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Background: Although about 15 to 50 percent of people with intellectual disabilities (ID) living in residential settings suffer from sleep problems, scant attention is paid to these problems. Most available studies focus on pharmaceutical solutions. In this study we focus on improving sleep in people with intellectual disabilities living in residential settings by non-pharmaceutical interventions. Method: The design is a multiple case study using actigraphy. Following a baseline measurement of people with ID, we recommended an intervention such as bedtime scheduling. This was followed by an effect measurement. Results: Sleep efficiency, sleep latency and rising latency improved significantly. The time spent in bed also decreased significantly and the hours of sleep while in bed increased significantly. Conclusion: For people with ID, sleep can be improved by non-pharmaceutical interventions. A multidisciplinary approach is helpful in selecting an adequate intervention.

The article discusses the development of an integrated care pathway for occupational pulmonary diseases. Occupational pulmonary diseases are a global issue, and it can be challenging to determine the causal link between exposure and disease. The care pathway consists of five steps, including medical consultation, an in-depth assessment of occupational history, standard diagnostic work-up, counseling, and follow-up. The pathway aims to improve early detection, organization of care, and collaboration between healthcare providers and occupational health professionals. The ultimate goal is to prevent and treat work-related pulmonary diseases effectively. [Extracted from the article]

As curative therapies for pediatric acute myleoid leukemia (AML) remain elusive, identifying potential new treatment targets is vital. We assessed the cell surface expression of CD74, also known as the major histocompatibility complex-II invariant chain, by multidimensional flow cytometry in 973 patients enrolled in the Children's Oncology Group AAML1031 clinical trial (clinicaltrials gov. Identifier: NCT01371981). Thirty-eight percent of pediatric AML patients expressed CD74 at any level and a comparison to normal hematopoietic cells revealed a subset with increased expression relative to normal myeloid progenitor cells. Pediatric AML patients expressing high intensity CD74 typically had an immature immunophenotype and an increased frequency of lymphoid antigen expression. Increased CD74 expression was associated with older patients with lower white blood cells and peripheral blood blast counts, and was enriched for t(8;21), trisomy 8, and CEBPA mutations. Overall, high CD74 expression was associated with low-risk status, however 26% of patients were allocated to high-risk protocol status and 5-year event-free survival was 53%, indicating that a significant number of high expressing patients had poor outcomes. In vitro preclinical studies indicate that anti-CD74 therapy demonstrates efficacy against AML cells but has little impact on normal CD34+ cells. Together, we demonstrate that CD74 is expressed on a subset of pediatric AML at increased levels compared to normal hematopoietic cells and is a promising target for therapy in expressing patients. Given that nearly half of patients expressing CD74 at high levels experience an adverse event within 5 years, and the availability of CD74 targeting drugs, this represents a promising line of therapy worthy of additional investigation.

Purpose: Optimized strategies for risk classification are essential to tailor therapy for patients with biologically distinctive disease. Risk classification in pediatric acute myeloid leukemia (pAML) relies on detection of translocations and gene mutations. Long noncoding RNA (lncRNA) transcripts have been shown to associate with and mediate malignant phenotypes in acute myeloid leukemia (AML) but have not been comprehensively evaluated in pAML., Methods: To identify lncRNA transcripts associated with outcomes, we evaluated the annotated lncRNA landscape by transcript sequencing of 1,298 pediatric and 96 adult AML specimens. Upregulated lncRNAs identified in the pAML training set were used to establish a regularized Cox regression model of event-free survival (EFS), yielding a 37 lncRNA signature (lncScore). Discretized lncScores were correlated with initial and postinduction treatment outcomes using Cox proportional hazards models in validation sets. Predictive model performance was compared with standard stratification methods by concordance analysis., Results: Training set cases with positive lncScores had 5-year EFS and overall survival rates of 26.7% and 42.7%, respectively, compared with 56.9% and 76.3% with negative lncScores (hazard ratio, 2.48 and 3.16; P < .001). Pediatric validation cohorts and an adult AML group yielded comparable results in magnitude and significance. lncScore remained independently prognostic in multivariable models, including key factors used in preinduction and postinduction risk stratification. Subgroup analysis suggested that lncScores provide additional outcome information in heterogeneous subgroups currently classified as indeterminate risk. Concordance analysis showed that lncScore adds to overall classification accuracy with at least comparable predictive performance to current stratification methods that rely on multiple assays., Conclusion: Inclusion of the lncScore enhances predictive power of traditional cytogenetic and mutation-defined stratification in pAML with potential, as a single assay, to replace these complex stratification schemes with comparable predictive accuracy.

Acute myeloid leukemia (AML) patients have a wide array of cytogenetic and molecular aberrations, which can influence response to therapy. Monosomy 7 is a rare subset within pediatric AML (prevalence of <2%) that is highly associated with poor outcomes. Fusions involving the anaplastic tyrosine kinase (ALK) gene were exclusively identified in 14.3% of this high-risk cohort, while absent across all other AML. Given the dismal outcomes of monosomy 7, we evaluated the use of crizotinib, an FDA-approved tyrosine kinase inhibitor, used to treat patients with ALK fusions. Our findings suggest that crizotinib may serve as a novel therapy for these patients., (© 2023 Wiley Periodicals LLC.)

