Publications by authors named "Michael Dean"

412 Publications

Frequency of Pathogenic Germline Variants in Cancer-Susceptibility Genes in the Childhood Cancer Survivor Study.

JNCI Cancer Spectr 2021 Apr 23;5(2):pkab007. Epub 2021 Jan 23.

Basic Research Subdirection, Instituto Nacional de Cancerología (INCan), Mexico City, Mexico.

Background: Pediatric cancers are the leading cause of death by disease in children despite improved survival rates overall. The contribution of germline genetic susceptibility to pediatric cancer survivors has not been extensively characterized. We assessed the frequency of pathogenic or likely pathogenic (P/LP) variants in 5451 long-term pediatric cancer survivors from the Childhood Cancer Survivor Study.

Methods: Exome sequencing was conducted on germline DNA from 5451 pediatric cancer survivors (cases who survived ≥5 years from diagnosis; n = 5105 European) and 597 European cancer-free adults (controls). Analyses focused on comparing the frequency of rare P/LP variants in 237 cancer-susceptibility genes and a subset of 60 autosomal dominant high-to-moderate penetrance genes, for both case-case and case-control comparisons.

Results: Of European cases, 4.1% harbored a P/LP variant in high-to-moderate penetrance autosomal dominant genes compared with 1.3% in controls (2-sided  = 3 × 10). The highest frequency of P/LP variants was in genes typically associated with adult onset rather than pediatric cancers, including , , , , and . A statistically significant excess of P/LP variants, after correction for multiple tests, was detected in patients with central nervous system cancers (, , , ), Wilms tumor (, ), non-Hodgkin lymphoma (), and soft tissue sarcomas (, , , , ) compared with other pediatric cancers.

Conclusion: In long-term pediatric cancer survivors, we identified P/LP variants in cancer-susceptibility genes not previously associated with pediatric cancer as well as confirmed known associations. Further characterization of variants in these genes in pediatric cancer will be important to provide optimal genetic counseling for patients and their families.
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http://dx.doi.org/10.1093/jncics/pkab007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023430PMC
April 2021

Tumor heterogeneity assessed by sequencing and fluorescence in situ hybridization (FISH) data.

Bioinformatics 2021 Jul 20. Epub 2021 Jul 20.

Computational Biology Dept, Carnegie Mellon University, Pittsburgh, PA, 15213, USA.

Motivation: Computational reconstruction of clonal evolution in cancers has become a crucial tool for understanding how tumors initiate and progress and how this process varies across patients. The field still struggles, however, with special challenges of applying phylogenetic methods to cancers, such as the prevalence and importance of copy number alteration (CNA) and structural variation (SV) events in tumor evolution, which are difficult to profile accurately by prevailing sequencing methods in such a way that subsequent reconstruction by phylogenetic inference algorithms is accurate.

Results: In the present work, we develop computational methods to combine sequencing with multiplex interphase fluorescence in situ hybridization (miFISH) to exploit the complementary advantages of each technology in inferring accurate models of clonal CNA evolution accounting for both focal changes and aneuploidy at whole-genome scales. By integrating such information in an integer linear programming (ILP) framework, we demonstrate on simulated data that incorporation of FISH data substantially improves accurate inference of focal CNA and ploidy changes in clonal evolution from deconvolving bulk sequence data. Analysis of real glioblastoma data for which FISH, bulk sequence, and single cell sequence are all available confirms the power of FISH to enhance accurate reconstruction of clonal copy number evolution in conjunction with bulk and optionally single-cell sequence data.

Availability: Source code is available on Github at https://github.com/CMUSchwartzLab/FISH_deconvolution.
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http://dx.doi.org/10.1093/bioinformatics/btab504DOI Listing
July 2021

scDPN for High-throughput Single-cell CNV Detection to Uncover Clonal Evolution During HCC Recurrence.

Genomics Proteomics Bioinformatics 2021 Jul 16. Epub 2021 Jul 16.

