Heated humidified high flow nasal cannula therapy in children with obstructive sleep apnea: A randomized cross-over trial.

OBJECTIVE/BACKGROUND: Moderate-to-severe obstructive sleep apnea (OSA) is highly prevalent in children with obesity and/or underlying medical complexity. The first line of therapy, adenotonsillectomy (AT), does not cure OSA in more than 50% of these children. Consequently, continuous positive airway pressure (CPAP) is the main therapeutic option but adherence is often poor. A potential alternative which may be associated with greater adherence is heated high-flow nasal cannula (HFNC) therapy; however, its efficacy in children with OSA has not been systematically investigated. The study aimed to compare the efficacy of HFNC with CPAP to treat moderate-to-severe OSA with the primary outcome measuring the change from baseline in the mean obstructive apnea/hypopnea index (OAHI). PARTICIPANTS/METHODS: This was a single-blinded randomized, two period crossover trial conducted from March 2019 to December 2021 at a Canadian pediatric quaternary care hospital. Children aged 2-18 years with obesity and medical complexity diagnosed with moderate-to-severe OSA via overnight polysomnography and recommended CPAP therapy were included in the study. Following diagnostic polysomnography, each participant completed two further sleep studies; a HFNC titration study and a CPAP titration study (9 received HFNC first, and 9 received CPAP first) in a random 1:1 allocation order. RESULTS: Eighteen participants with a mean ± SD age of 11.9 ± 3.8 years and OAHI 23.1 ± 21.7 events/hour completed the study. The mean [95% CI] reductions in OAHI (-19.8[-29.2, -10.5] vs. -18.8 [-28.2, -9.4] events/hour, p = 0.9), nadir oxygen saturation (7.1[2.2, 11.9] vs. 8.4[3.5, 13.2], p = 0.8), oxygen desaturation index (-11.6[-21.0, -2.3] vs. -16.0[-25.3, -6.6], p = 0.5) and sleep efficiency (3.5[-4.8, 11.8] vs. 9.2[0.9, 15.5], p = 0.2) with HFNC and CPAP therapy were comparable between conditions. CONCLUSION: HFNC and CPAP therapy yield similar reductions in polysomnography quantified measures of OSA severity among children with obesity and medical complexities. TRIAL REGISTRATION: NCT05354401 ClinicalTrials.gov.

To Wear or Not Wear the Mask: Decline in Positive Airway Pressure Usage in Children with Sleep Disordered Breathing During the COVID-19 Pandemic.

Purpose: Positive airway pressure (PAP) therapy is an effective treatment prescribed to children with sleep disordered breathing (SDB); however, PAP adherence remains challenging. Given that COVID-19 pandemic continues to impact sleep and daily life, the aim of this study was to evaluate longitudinal trajectory of PAP usage in children during the COVID-19 pandemic. Patients and Methods: This was a retrospective study. Children aged 1-18 years with SDB prescribed PAP at The Hospital for Sick Children (Toronto, Canada) were evaluated for PAP adherence. Demographics, medical history and PAP adherence data during four consecutive 3-month time periods from December 2019 to December 2020 were collected. These four time periods included i) prior to COVID-19 lockdown, ii) during the first three months of lockdown, iii) summer and iv) return to school period. Percentage of days where PAP was used for ≥4 hours and average nightly usage of PAP were primary outcomes. Results: A total of 149 children (61.7% male, mean (±SD) age=12.8 ± 4.1 years, BMI (±SD) z-score=1.45±1.43) were enrolled. Compared to prior to lockdown, the median (IQR) of percentage of PAP usage ≥4 hours and average nightly usage of PAP declined significantly during the summer and return to school periods (p<0.001 for all). By the end of the return to school period, only 69/149 (46%) showed sustained PAP usage and 80/149 (54%) had decreased PAP usage. Obesity was a risk factor for a decline in PAP usage after returning to school (ß=-15.36, p=0.03). Conclusion: Compared to COVID-19 pre-pandemic PAP usage, there was a significant decline in PAP usage across COVID-19 pandemic. There is critical under usage of PAP in children diagnosed with SDB, resulting in an urgent need to address barriers to mitigate poor adherence to PAP long-term. Targeted strategies are required to optimize PAP adherence in children with SDB.

The impact of the COVID-19 pandemic on positive airway pressure usage in children with sleep-disordered breathing.