High levels of the inflammatory cytokine IL-6 in the bone marrow are associated with poor outcomes in pediatric acute myeloid leukemia (pAML), but its etiology remains unknown. Using RNA-seq data from pre-treatment bone marrows of 1489 children with pAML, we show that > 20% of patients have concurrent IL-6, IL-1, IFNα/β, and TNFα signaling activity and poorer outcomes. Targeted sequencing of pre-treatment bone marrow samples from affected patients (n = 181) revealed 5 highly recurrent patterns of somatic mutation. Using differential expression analyses of the most common genomic subtypes (~60% of total), we identify high expression of multiple potential drivers of inflammation-related treatment resistance. Regardless of genomic subtype, we show that JAK1/2 inhibition reduces receptor-mediated inflammatory signaling by leukemic cells in-vitro. The large number of high-risk pAML genomic subtypes presents an obstacle to the development of mutation-specific therapies. Our findings suggest that therapies targeting inflammatory signaling may be effective across multiple genomic subtypes of pAML., (© 2022. The Author(s).)

Infant Acute Myeloid Leukemia (AML) is a poorly-addressed, heterogeneous malignancy distinguished by surprisingly few mutations per patient but accompanied by myriad age-specific translocations. These characteristics make treatment of infant AML challenging. While infant AML is a relatively rare disease, it has enormous impact on families, and in terms of life-years-lost and life limiting morbidities. To better understand the mechanisms that drive infant AML, we performed integrative analyses of genome-wide mRNA, miRNA, and DNA-methylation data in diagnosis-stage patient samples. Here, we report the activation of an onco-fetal B-cell developmental gene regulatory network in infant AML. AML in infants is genomically distinct from AML in older children/adults in that it has more structural genomic aberrations and fewer mutations. Differential expression analysis of ~1500 pediatric AML samples revealed a large number of infant-specific genes, many of which are associated with B cell development and function. 18 of these genes form a well-studied B-cell gene regulatory network that includes the epigenetic regulators BRD4 and POU2AF1, and their onco-fetal targets LIN28B and IGF2BP3. All four genes are hypo-methylated in infant AML. Moreover, micro-RNA Let7a-2 is expressed in a mutually exclusive manner with its target and regulator LIN28B. These findings suggest infant AML may respond to bromodomain inhibitors and immune therapies targeting CD19, CD20, CD22, and CD79A., Competing Interests: ML is an employee of and has equity ownership in Hematologics Inc. and LP is an employee of Hematologics Inc. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The remaining authors declare no competing financial interests.

Purpose: We previously identified mesothelin (MSLN) as highly expressed in a significant fraction of acute myeloid leukemia (AML) but entirely silent in normal hematopoiesis, providing a promising antigen for immunotherapeutic targeting that avoids hematopoietic toxicity. Given that T cells genetically modified to express chimeric antigen receptors (CAR) are effective at eradicating relapsed/refractory acute lymphocytic leukemia, we developed MSLN-directed CAR T cells for preclinical evaluation in AML., Experimental Design: The variable light (VL) and heavy (VH) sequences from the MSLN-targeting SS1P immunotoxin were used to construct the single-chain variable fragment of the standard CAR containing 41-BB costimulatory and CD3Zeta stimulatory domains. The preclinical efficacy of MSLN CAR T cells was evaluated against AML cell lines and patient samples expressing various levels of MSLN in vitro and in vivo ., Results: We demonstrate that MSLN is expressed on the cell surface of AML blasts and leukemic stem cell-enriched CD34 + CD38 - subset, but not on normal hematopoietic stem and progenitor cells (HSPC). We further establish that MSLN CAR T cells are highly effective in eliminating MSLN-positive AML cells in cell line- and patient-derived xenograft models. Importantly, MSLN CAR T cells can target and eradicate CD34 + CD38 - cells without impacting the viability of normal HSPCs. Finally, we show that CAR T-cell functionality can be improved by inhibition of the ADAM17 metalloprotease that promotes shedding of MSLN., Conclusions: These findings demonstrate that MSLN is a viable target for CAR T-cell therapy in AML and that inhibiting MSLN shedding is a promising approach to improve CAR T-cell efficacy., (©2021 The Authors; Published by the American Association for Cancer Research.)

Background: Return to work (RTW) is an important outcome in Total Knee Arthroplasty (TKA). At present, 70-80%of TKA patients return to work within three to six months., Objective: What are patients' perspectives regarding beneficial and limiting factors in RTW after TKA?, Methods: Focus groups were formed in accordance with the Consolidated Criteria for Reporting Qualitative Research (COREQ) checklist. Three major topics were explored: 1. What was beneficial for RTW after TKA; 2. What was limiting for RTW after TKA; and 3. What additional care would benefit RTW after TKA?, Results: Data saturation was reached after four focus groups, comprising 17 participants-nine men and eight women (median age 58, range 52-65). The focus group study identified four main themes that contributed to a successful RTW namely rehabilitation (medical) like post-operative physical therapy, patient characteristics (personal), like motivation to RTW, occupational characteristics (work-related) like build-up in work tasks and medical support (medical) like availability of a walker or crutches., Conclusion: According to participants, factors within the following four themes can contribute to a successful return to work: occupational, patient, rehabilitation and medical care. Incorporating these factors into the integrated care pathway for the "young" TKA patients may increase the chances of a successful RTW.