BGI Education Center, University of Chinese Academy of Sciences, Shenzhen 518083, China; BGI-Shenzhen, Beishan Industrial Zone, Shenzhen 518083, China; Shenzhen Key Laboratory of Single-Cell Omics, BGI-Shenzhen, Shenzhen 518100, China. Electronic address:

Single-cell genomics provides substantial resources for dissecting cellular heterogeneity and cancer evolution. Unfortunately, classical DNA amplification-based methods have low throughput and introduce coverage bias during sample preamplification. We developed a single-cell DNA library preparation method without preamplification in nanolitre scale (scDPN) to address these issues. The method achieved a throughput of up to 1800 cells per run for copy number variation (CNV) detection. Also, our approach demonstrated a lower level of amplification bias and noise than the multiple displacement amplification (MDA) method and showed high sensitivity and accuracy for cell line and tumour tissue evaluation. We used this approach to profile the tumour clones in paired primary and relapsed tumour samples of hepatocellular carcinoma (HCC). We identified three clonal subpopulations with a multitude of aneuploid alterations across the genome. Furthermore, we observed that a minor clone of the primary tumour containing additional alterations in chromosomes 1q, 10q, and 14q developed into the dominant clone in the recurrent tumour, indicating clonal selection during recurrence in HCC. Overall, this approach provides a comprehensive and scalable solution to understand genome heterogeneity and evolution.
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http://dx.doi.org/10.1016/j.gpb.2021.03.008DOI Listing
July 2021

Adolescent alcohol use predicts cannabis use over a three year follow-up period.

Subst Abus 2021 Jul 8:1-6. Epub 2021 Jul 8.

Department of Psychiatry and Human Behavior, The Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA.

Background: Alcohol and cannabis use frequently co-occur, which can result in problems from social and academic impairment to dependence (i.e., alcohol use disorder [AUD] and/or cannabis use disorder [CUD]). The Emergency Department (ED) is an excellent site to identify adolescents with alcohol misuse, conduct a brief intervention, and refer to treatment; however, given time constraints, alcohol use may be the only substance assessed due to its common role in unintentional injury. The current study, a secondary data analysis, assessed the relationship between adolescent alcohol and cannabis use by examining the National Institute of Alcohol Abuse and Alcoholism (NIAAA) two question screen's (2QS) ability to predict future CUD at one, two, and three years post-ED visit. At baseline, data was collected via tablet self-report surveys from medically and behaviorally stable adolescents 12-17 years old ( = 1,689) treated in 16 pediatric EDs for non-life-threatening injury, illness, or mental health condition. Follow-up surveys were completed via telephone or web-based survey. Logistic regression compared CUD diagnosis odds at one, two, or three-year follow-up between levels constituting a single-level change in baseline risk categorization on the NIAAA 2QS (nondrinker versus low-risk, low- versus moderate-risk, moderate- versus high-risk). Receiver operating characteristic curve methods examined the predictive ability of the baseline NIAAA 2QS cut points for CUD at one, two, or three-year follow-up. Adolescents with low alcohol risk had significantly higher rates of CUD versus nondrinkers (OR range: 1.94-2.76, < .0001). For low and moderate alcohol risk, there was no difference in CUD rates (OR range: 1.00-1.08). CUD rates were higher in adolescents with high alcohol risk versus moderate risk (OR range: 2.39-4.81, < .05). Even low levels of baseline alcohol use are associated with risk for a later CUD. The NIAAA 2QS is an appropriate assessment measure to gauge risk for future cannabis use.
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http://dx.doi.org/10.1080/08897077.2021.1949665DOI Listing
July 2021

Dissecting spatial heterogeneity and the immune-evasion mechanism of CTCs by single-cell RNA-seq in hepatocellular carcinoma.

Nat Commun 2021 07 2;12(1):4091. Epub 2021 Jul 2.

Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, People's Republic of China.

Little is known about the transcriptomic plasticity and adaptive mechanisms of circulating tumor cells (CTCs) during hematogeneous dissemination. Here we interrogate the transcriptome of 113 single CTCs from 4 different vascular sites, including hepatic vein (HV), peripheral artery (PA), peripheral vein (PV) and portal vein (PoV) using single-cell full-length RNA sequencing in hepatocellular carcinoma (HCC) patients. We reveal that the transcriptional dynamics of CTCs were associated with stress response, cell cycle and immune-evasion signaling during hematogeneous transportation. Besides, we identify chemokine CCL5 as an important mediator for CTC immune evasion. Mechanistically, overexpression of CCL5 in CTCs is transcriptionally regulated by p38-MAX signaling, which recruites regulatory T cells (Tregs) to facilitate immune escape and metastatic seeding of CTCs. Collectively, our results reveal a previously unappreciated spatial heterogeneity and an immune-escape mechanism of CTC, which may aid in designing new anti-metastasis therapeutic strategies in HCC.
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http://dx.doi.org/10.1038/s41467-021-24386-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253833PMC
July 2021

Germline variants in hereditary breast cancer genes are associated with early age at diagnosis and family history in Guatemalan breast cancer.

