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.
The COVID‐19 pandemic created challenges to maintain and scale‐up an ongoing quality improvement initiative, a Pediatric Early Warning System (PEWS), in five pediatric oncology hospitals in Latin America. Identified factors mitigate these challenges and promote ongoing PEWS use can be leveraged to support sustainability of programs to reduce global disparities in childhood cancer during future health crises.
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.
This multicenter, multinational qualitative study identifies strategies used by implementation leaders to promote hospital staff's decision to adopt a Pediatric Early Warning System (PEWS) in resource‐limited pediatric oncology centers. These findings can guide efforts to implement PEWS and other quality improvement tools that improve childhood cancer outcomes globally.
During the first postnatal week of mouse development, radial glial cells lining the ventricles of the brain differentiate into ependymal cells, undergoing a morphological change from pseudostratified ...cuboidal cells to a flattened monolayer. Concomitant with this change, multiple motile cilia are generated and aligned on each nascent ependymal cell. Proper ependymal cell development is crucial to forming the brain tissue:CSF barrier, and to the establishment of ciliary CSF flow, but the mechanisms that regulate this differentiation event are poorly understood. The JhylacZ mouse line carries an insertional mutation in the Jhy gene (formerly 4931429I11Rik), and homozygous JhylacZ/lacZ mice develop a rapidly progressive juvenile hydrocephalus, with defects in ependymal cilia morphology and ultrastructure. Here we show that beyond just defective motile cilia, JhylacZ/lacZ mice display abnormal ependymal cell differentiation. Ventricular ependyma in JhylacZ/lacZ mice retain an unorganized and multi-layered morphology, representative of undifferentiated ependymal (radial glial) cells, and they show altered expression of differentiation markers. Most JhylacZ/lacZ ependymal cells do eventually acquire some differentiated ependymal characteristics, suggesting a delay, rather than a block, in the differentiation process, but ciliogenesis remains perturbed. JhylacZ/lacZ ependymal cells also manifest disruptions in adherens junction formation, with altered N-cadherin localization, and have defects in the polarized organization of the apical motile cilia that do form. Functional studies showed that cilia of JhylacZ/lacZ mice have severely reduced motility, a potential cause for the development of hydrocephalus. This work shows that JHY does not only control ciliogenesis, but is a crucial component of the ependymal differentiation process, with ciliary defects likely a consequence of altered ependymal differentiation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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.
Précis
Proyecto EVAT is a multicenter, multinational quality‐improvement collaborative that supported successful regional implementation and scale‐up of an evidence‐based intervention—a pediatric early warning system—at 36 pediatric oncology hospitals in Latin America. The knowledge‐to‐action framework was used to explain the project’s implementation strategy and to assess implementation outcomes, including the quality, the time required, and the global impact.
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.
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.
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
and novel codes. Thematic content analysis explored the impact of
and
on time required for PEWS implementation and was supplemented by quantitative analysis exploring the relationship between hospital characteristics and implementation time.
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.
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.
Congenital hydrocephalus, the accumulation of excess cerebrospinal fluid (CSF) in the ventricles of the brain, affects one of every 1000 children born today, making it one of the most common human ...developmental disorders. Genetic causes of hydrocephalus are poorly understood in humans, but animal models suggest a broad genetic program underlying the regulation of CSF balance. In this study, the random integration of a transgene into the mouse genome led to the development of an early onset and rapidly progressive hydrocephalus. Juvenile hydrocephalus transgenic mice (JhylacZ) inherit communicating hydrocephalus in an autosomal recessive fashion with dilation of the lateral ventricles observed as early as postnatal day 1.5. Ventricular dilation increases in severity over time, becoming fatal at 4–8 weeks of age. The ependymal cilia lining the lateral ventricles are morphologically abnormal and reduced in number in JhylacZ/lacZ brains, and ultrastructural analysis revealed disorganization of the expected 9+2 microtubule pattern. Rather, the majority of JhylacZ/lacZ cilia develop axonemes with 9+0 or 8+2 microtubule structures. Disruption of an unstudied gene, 4931429I11Rik (now named Jhy) appears to underlie the hydrocephalus of JhylacZ/lacZ mice, and the Jhy transcript and protein are decreased in JhylacZ/lacZ mice. Partial phenotypic rescue was achieved in JhylacZ/lacZ mice by the introduction of a bacterial artificial chromosome (BAC) carrying 60–70% of the JHY protein coding sequence. Jhy is evolutionarily conserved from humans to basal vertebrates, but the predicted JHY protein lacks identifiable functional domains. Ongoing studies are directed at uncovering the physiological function of JHY and its role in CSF homeostasis.
•JhylacZ transgenic mice develop autosomal recessive communicating hydrocephalus.•The Jhy gene produces a conserved protein with no known functional domains.•Ependymal cilia in JhylacZ brains are disorganized and randomly oriented.•JhylacZ cilia have abnormal 9+0 and 8+2 microtubule organization patterns.