The aim of this study was to establish the therapeutic relevance of the CD33 D2 isoform by developing novel antibodies targeting the IgC domain of CD33. Two novel IgC-targeting antibodies, HL2541 and 5C11-2, were developed, and CD33 isoforms were assessed using multiple assays in cells overexpressing either CD33 FL or CD33 D2 isoforms, unmodified acute myeloid leukemia (AML) cell lines and primary AML specimens representing different genotypes for the CD33 splicing single nucleotide polymorphism. CD33 D2 was recognized on cells overexpressing CD33 D2 and unmodified AML cell lines; however, minimal/no cell surface detection of CD33 D2 was observed in primary AML specimens. Both isoforms were detected intracellularly using novel antibodies. Minimal cell surface expression of CD33 D2 on primary AML/progenitor cells warrants further studies on anti-CD33 D2 immunotherapeutics.

Purpose: A cryptic inv(16)(p13.3q24.3) encoding the CBFA2T3-GLIS2 fusion is associated with poor outcome in infants with acute megakaryocytic leukemia. We aimed to broaden our understanding of the pathogenesis of this fusion through transcriptome profiling., Experimental Design: Available RNA from children and young adults with de novo acute myeloid leukemia (AML; N = 1,049) underwent transcriptome sequencing (mRNA and miRNA). Transcriptome profiles for those with the CBFA2T3-GLIS2 fusion ( N = 24) and without ( N = 1,025) were contrasted to define fusion-specific miRNAs, genes, and pathways. Clinical annotations defined distinct fusion-associated disease characteristics and outcomes., Results: The CBFA2T3-GLIS2 fusion was restricted to infants <3 years old ( P < 0.001), and the presence of this fusion was highly associated with adverse outcome ( P < 0.001) across all morphologic classifications. Further, there was a striking paucity of recurrent cooperating mutations, and transduction of cord blood stem cells with this fusion was sufficient for malignant transformation. CBFA2T3-GLIS2 positive cases displayed marked upregulation of genes with cell membrane/extracellular matrix localization potential, including NCAM1 and GABRE . Additionally, miRNA profiling revealed significant overexpression of mature miR-224 and miR-452 , which are intronic miRNAs transcribed from the GABRE locus. Gene-set enrichment identified dysregulated Hippo, TGFβ, and hedgehog signaling, as well as NCAM1 (CD56) interaction pathways. Therapeutic targeting of fusion-positive leukemic cells with CD56-directed antibody-drug conjugate caused significant cytotoxicity in leukemic blasts., Conclusions: The CBFA2T3-GLIS2 fusion defines a highly refractory entity limited to infants that appears to be sufficient for malignant transformation. Transcriptome profiling elucidated several highly targetable genes and pathways, including the identification of CD56, providing a highly plausible target for therapeutic intervention., (©2019 American Association for Cancer Research.)

Purpose: KIT mutations ( KIT + ) are common in core binding factor (CBF) AML and have been associated with varying prognostic significance. We sought to define the functional and clinical significance of distinct KIT mutations in CBF pediatric AML., Experimental Design: Following transfection of exon 17 (E17) and exon 8 (E8) mutations into HEK293 and Ba/F3 cells, KIT phosphorylation, cytokine-independent growth, and response to tyrosine kinase inhibitors (TKI) were evaluated. Clinical outcomes of patients treated on COG AAML0531 (NCT01407757), a phase III study of gemtuzumab ozogamicin (GO), were analyzed according to mutation status [ KIT + vs. wild-type KIT ( KIT - )] and mutation location (E8 vs. E17)., Results: KIT mutations were detected in 63 of 205 patients (31%); 22 (35%) involved only E8, 32 (51%) only E17, 6 (10%) both exons, and 3 (5%) alternative exons. Functional studies demonstrated that E17, but not E8, mutations result in aberrant KIT phosphorylation and growth. TKI exposure significantly affected growth of E17, but not E8, transfected cells. Patients with KIT + CBF AML had overall survival similar to those with KIT - (78% vs. 81%, P = 0.905) but higher relapse rates (RR = 43% vs. 21%; P = 0.005). E17 KIT + outcomes were inferior to KIT - patients [disease-free survival (DFS), 51% vs. 73%, P = 0.027; RR = 21% vs. 46%, P = 0.007)], although gemtuzumab ozogamicin abrogated this negative prognostic impact. E8 mutations lacked significant prognostic effect, and GO failed to significantly improve outcome., Conclusions: E17 mutations affect prognosis in CBF AML, as well as response to GO and TKIs; thus, clinical trials using both agents should be considered for KIT + patients., (©2019 American Association for Cancer Research.)