Breast Cancer Res Treat 2021 Sep 1;189(2):533-539. Epub 2021 Jul 1.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Gaithersburg, MD, USA.

Purpose: Mutations in hereditary breast cancer genes play an important role in the risk for cancer.

Methods: Cancer susceptibility genes were sequenced in 664 unselected breast cancer cases from Guatemala. Variants were annotated with ClinVar and VarSome.

Results: A total of 73 out of 664 subjects (11%) had a pathogenic variant in a high or moderate penetrance gene. The most frequently mutated genes were BRCA1 (37/664, 5.6%) followed by BRCA2 (15/664, 2.3%), PALB2 (5/664, 0.8%), and TP53 (5/664, 0.8%). Pathogenic variants were also detected in the moderate penetrance genes ATM, BARD1, CHEK2, and MSH6. The high ratio of BRCA1/BRCA2 mutations is due to two potential founder mutations: BRCA1 c.212 + 1G > A splice mutation (15 cases) and BRCA1 c.799delT (9 cases). Cases with pathogenic mutations had a significantly earlier age at diagnosis (45 vs 51 years, P < 0.001), are more likely to have had diagnosis before menopause, and a higher percentage had a relative with any cancer (51% vs 37%, P = 0.038) or breast cancer (33% vs 15%, P < 0.001).

Conclusions: Hereditary breast cancer mutations were observed among Guatemalan women, and these women are more likely to have early age at diagnosis and family history of cancer. These data suggest the use of genetic testing in breast cancer patients and those at high risk as part of a strategy to reduce breast cancer mortality in Guatemala.
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http://dx.doi.org/10.1007/s10549-021-06305-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357728PMC
September 2021

Response of the trial innovation network to the COVID-19 pandemic.

J Clin Transl Sci 2021 Apr 20;5(1):e100. Epub 2021 Apr 20.

Duke Clinical Research Institute, Durham, NC, USA.

Introduction: The COVID-19 pandemic prompted the development and implementation of hundreds of clinical trials across the USA. The Trial Innovation Network (TIN), funded by the National Center for Advancing Translational Sciences, was an established clinical research network that pivoted to respond to the pandemic.

Methods: The TIN's three Trial Innovation Centers, Recruitment Innovation Center, and 66 Clinical and Translational Science Award Hub institutions, collaborated to adapt to the pandemic's rapidly changing landscape, playing central roles in the planning and execution of pivotal studies addressing COVID-19. Our objective was to summarize the results of these collaborations and lessons learned.

Results: The TIN provided 29 COVID-related consults between March 2020 and December 2020, including 6 trial participation expressions of interest and 8 community engagement studios from the Recruitment Innovation Center. Key lessons learned from these experiences include the benefits of leveraging an established infrastructure, innovations surrounding remote research activities, data harmonization and central safety reviews, and early community engagement and involvement.

Conclusions: Our experience highlighted the benefits and challenges of a multi-institutional approach to clinical research during a pandemic.
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http://dx.doi.org/10.1017/cts.2021.782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185427PMC
April 2021

Outcomes following the delayed management of open tibial fractures.

Injury 2021 Aug 2;52(8):2434-2438. Epub 2021 Jun 2.

Trauma & Orthopaedic Department, University Hospital Southampton, Tremona Road, Southampton SO16 6YD United Kingdom. Electronic address:

Aims: National guidelines set standards for the definitive management of open fractures within 72 h. This study aims to investigate our outcomes where this timeline was unachievable for most cases due to a split-site orthoplastic service.