Abstract
Medulloblastoma (MB) is the most common malignant childhood brain tumor. Our recent analysis of the MB genomic landscape in a cohort of 500 patients discovered subgroup-specific hotspot ...mutations targeting KBTBD4, a poorly characterized member of the BTB-BACK-Kelch domain family of proteins. Based on homology with other family members, KBTBD4 is predicted to function as a substrate adaptor for E3 ubiquitin ligases, facilitating substrate recruitment via its C-terminal Kelch domain. KBTBD4 mutations occurred exclusively in Group 3 and Group 4 patients as in-frame insertions clustered in the Kelch domain, suggesting these variants may disrupt physiological KBTBD4-substrate interactions. Herein, we used a combination of advanced proteomic and gene targeting strategies to determine the normal physiological function of KBTBD4 and elucidate its role in MB pathogenesis. IP-MS/MS results identified proteins associated with the ubiquitin-proteasome system (UPS), including E3 ubiquitin ligases (CUL3, CHIP, UBR4), ubiquitin-associated proteins (CACUL1, RPS27A), as well as chaperone-associated proteins (HSP90, TCP1, BAG2, NUDC3). Candidate interacting partners were subsequently confirmed through co-IP/Western-blot experiments, substantiating preliminary hypotheses related to KBTBD4 function. To investigate the role of mutant KBTBD4 in MB progression, we aim to target KBTBD4 in MB PDX models harboring prototypic insertions. Parallel studies encompassing a complete phenotypic characterization of Kbtbd4 knock-out and knock-in mice carrying MB-specific mutations will further validate KBTBD4 as a bona fide MB driver gene, and mechanistically disentangle how KBTBD4 Kelch domain mutations promote tumorigenesis. These studies will provide new insights into MB biology with the potential to disclose novel therapeutic vulnerabilities for treating mutant KBTBD4-driven MB.
Paediatric early warning systems (PEWS) aid in the early identification of clinical deterioration events in children admitted to hospital. We aimed to investigate the effect of PEWS implementation on ...mortality due to clinical deterioration in children with cancer in 32 resource-limited hospitals across Latin America.
Proyecto Escala de Valoración de Alerta Temprana (Proyecto EVAT) is a quality improvement collaborative to implement PEWS in hospitals providing childhood cancer care. In this prospective, multicentre cohort study, centres joining Proyecto EVAT and completing PEWS implementation between April 1, 2017, and May 31, 2021, prospectively tracked clinical deterioration events and monthly inpatient-days in children admitted to hospital with cancer. De-identified registry data reported between April 17, 2017, and Nov 30, 2021, from all hospitals were included in analyses; children with limitations on escalation of care were excluded. The primary outcome was clinical deterioration event mortality. Incidence rate ratios (IRRs) were used to compare clinical deterioration event mortality before and after PEWS implementation; multivariable analyses assessed the correlation between clinical deterioration event mortality and centre characteristics.
Between April 1, 2017, and May 31, 2021, 32 paediatric oncology centres from 11 countries in Latin America successfully implemented PEWS through Proyecto EVAT; these centres documented 2020 clinical deterioration events in 1651 patients over 556 400 inpatient-days. Overall clinical deterioration event mortality was 32·9% (664 of 2020 events). The median age of patients with clinical deterioration events was 8·5 years (IQR 3·9–13·2), and 1095 (54·2%) of 2020 clinical deterioration events were reported in male patients; data on race or ethnicity were not collected. Data were reported per centre for a median of 12 months (IQR 10–13) before PEWS implementation and 18 months (16–18) after PEWS implementation. The mortality rate due to a clinical deterioration event was 1·33 events per 1000 patient-days before PEWS implementation and 1·09 events per 1000 patient-days after PEWS implementation (IRR 0·82 95% CI 0·69–0·97; p=0·021). In the multivariable analysis of centre characteristics, higher clinical deterioration event mortality rates before PEWS implementation (IRR 1·32 95% CI 1·22–1·43; p<0·0001), being a teaching hospital (1·18 1·09–1·27; p<0·0001), not having a separate paediatric haematology-oncology unit (1·38 1·21–1·57; p<0·0001), and having fewer PEWS omissions (0·95 0·92–0·99; p=0·0091) were associated with a greater reduction in clinical deterioration event mortality after PEWS implementation; no association was found with country income level (IRR 0·86 95% CI 0·68–1·09; p=0·22) or clinical deterioration event rates before PEWS implementation (1·04 0·97–1·12; p=0·29).
PEWS implementation was associated with reduced clinical deterioration event mortality in paediatric patients with cancer across 32 resource-limited hospitals in Latin America. These data support the use of PEWS as an effective evidence-based intervention to reduce disparities in global survival for children with cancer.
American Lebanese Syrian Associated Charities, US National Institutes of Health, and Conquer Cancer Foundation.
For the Spanish and Portuguese translations of the abstract see Supplementary Materials section.
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