PURPOSE: To evaluate the impact of the COVID-19 pandemic on non-invasive positive airway pressure (PAP) usage among children with sleep-disordered breathing (SDB). METHODS: PAP usage data in children with SDB aged 1 to 18 years old at The Hospital for Sick Children, Canada, were analyzed. The PAP usage data were recorded for 3 months prior to and 3 months following the COVID-19 lockdown in Ontario, Canada. The primary outcomes of interest were (i) percentage of days that PAP was used for ≥ 4 h and (ii) average daily usage of PAP based on days when PAP was used. RESULTS: A total of 151 children were included. The mean (± SD) age and BMI were 12.6 ± 4.1 years and 28.7 ± 12.4 kg/m2, respectively. The median (IQR) percentage of days of PAP usage for ≥ 4 h and average nightly PAP usage was significantly higher during compared with prior to the pandemic (76.7 [19.0-94.0] vs 62.0 [15.5-89.0]%, p = 0.02, and 406.0 [244.0-525.0] vs 367.0 [218.0-496.0] min, p = 0.006, respectively). Within this cohort, 95/151 (63%) children with SDB showed increased PAP usage and 56/151 (37%) either decreased the amount of time they used PAP or stopped PAP use altogether. CONCLUSIONS: COVID-19 pandemic has provided opportunities for increased PAP usage in a significant number of children with SDB. A subset of children with prior evidence for suboptimal PAP usage showed further decreases in PAP usage during the pandemic. This information is critical for clinicians to provide anticipatory guidance to encourage PAP usage both during the pandemic and beyond.

Positional device therapy for the treatment of positional obstructive sleep apnea in children: a pilot study.

BACKGROUND: There is a critical gap in identifying effective interventions for children with obstructive sleep apnea (OSA) who do not tolerate continuous positive airway pressure therapy. Positional OSA (POSA) is a common clinical phenotype whereby OSA occurs predominantly while sleeping in supine position. POSA may be amenable to treatment with a positional device, a belt worn around the chest with cushions on the back to prevent supine positioning, but no data exists in children. The primary aim of this study was to evaluate the efficacy of positional device therapy for the treatment of POSA in children. METHODS: This observational study included children aged 4-18 years with POSA and an obstructive apnea-hypopnea index (OAHI) ≥ 5 events/hour on baseline polysomnogram (PSG) who underwent a second PSG to evaluate the efficacy of a positional device. The primary outcome was the change in OAHI. RESULTS: Ten children were included (8 male, median age 11.2 years, median body mass index z-score 1.6). Compared to the baseline PSG, PSG data obtained while using a positional device showed a reduced median (interquartile range) OAHI (15.2 [8.3-25.6] versus 6.7 [1.0-13.7] events/hour respectively; p = 0.004) and percentage of total sleep time in supine position (54.4 [35.0-80.6]% versus 4.2 [1.1-25.2]% respectively; p = 0.04). Despite observed improvements in the oxygen desaturation index, these results were not statistically significant. SIGNIFICANCE AND CONCLUSIONS: In this novel pilot study, positional device therapy was effective for the treatment of POSA. Positional device therapy may potentially change clinical practice as a cost-efficient and non-invasive treatment option for POSA.

Caregiver support and positive airway pressure therapy adherence among adolescents with obstructive sleep apnea.

INTRODUCTION: Positive airway therapy (PAP) adherence rates are suboptimal among adolescents with obstructive sleep apnea (OSA) and strategies to increase PAP adherence is a clinical priority. This study evaluates if caregiver support is associated with PAP adherence rates among adolescents with OSA. METHODS: We conducted a retrospective study and evaluated PAP adherence rates among adolescents with OSA from 2012 to 2017. Adherence was measured as continuous variables: average PAP usage (minutes per night) and average PAP usage >4 hours/night (% of all nights). We evaluated if adolescents with OSA who were receiving practical caregiver support with PAP had higher adherence than adolescents with OSA without caregiver support. RESULTS: One hundred and seven adolescents with OSA (mean age=14.1±2.5 years, 64.5% male, mean BMI percentile=89.0±21.8) seen between January 2012 and August 2017 at our institution were included. In this study, 60.7% (n=65) of adolescents with OSA were receiving practical caregiver support with PAP therapy. Adolescents with OSA receiving practical caregiver support with PAP used therapy for a significantly greater duration each night compared to adolescents who were not receiving practical caregiver support (298.5±206.7 versus 211.9±187.2 minutes; P=0.02). Greater time since the initial PAP prescription was independently associated with PAP adherence. CONCLUSION: Focusing on PAP adherence early may help adolescents with OSA incorporate therapy into their nightly routine, which may improve adherence and lead to improved health outcomes in adolescents with OSA. Practical caregiver support may be an essential component of ensuring optimal PAP adherence among adolescents with OSA.