Patients & Methods: 116 consecutive Gustilo-Anderson grade IIIB & IIIC open tibial fractures presenting to our major trauma centre (MTC) between September 2012 and April 2018 were reviewed. The mean follow up was 46 months (17 to 88). 110 (95%) were grade IIIB and 6 (5%) grade IIIC. The most common injury mechanism included road traffic accidents (59%) and falls (28%). Primary outcomes were recorded according to; timing of initial debridement and definitive cover, rates of superficial and deep infection, non-union and amputation. Subgroups were statistically analysed according to time to initial debridement, definitive soft-tissue cover and injury severity score (ISS).

Results: The mean time to initial debridement was 11.3 h (2.9 to 38.9) and definitive soft-tissue cover 9.9 days (0 to 37). We recorded rates of: superficial infection; 42 cases (36%), deep infection; 14 cases (12%) and non-union requiring revision; 19 cases (16%). There were 20 amputations (17%) with 9 (8.6%) performed early and 11 (9.5%) delayed. Subgroup analysis showed higher rates of superficial infection (50%, p = 0.002) and amputation (26.6%, p = 0.01) for those debrided <12 h. A greater presenting ISS related to a delay to definitive cover >7 days (p = 0.05). Primary outcomes trended worse for those covered >7 days but did not reach significance.

Conclusion: Major trauma patients are particularly vulnerable to poor outcomes resulting from the delay in definitive management of open fractures. MTC's need resources and a co-located orthoplastic service to achieve national standards and better outcomes. Current guidelines do not advise for the management of patients where a delay in definitive surgery is anticipated.
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http://dx.doi.org/10.1016/j.injury.2021.05.042DOI Listing
August 2021

Factors Associated With Functional Impairment After Pediatric Injury.

JAMA Surg 2021 Aug 11;156(8):e212058. Epub 2021 Aug 11.

Department of Pediatrics, Nationwide Children's Hospital, The Ohio State University, Columbus.

Importance: Short- and long-term functional impairment after pediatric injury may be more sensitive for measuring quality of care compared with mortality alone. The characteristics of injured children and adolescents who are at the highest risk for functional impairment are unknown.

Objective: To evaluate categories of injuries associated with higher prevalence of impaired functional status at hospital discharge among children and adolescents and to estimate the number of those with injuries in these categories who received treatment at pediatric trauma centers.

Design, Setting, And Participants: This prospective cohort study (Assessment of Functional Outcomes and Health-Related Quality of Life After Pediatric Trauma) included children and adolescents younger than 15 years who were hospitalized with at least 1 serious injury at 1 of 7 level 1 pediatric trauma centers from March 2018 to February 2020.

Exposure: At least 1 serious injury (Abbreviated Injury Scale score, ≥3 [scores range from 1 to 6, with higher scores indicating more severe injury]) classified into 9 categories based on the body region injured and the presence of a severe traumatic brain injury (Glasgow Coma Scale score <9 or Glasgow Coma Scale motor score <5).

Main Outcomes And Measures: New domain morbidity defined as a 2 points or more change in any of 6 domains (mental status, sensory, communication, motor function, feeding, and respiratory) measured using the Functional Status Scale (FSS) (scores range from 1 [normal] to 5 [very severe dysfunction] for each domain) in each injury category at hospital discharge. The estimated prevalence of impairment associated with each injury category was assessed in the population of seriously injured children and adolescents treated at participating sites.

Results: This study included a sample of 427 injured children and adolescents (271 [63.5%] male; median age, 7.2 years [interquartile range, 2.5-11.7 years]), 74 (17.3%) of whom had new FSS domain morbidity at discharge. The proportion of new FSS domain morbidity was highest among those with multiple injured body regions and severe head injury (20 of 24 [83.3%]) and lowest among those with an isolated head injury of mild or moderate severity (1 of 84 [1.2%]). After adjusting for oversampling of specific injuries in the study sample, 749 of 5195 seriously injured children and adolescents (14.4%) were estimated to have functional impairment at hospital discharge. Children and adolescents with extremity injuries (302 of 749 [40.3%]) and those with severe traumatic brain injuries (258 of 749 [34.4%]) comprised the largest proportions of those estimated to have impairment at discharge.

Conclusions And Relevance: In this cohort study, most injured children and adolescents returned to baseline functional status by hospital discharge. These findings suggest that functional status assessments can be limited to cohorts of injured children and adolescents at the highest risk for impairment.
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http://dx.doi.org/10.1001/jamasurg.2021.2058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173466PMC
August 2021

Complicated Grief, Depression and Post-Traumatic Stress Symptoms Among Bereaved Parents following their Child's Death in the Pediatric Intensive Care Unit: A Follow-Up Study.

