimbriae regulation and glycan receptor specificity contribute to gut colonisation by extra-intestinal pathogenic Escherichia coli.

Extra-intestinal pathogenic Escherichia coli (ExPEC) belong to a critical priority group of antibiotic resistant pathogens. ExPEC establish gut reservoirs that seed infection of the urinary tract and bloodstream, but the mechanisms of gut colonisation remain to be properly understood. Ucl fimbriae are attachment organelles that facilitate ExPEC adherence. Here, we investigated cellular receptors for Ucl fimbriae and Ucl expression to define molecular mechanisms of Ucl-mediated ExPEC colonisation of the gut. We demonstrate differential expression of Ucl fimbriae in ExPEC sequence types associated with disseminated infection. Genome editing of strains from two common sequence types, F11 (ST127) and UTI89 (ST95), identified a single nucleotide polymorphism in the ucl promoter that changes fimbriae expression via activation by the global stress-response regulator OxyR, leading to altered gut colonisation. Structure-function analysis of the Ucl fimbriae tip-adhesin (UclD) identified high-affinity glycan receptor targets, with highest affinity for sialyllacto-N-fucopentose VI, a structure likely to be expressed on the gut epithelium. Comparison of the UclD adhesin to the homologous UcaD tip-adhesin from Proteus mirabilis revealed that although they possess a similar tertiary structure, apart from lacto-N-fucopentose VI that bound to both adhesins at low-micromolar affinity, they recognize different fucose- and glucose-containing oligosaccharides. Competitive surface plasmon resonance analysis together with co-structural investigation of UcaD in complex with monosaccharides revealed a broad-specificity glycan binding pocket shared between UcaD and UclD that could accommodate these interactions. Overall, our study describes a mechanism of adaptation that augments establishment of an ExPEC gut reservoir to seed disseminated infections, providing a pathway for the development of targeted anti-adhesion therapeutics.