How to use noninvasive positive airway pressure device data reports to guide clinical care.

There has been a significant increase in the past few decades in the number of children receiving noninvasive positive airway pressure (PAP) therapy at home. At present, PAP therapy can be successfully used in children of all ages, for a variety of indications. Data acquired from PAP devices is clinically useful, providing objective information regarding adherence, leak, and efficacy of PAP therapy. However, guidelines outlining a standardized approach to interpretation of PAP device data in pediatrics is currently lacking. Given the rapidly expanding use of PAP therapy in pediatric practice, we aim to provide an overview of the interpretation of data reports, otherwise called "data downloads," from PAP devices and illustrate how they can be used to guide clinical care.

Positive airway pressure in pediatric obstructive sleep apnea.

Obstructive sleep apnea (OSA) is characterized by snoring, recurrent obstruction (apneas) of the upper airway which disrupts normal ventilation during sleep. In the last decade, there has been a increase in children diagnosed with persistent, severe OSA attributed to (1) the obesity epidemic as 25-60% of obese children will have obesity related OSA (2) advances in medical technology that have increased life expectancy of medically complex children (3) improved diagnostics and (4) increased awareness. Positive airway pressure (PAP) is commonly used to treat persistent, severe OSA. PAP devices deliver pressurized air via nasal or oronasal interfaces to distend the upper airway and ameliorate OSA. Although effective in treating OSA, PAP adherence is suboptimal. This review article provides an overview of (1) PAP use in pediatric OSA (2) PAP devices (3) PAP adherence, (4) strategies and interventions to improve adherence and (5) Optimizing PAP delivery during pediatric to adult transition.

Facilitators and Barriers to Positive Airway Pressure Adherence for Adolescents. A Qualitative Study.

RATIONALE: Low adherence to positive airway pressure (PAP) treatment for adolescents with obstructive sleep apnea (OSA) can have long-term cardiometabolic and developmental impact. OBJECTIVES: To explore the facilitators and barriers to PAP use in adolescents with OSA. METHODS: We conducted a qualitative study using a descriptive thematic analysis approach. A total of 21 interviews were conducted in the clinical setting with adolescents prescribed PAP to treat OSA within the previous 12 months. Interview audio recordings were transcribed verbatim for analysis. Transcripts were reviewed, and data were categorized using a coding framework developed by the research team. Codes were structured into themes related to the barriers and facilitators to using PAP. RESULTS: Participants described numerous challenges with the physical design of the PAP machine, including the restriction of the tubing, the discomfort of the mask, and concerns with its size and weight. A period of adjustment to wearing and preparing the PAP machine was described whereby participants had to develop their own strategies to improve comfort. After initiating the therapy, the challenges experienced by participants were cited more often than the perceived benefits, particularly for those who were less adherent. Finally, the unique needs of adolescents were highlighted, which impacted the amount of family support desired in using PAP. CONCLUSIONS: This study identifies factors affecting PAP adherence when prescribed in adolescence and highlights the need for ongoing dialogue between adolescents and their clinical team with respect to challenges encountered, troubleshooting, adherence strategies, and parental engagement.

Inhibition of Pol I transcription treats murine and human AML by targeting the leukemia-initiating cell population.

Despite the development of novel drugs, the prospects for many patients with acute myeloid leukemia (AML) remain dismal. This study reveals that the selective inhibitor of RNA polymerase I (Pol I) transcription, CX-5461, effectively treats aggressive AML, including mixed-lineage leukemia-driven AML, and outperforms standard chemotherapies. In addition to the previously characterized mechanism of action of CX-5461 (ie, the induction of p53-dependent apoptotic cell death), the inhibition of Pol I transcription also demonstrates potent efficacy in p53null AML in vivo. This significant survival advantage in both p53WT and p53null leukemic mice treated with CX-5461 is associated with activation of the checkpoint kinases 1/2, an aberrant G2/M cell-cycle progression and induction of myeloid differentiation of the leukemic blasts. The ability to target the leukemic-initiating cell population is thought to be essential for lasting therapeutic benefit. Most strikingly, the acute inhibition of Pol I transcription reduces both the leukemic granulocyte-macrophage progenitor and leukemia-initiating cell (LIC) populations, and suppresses their clonogenic capacity. This suggests that dysregulated Pol I transcription is essential for the maintenance of their leukemia-initiating potential. Together, these findings demonstrate the therapeutic utility of this new class of inhibitors to treat highly aggressive AML by targeting LICs.