Am J Hosp Palliat Care 2021 May 5:10499091211015913. Epub 2021 May 5.

Department of Pediatrics, Children's Hospital of Michigan, Detroit, MI, Central Michigan University, Mt. Pleasant, MI, USA.

Background: Parents often suffer reduced mental health after their child's death; however, the trajectory and risk factors are not well described.

Objective: Describe the change in complicated grief, depression, and post-traumatic stress symptoms among parents between 6 and 13 months after their child's death in a pediatric intensive care unit (PICU), and factors associated with 13-month symptoms.

Methods: Parents whose children died in 1 of 8 PICUs affiliated with the Collaborative Pediatric Critical Care Research Network completed surveys 6 and 13 months after their child's death. Surveys included the Inventory of Complicated Grief (ICG), the Patient Health Questionnaire-8 (PHQ-8) for depression, and the Short Post-Traumatic Stress Disorder Rating Interview (SPRINT). Parents provided sociodemographics. Charts were reviewed for child characteristics.

Results: One-hundred and fifty seven parents of 104 deceased children completed surveys at both time points. Mental health symptoms declined over time (mean (SD)): ICG (33.8 (15.4) vs. 30.5 (15.2), p < 0.001), PHQ-8 (9.0 (6.4) vs. 7.3 (5.8), p < 0.001), and SPRINT (14.1 (8.3) vs. 12.0 (8.2), p < 0.001). After controlling for 6-month scores, higher 13-month ICG was independently associated with sudden unexpected death; higher PHQ-8 with Black race, insecure attachment style, and sudden unexpected death; and higher SPRINT with having a high school level of education (compared to college degree or higher).

Conclusion: Mental health symptoms improve among parents during the first 13 months after their child's death; however, symptoms persist for many. Black parents and those whose children die suddenly may be high risk for poor adjustment during bereavement.
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http://dx.doi.org/10.1177/10499091211015913DOI Listing
May 2021

Lack of transgenerational effects of ionizing radiation exposure from the Chernobyl accident.

Science 2021 05 22;372(6543):725-729. Epub 2021 Apr 22.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20892, USA.

Effects of radiation exposure from the Chernobyl nuclear accident remain a topic of interest. We investigated germline de novo mutations (DNMs) in children born to parents employed as cleanup workers or exposed to occupational and environmental ionizing radiation after the accident. Whole-genome sequencing of 130 children (born 1987-2002) and their parents did not reveal an increase in the rates, distributions, or types of DNMs relative to the results of previous studies. We find no elevation in total DNMs, regardless of cumulative preconception gonadal paternal [mean = 365 milligrays (mGy), range = 0 to 4080 mGy] or maternal (mean = 19 mGy, range = 0 to 550 mGy) exposure to ionizing radiation. Thus, we conclude that, over this exposure range, evidence is lacking for a substantial effect on germline DNMs in humans, suggesting minimal impact from transgenerational genetic effects.
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http://dx.doi.org/10.1126/science.abg2365DOI Listing
May 2021

Targeted Deep Sequencing of Bladder Tumors Reveals Novel Associations between Cancer Gene Mutations and Mutational Signatures with Major Risk Factors.

Clin Cancer Res 2021 Jul 13;27(13):3725-3733. Epub 2021 Apr 13.

Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland.

Purpose: Exome- and whole-genome sequencing of muscle-invasive bladder cancer has revealed important insights into the molecular landscape; however, there are few studies of non-muscle-invasive bladder cancer with detailed risk factor information.

Experimental Design: We examined the relationship between smoking and other bladder cancer risk factors and somatic mutations and mutational signatures in bladder tumors. Targeted sequencing of frequently mutated genes in bladder cancer was conducted in 322 formalin-fixed paraffin-embedded bladder tumors from a population-based case-control study. Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI), evaluating mutations and risk factors. We used SignatureEstimation to extract four known single base substitution mutational signatures and Poisson regression to calculate risk ratios (RR) and 95% CIs, evaluating signatures and risk factors.

