Background Previous studies have shown that children and adolescents with COVID-19 generally have mild disease. Children and adolescents with cancer, however, can have severe disease when infected with respiratory viruses. In this study, we aimed to understand the clinical course and outcomes of SARS-CoV-2 infection in children and adolescents with cancer. Methods We did a cohort study with data from 131 institutions in 45 countries. We created the Global Registry of COVID-19 in Childhood Cancer to capture de-identified data pertaining to laboratory-confirmed SARS-CoV-2 infections in children and adolescents (<19 years) with cancer or having received a haematopoietic stem-cell transplantation. There were no centre-specific exclusion criteria. The registry was disseminated through professional networks through email and conferences and health-care providers were invited to submit all qualifying cases. Data for demographics, oncological diagnosis, clinical course, and cancer therapy details were collected. Primary outcomes were disease severity and modification to cancer-directed therapy. The registry remains open to data collection. Findings Of 1520 submitted episodes, 1500 patients were included in the study between April 15, 2020, and Feb 1, 2021. 1319 patients had complete 30-day follow-up. 259 (19•9%) of 1301 patients had a severe or critical infection, and 50 (3•8%) of 1319 died with the cause attributed to COVID-19 infection. Modifications to cancer-directed therapy occurred in 609 (55•8%) of 1092 patients receiving active oncological treatment. Multivariable analysis revealed several factors associated with severe or critical illness, including World Bank low-income or lower-middle-income (odds ratio [OR] 5•8 [95% CI 3•8-8•8]; p<0•0001) and upper-middle-income (1•6 [1•2-2•2]; p=0•0024) country status; age 15-18 years (1•6 [1•1-2•2]; p=0•013); absolute lymphocyte count of 300 or less cells per mm³ (2•5 [1•8-3•4]; p<0•0001), absolute neutrophil count of 500 or less cells per mm³ (1•8 [1•3-2•4]; p=0•0001), and intensive treatment (1•8 [1•3-2•3]; p=0•0005). Factors associated with treatment modification included upper-middle-income country status (OR 0•5 [95% CI 0•3-0•7]; p=0•0004), primary diagnosis of other haematological malignancies (0•5 [0•3-0•8]; p=0•0088), the presence of one of more COVID-19 symptoms at the time of presentation (1•8 [1•3-2•4]; p=0•0002), and the presence of one or more comorbidities (1•6 [1•1-2•3]; p=0•020).Interpretation In this global cohort of children and adolescents with cancer and COVID-19, severe and critical illness occurred in one fifth of patients and deaths occurred in a higher proportion than is reported in the literature in the general paediatric population. Additionally, we found that variables associated with treatment modification were not the same as those associated with greater disease severity. These data could inform clinical practice guidelines and raise awareness globally that children and adolescents with cancer are at high-risk of developing severe COVID-19 illn...

IMPORTANCE Pediatric early warning systems (PEWS) aid with early identification of clinical deterioration and improve outcomes in children with cancer hospitalized in resource-limited settings; however, there may be barriers to implementation. OBJECTIVE To evaluate stakeholder-reported barriers and enablers to PEWS implementation in resource-limited hospitals. DESIGN, SETTING, AND PARTICIPANTSIn this qualitative study, semistructured stakeholder interviews were conducted at 5 resource-limited pediatric oncology centers in 4 countries in Latin America. Hospitals participating in a multicenter collaborative to implement PEWS were purposefully sampled based on time required for implementation (fast vs slow), and stakeholders interviewed included physicians, nurses, and administrators, involved in PEWS implementation. An interview guide was developed using the Consolidated Framework for Implementation Research (CFIR).Interviews were conducted virtually in Spanish, audiorecorded, and professionally transcribed and translated into English. A codebook was developed a priori using the CFIR and supplemented with codes inductively derived from transcript review. Two coders independently analyzed all transcripts, achieving a κ of 0.8 to 0.9. The study was conducted from June 1 to August 31, 2020. MAIN OUTCOMES AND MEASURES Thematic analysis was conducted based on CFIR domains(inner setting, characteristics of individuals, outer setting, intervention characteristics, and implementation process) to identify barriers and enablers to PEWS implementation. RESULTSSeventy-one staff involved in PEWS implementation were interviewed, including 32 physicians (45%), 32 nurses (45%), and 7 administrators (10%). Of these, 50 were women (70%).Components of the 5 CFIR domains were mentioned by participants as barriers and enablers to PEWS implementation at both fast-and slow-implementing centers. Participants emphasized barriers at the level of the clinical staff, hospital, external factors, and PEWS intervention. These barriers included staff resistance to change, inadequate resources, components of health systems, and the perceived origin and complexity of PEWS. At all centers, most barriers were successfully converted to enablers during the implementation process through targeted strategies, such as early stakeholder engagement and adaptation, including adapting PEWS to better fit the local context and changing the hospital setting to support ongoing use of PEWS. CONCLUSIONS AND RELEVANCETo date, this is the first multicenter, multinational study describing barriers and enablers to PEWS implementation in resource-limited settings. Findings suggest that many barriers are not immutable and can be converted to enablers during the (continued) Key Points Question What barriers and enablers to pediatric early warning systems (PEWS) implementation in resource-limited hospitals are reported by health care professionals? Findings In this qualitative study including 5 resource-limited pediatric oncology centers in 4 countries in Latin America, ma...

Numerous studies have implicated Delta-like 1 (DLK1), a transmembrane protein that shares homology with Notch ligands, in embryonic growth and differentiation. Dlk1 expression is widespread, though not ubiquitous, during early development, but is confined to a few specific cell types in adults. Adult Dlk1-expressing tissues include the Insulin-producing β-cells of the pancreas and the Growth hormone-producing somatotrophs of the pituitary gland. Previously generated Dlk1 null mice (Dlk1Sul-pat), display a partially penetrant neonatal lethality and a complex pattern of developmental and adult phenotypes. Here we describe the generation of a conditional Dlk1 mouse line (Dlk1flox) to facilitate cell type-specific deletion of the Dlk1 gene, providing a powerful system to explore each aspect of the Dlk1 null phenotype. Four tissue-specific Cre mouse lines were used to produce individual Dlk1 deletions in pancreatic β-cells, pituitary somatotrophs and the endothelial cells of the embryo and placenta, key candidates for the Dlk1 phenotype. Contrary to expectations, all of these conditional mice were fully viable, and none recapitulated any aspect of the Dlk1Sul-pat null mice. Dlk1 expression is therefore not essential for the normal development of β-cells, somatotrophs and endothelial cells, and the tissues responsible for the Dlk1 null phenotype remain to be identified. Dlk1flox mice will continue to provide an important tool for further research into the function of Dlk1.

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. Cancer 2022;128:4004-4016.