Factors Associated with Changes in Invasive and Noninvasive Positive Airway Pressure Therapy Settings during Pediatric Polysomnograms.

STUDY OBJECTIVES: Our aim was to identify clinical predictors associated with changes in settings for pediatric invasive and noninvasive positive airway pressure therapy, which could help inform the allocation of limited polysomnogram (PSG) resources. METHODS: A retrospective review was conducted in children who underwent one or more PSGs for technology titration. Children were included if they were using continuous positive airway pressure (CPAP) therapy, bilevel positive airway pressure (BPAP) therapy, or invasive positive pressure ventilation (IPPV) the night of the PSG. The primary outcome measure for the study were predictors of change in settings during IPPV, CPAP, and BPAP titration studies. RESULTS: During the study period, 274 children using CPAP, BPAP, or IPPV underwent one or more titration PSGs. The mean (standard deviation [SD]) age of the children at the time of the first titration PSG was 10.52 (5.11) y. Fifty percent (n = 136) of the study participants were male. Most patients underwent BPAP titration studies (n = 166), followed by CPAP (n = 83) and then IPPV (n = 25). A total of 623 technology titration PSGs were completed. Reason for respiratory technology, type of respiratory technology, and time between ventilation initiation and the PSG were significant predictors of a change in settings in the multivariable regression model. CONCLUSIONS: Children were more likely to have a change in their technology settings during a PSG if there was a shorter period of time from the original technology initiation, if they were using BPAP (as compared to CPAP or IPPV) and/or if they had a primary central nervous system or musculoskeletal diagnosis.

The CDK9 Inhibitor Dinaciclib Exerts Potent Apoptotic and Antitumor Effects in Preclinical Models of MLL-Rearranged Acute Myeloid Leukemia.

Translocations of the mixed lineage leukemia (MLL) gene occur in 60% to 80% of all infant acute leukemias and are markers of poor prognosis. MLL-AF9 and other MLL fusion proteins aberrantly recruit epigenetic regulatory proteins, including histone deacetylases (HDAC), histone methyltransferases, bromodomain-containing proteins, and transcription elongation factors to mediate chromatin remodeling and regulate tumorigenic gene expression programs. We conducted a small-molecule inhibitor screen to test the ability of candidate pharmacologic agents targeting epigenetic and transcriptional regulatory proteins to induce apoptosis in leukemic cells derived from genetically engineered mouse models of MLL-AF9-driven acute myeloid leukemia (AML). We found that the CDK inhibitor dinaciclib and HDAC inhibitor panobinostat were the most potent inducers of apoptosis in short-term in vitro assays. Treatment of MLL-rearranged leukemic cells with dinaciclib resulted in rapidly decreased expression of the prosurvival protein Mcl-1, and accordingly, overexpression of Mcl-1 protected AML cells from dinaciclib-induced apoptosis. Administration of dinaciclib to mice bearing MLL-AF9-driven human and mouse leukemias elicited potent antitumor responses and significantly prolonged survival. Collectively, these studies highlight a new therapeutic approach to potentially overcome the resistance of MLL-rearranged AML to conventional chemotherapies and prompt further clinical evaluation of CDK inhibitors in AML patients harboring MLL fusion proteins.

Differentiation therapy for the treatment of t(8;21) acute myeloid leukemia using histone deacetylase inhibitors.

Epigenetic modifying enzymes such as histone deacetylases (HDACs), p300, and PRMT1 are recruited by AML1/ETO, the pathogenic protein for t(8;21) acute myeloid leukemia (AML), providing a strong molecular rationale for targeting these enzymes to treat this disease. Although early phase clinical assessment indicated that treatment with HDAC inhibitors (HDACis) may be effective in t(8;21) AML patients, rigorous preclinical studies to identify the molecular and biological events that may determine therapeutic responses have not been performed. Using an AML mouse model driven by expression of AML1/ETO9a (A/E9a), we demonstrated that treatment of mice bearing t(8;21) AML with the HDACi panobinostat caused a robust antileukemic response that did not require functional p53 nor activation of conventional apoptotic pathways. Panobinostat triggered terminal myeloid differentiation via proteasomal degradation of A/E9a. Importantly, conditional A/E9a deletion phenocopied the effects of panobinostat and other HDACis, indicating that destabilization of A/E9a is critical for the antileukemic activity of these agents.

Targeting acute myeloid leukemia by dual inhibition of PI3K signaling and Cdk9-mediated Mcl-1 transcription.