Results: Non-silent mutations were more common in females than males (OR = 1.83; 95% CI, 1.05-3.19). There was striking heterogeneity in the relationship between smoking status and established single base substitution signatures: current smoking status was associated with greater Signature mutations compared with former ( = 0.024) and never smoking (RR = 1.40; 95% CI, 1.09-1.80; = 0.008), former smoking was associated with greater APOBEC-Signature13 mutations ( = 0.05), and never smoking was associated with greater APOBEC-Signature2 mutations (RR = 1.54; 95% CI, 1.17-2.01; = 0.002). There was evidence that smoking duration (the component most strongly associated with bladder cancer risk) was associated with Signature mutations and APOBEC-Signature13 mutations among current ( = 0.005) and former smokers ( = 0.0004), respectively.

Conclusions: These data quantify the contribution of bladder cancer risk factors to mutational burden and suggest different signature enrichments among never, former, and current smokers.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8254772PMC
July 2021

Efficacy of LGE-MRI-guided fibrosis ablation versus conventional catheter ablation of atrial fibrillation: The DECAAF II trial: Study design.

J Cardiovasc Electrophysiol 2021 04 2;32(4):916-924. Epub 2021 Mar 2.

Department of Cardiology, University of Washington Medical Center, Seattle, Washington, USA.

Introduction: Success rates of catheter ablation in persistent atrial fibrillation (AF) remain suboptimal. A better and more targeted ablation strategy is urgently needed to optimize outcomes of AF treatment. We sought to assess the safety and efficacy of targeting atrial fibrosis during ablation of persistent AF patients in improving procedural outcomes.

Methods: The DECAAF II trial (ClinicalTrials. gov identifier number NCT02529319) is a prospective, randomized, multicenter trial of patients with persistent AF. Patients with persistent AF undergoing a first-time ablation procedure were randomized in a 1:1 fashion to receive conventional pulmonary vein isolation (PVI) ablation (Group 1) or PVI + fibrosis-guided ablation (Group 2). Left atrial fibrosis and ablation induced scarring were defined by late gadolinium enhancement magnetic resonance imaging at baseline and at 3-12 months postablation, respectively. The primary endpoint is the recurrence of atrial arrhythmia postablation, including atrial fibrillation, atrial flutter, or atrial tachycardia after the 90-day postablation blanking period. Patients were followed for a period of 12-18 months with a smartphone ECG Device (ECG Check Device, Cardiac Designs Inc.). With an anticipated enrollment of 900 patients, this study has an 80% power to detect a 26% reduction in the hazard ratio of the primary endpoint.

Results And Conclusion: The DECAAF II trial is the first prospective, randomized, multicenter trial of patients with persistent AF using imaging defined atrial fibrosis as a treatment target. The trial will help define an optimal approach to catheter ablation of persistent AF, further our understanding of influencers of ablation lesion formation, and refine selection criteria for ablation based on atrial myopathy burden.
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http://dx.doi.org/10.1111/jce.14957DOI Listing
April 2021

Metformin and Androgen Receptor-Axis-Targeted (ARAT) Agents Induce Two PARP-1-Dependent Cell Death Pathways in Androgen-Sensitive Human Prostate Cancer Cells.

Cancers (Basel) 2021 Feb 5;13(4). Epub 2021 Feb 5.

Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD 21201, USA.

We explored whether the anti-prostate cancer (PC) activity of the androgen receptor-axis-targeted agents (ARATs) abiraterone and enzalutamide is enhanced by metformin. Using complementary biological and molecular approaches, we determined the associated underlying mechanisms in pre-clinical androgen-sensitive PC models. ARATs increased androgren receptors (ARs) in LNCaP and AR/ARv7 (AR variant) in VCaP cells, inhibited cell proliferation in both, and induced poly(ADP-ribose) polymerase-1 (PARP-1) cleavage and death in VCaP but not LNCaP cells. Metformin decreased AR and ARv7 expression and induced cleaved PARP-1-associated death in both cell lines. Metformin with abiraterone or enzalutamide decreased AR and ARv7 expression showed greater inhibition of cell proliferation and greater induction of cell death than single agent treatments. Combination treatments led to increased cleaved PARP-1 and enhanced PARP-1 activity manifested by increases in poly(ADP-ribose) (PAR) and nuclear accumulation of apoptosis inducing factor (AIF). Enhanced annexin V staining occurred in LNCaP cells only with metformin/ARAT combinations, but no caspase 3 recruitment occurred in either cell line. Finally, metformin and metformin/ARAT combinations increased lysosomal permeability resulting in cathepsin G-mediated PARP-1 cleavage and cell death. In conclusion, metformin enhances the efficacy of abiraterone and enzalutamide via two PARP-1-dependent, caspase 3-independent pathways, providing a rationale to evaluate these combinations in castration-sensitive PC.
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http://dx.doi.org/10.3390/cancers13040633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914929PMC
February 2021