Resistance to cell death is a hallmark of cancer and renders transformed cells resistant to multiple apoptotic triggers. The Bcl-2 family member, Mcl-1, is a key driver of cell survival in diverse cancers, including acute myeloid leukemia (AML). A screen for compounds that downregulate Mcl-1 identified the kinase inhibitor, PIK-75, which demonstrates marked proapoptotic activity against a panel of cytogenetically diverse primary human AML patient samples. We show that PIK-75 transiently blocks Cdk7/9, leading to transcriptional suppression of MCL-1, rapid loss of Mcl-1 protein, and alleviation of its inhibition of proapoptotic Bak. PIK-75 also targets the p110α isoform of PI3K, which leads to a loss of association between Bcl-xL and Bak. The simultaneous loss of Mcl-1 and Bcl-xL association with Bak leads to rapid apoptosis of AML cells. Concordantly, low Bak expression in AML confers resistance to PIK-75-mediated killing. On the other hand, the induction of apoptosis by PIK-75 did not require the expression of the BH3 proteins Bim, Bid, Bad, Noxa, or Puma. PIK-75 significantly reduced leukemia burden and increased the survival of mice engrafted with human AML without inducing overt toxicity. Future efforts to cotarget PI3K and Cdk9 with drugs such as PIK-75 in AML are warranted.

Combined inhibition of PI3K-related DNA damage response kinases and mTORC1 induces apoptosis in MYC-driven B-cell lymphomas.

Pharmacological strategies capable of directly targeting MYC are elusive. Previous studies have shown that MYC-driven lymphomagenesis is associated with mammalian target of rapamycin (mTOR) activation and a MYC-evoked DNA damage response (DDR) transduced by phosphatidylinositol-3-kinase (PI3K)-related kinases (DNA-PK, ATM, and ATR). Here we report that BEZ235, a multitargeted pan-PI3K/dual-mTOR inhibitor, potently killed primary Myc-driven B-cell lymphomas and human cell lines bearing IG-cMYC translocations. Using pharmacologic and genetic dissection of PI3K/mTOR signaling, dual DDR/mTORC1 inhibition was identified as a key mediator of apoptosis. Moreover, apoptosis was initiated at drug concentrations insufficient to antagonize PI3K/mTORC2-regulated AKT phosphorylation. p53-independent induction of the proapoptotic BH3-only protein BMF was identified as a mechanism by which dual DDR/mTORC1 inhibition caused lymphoma cell death. BEZ235 treatment induced apoptotic tumor regressions in vivo that correlated with suppression of mTORC1-regulated substrates and reduced H2AX phosphorylation and also with feedback phosphorylation of AKT. These mechanistic studies hold important implications for the use of multitargeted PI3K inhibitors in the treatment of hematologic malignancies. In particular, the newly elucidated role of PI3K-related DDR kinases in response to PI3K inhibitors offers a novel therapeutic opportunity for the treatment of hematologic malignancies with an MYC-driven DDR.

RTKN2 Induces NF-KappaB Dependent Resistance to Intrinsic Apoptosis in HEK Cells and Regulates BCL-2 Genes in Human CD4(+) Lymphocytes.

The gene for Rhotekin 2 (RTKN2) was originally identified in a promyelocytic cell line resistant to oxysterol-induced apoptosis. It is differentially expressed in freshly isolated CD4(+) T-cells compared with other hematopoietic cells and is down-regulated following activation of the T-cell receptor. However, very little is known about the function of RTKN2 other than its homology to Rho-GTPase effector, rhotekin, and the possibility that they may have similar roles. Here we show that stable expression of RTKN2 in HEK cells enhanced survival in response to intrinsic apoptotic agents; 25-hydroxy cholesterol and camptothecin, but not the extrinsic agent, TNFα. Inhibitors of NF-KappaB, but not MAPK, reversed the resistance and mitochondrial pro-apoptotic genes, Bax and Bim, were down regulated. In these cells, there was no evidence of RTKN2 binding to the GTPases, RhoA or Rac2. Consistent with the role of RTKN2 in HEK over-expressing cells, suppression of RTKN2 in primary human CD4(+) T-cells reduced viability and increased sensitivity to 25-OHC. The expression of the pro-apoptotic genes, Bax and Bim were increased while BCL-2 was decreased. In both cell models RTKN2 played a role in the process of intrinsic apoptosis and this was dependent on either NF-KappaB signaling or expression of downstream BCL-2 genes. As RTKN2 is a highly expressed in CD4(+) T-cells it may play a role as a key signaling switch for regulation of genes involved in T-cell survival.