Metformin and Androgen Receptor-Axis-Targeted (ARAT) Agents Induce Two PARP-1-Dependent Cell Death Pathways in Androgen-Sensitive Human Prostate Cancer Cells.

Cancers (Basel) 2021 Feb 5;13(4). Epub 2021 Feb 5.

Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD 21201, USA.

We explored whether the anti-prostate cancer (PC) activity of the androgen receptor-axis-targeted agents (ARATs) abiraterone and enzalutamide is enhanced by metformin. Using complementary biological and molecular approaches, we determined the associated underlying mechanisms in pre-clinical androgen-sensitive PC models. ARATs increased androgren receptors (ARs) in LNCaP and AR/ARv7 (AR variant) in VCaP cells, inhibited cell proliferation in both, and induced poly(ADP-ribose) polymerase-1 (PARP-1) cleavage and death in VCaP but not LNCaP cells. Metformin decreased AR and ARv7 expression and induced cleaved PARP-1-associated death in both cell lines. Metformin with abiraterone or enzalutamide decreased AR and ARv7 expression showed greater inhibition of cell proliferation and greater induction of cell death than single agent treatments. Combination treatments led to increased cleaved PARP-1 and enhanced PARP-1 activity manifested by increases in poly(ADP-ribose) (PAR) and nuclear accumulation of apoptosis inducing factor (AIF). Enhanced annexin V staining occurred in LNCaP cells only with metformin/ARAT combinations, but no caspase 3 recruitment occurred in either cell line. Finally, metformin and metformin/ARAT combinations increased lysosomal permeability resulting in cathepsin G-mediated PARP-1 cleavage and cell death. In conclusion, metformin enhances the efficacy of abiraterone and enzalutamide via two PARP-1-dependent, caspase 3-independent pathways, providing a rationale to evaluate these combinations in castration-sensitive PC.
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http://dx.doi.org/10.3390/cancers13040633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914929PMC
February 2021

Acute kidney injury after in-hospital cardiac arrest.

Resuscitation 2021 03 12;160:49-58. Epub 2021 Jan 12.

Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI, United States.

Aim: Determine 1) frequency and risk factors for acute kidney injury (AKI) after in-hospital cardiac arrest (IHCA) in the Therapeutic Hypothermia after Pediatric Cardiac Arrest In-Hospital (THAPCA-IH) trial and associated outcomes; 2) impact of temperature management on post-IHCA AKI.

Methods: Secondary analysis of THAPCA-IH; a randomized controlled multi-national trial at 37 children's hospitals.

Eligibility: Serum creatinine (Cr) within 24 h of randomization.

Outcomes: Prevalence of severe AKI defined by Stage 2 or 3 Kidney Disease Improving Global Outcomes Cr criteria. 12-month survival with favorable neurobehavioral outcome. Analyses stratified by entire cohort and cardiac subgroup. Risk factors and outcomes compared among cohorts with and without severe AKI.

Results: Subject randomization: 159 to hypothermia, 154 to normothermia. Overall, 80% (249) developed AKI (any stage), and 66% (207) developed severe AKI. Cardiac patients (204, 65%) were more likely to develop severe AKI (72% vs 56%,p = 0.006). Preexisting cardiac or renal conditions, baseline lactate, vasoactive support, and systolic blood pressure were associated with severe AKI. Comparing hypothermia versus normothermia, there were no differences in severe AKI rate (63% vs 70%,p = 0.23), peak Cr, time to peak Cr, or freedom from mortality or severe AKI (p = 0.14). Severe AKI was associated with decreased hospital survival (48% vs 65%,p = 0.006) and decreased 12-month survival with favorable neurobehavioral outcome (30% vs 53%,p < 0.001).

Conclusion: Severe post-IHCA AKI occurred frequently especially in those with preexisting cardiac or renal conditions and peri-arrest hemodynamic instability. Severe AKI was associated with decreased survival with favorable neurobehavioral outcome. Hypothermia did not decrease incidence of severe AKI post-IHCA.
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http://dx.doi.org/10.1016/j.resuscitation.2020.12.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902429PMC
March 2021

Genome diversity in Ukraine.

Gigascience 2021 01;10(1)

Department of Medicine, Uzhhorod National University, Uzhhorod 88000, Ukraine.

Background: The main goal of this collaborative effort is to provide genome-wide data for the previously underrepresented population in Eastern Europe, and to provide cross-validation of the data from genome sequences and genotypes of the same individuals acquired by different technologies. We collected 97 genome-grade DNA samples from consented individuals representing major regions of Ukraine that were consented for public data release. BGISEQ-500 sequence data and genotypes by an Illumina GWAS chip were cross-validated on multiple samples and additionally referenced to 1 sample that has been resequenced by Illumina NovaSeq6000 S4 at high coverage.

Results: The genome data have been searched for genomic variation represented in this population, and a number of variants have been reported: large structural variants, indels, copy number variations, single-nucletide polymorphisms, and microsatellites. To our knowledge, this study provides the largest to-date survey of genetic variation in Ukraine, creating a public reference resource aiming to provide data for medical research in a large understudied population.

Conclusions: Our results indicate that the genetic diversity of the Ukrainian population is uniquely shaped by evolutionary and demographic forces and cannot be ignored in future genetic and biomedical studies. These data will contribute a wealth of new information bringing forth a wealth of novel, endemic and medically related alleles.
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http://dx.doi.org/10.1093/gigascience/giaa159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804371PMC
January 2021

Single-cell landscape of the ecosystem in early-relapse hepatocellular carcinoma.

Cell 2021 01 23;184(2):404-421.e16. Epub 2020 Dec 23.

Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute Rockville, MD 20850, USA.

Hepatocellular carcinoma (HCC) has high relapse and low 5-year survival rates. Single-cell profiling in relapsed HCC may aid in the design of effective anticancer therapies, including immunotherapies. We profiled the transcriptomes of ∼17,000 cells from 18 primary or early-relapse HCC cases. Early-relapse tumors have reduced levels of regulatory T cells, increased dendritic cells (DCs), and increased infiltrated CD8 T cells, compared with primary tumors, in two independent cohorts. Remarkably, CD8 T cells in recurrent tumors overexpressed KLRB1 (CD161) and displayed an innate-like low cytotoxic state, with low clonal expansion, unlike the classical exhausted state observed in primary HCC. The enrichment of these cells was associated with a worse prognosis. Differential gene expression and interaction analyses revealed potential immune evasion mechanisms in recurrent tumor cells that dampen DC antigen presentation and recruit innate-like CD8 T cells. Our comprehensive picture of the HCC ecosystem provides deeper insights into immune evasion mechanisms associated with tumor relapse.
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http://dx.doi.org/10.1016/j.cell.2020.11.041DOI Listing
January 2021

The genetic structure and adaptation of Andean highlanders and Amazonians are influenced by the interplay between geography and culture.

Proc Natl Acad Sci U S A 2020 12 4;117(51):32557-32565. Epub 2020 Dec 4.

Laboratorio de Biotecnología y Biología Molecular, Instituto Nacional de Salud, Lima 9, Peru;

Western South America was one of the worldwide cradles of civilization. The well-known Inca Empire was the tip of the iceberg of an evolutionary process that started 11,000 to 14,000 years ago. Genetic data from 18 Peruvian populations reveal the following: 1) The between-population homogenization of the central southern Andes and its differentiation with respect to Amazonian populations of similar latitudes do not extend northward. Instead, longitudinal gene flow between the northern coast of Peru, Andes, and Amazonia accompanied cultural and socioeconomic interactions revealed by archeology. This pattern recapitulates the environmental and cultural differentiation between the fertile north, where altitudes are lower, and the arid south, where the Andes are higher, acting as a genetic barrier between the sharply different environments of the Andes and Amazonia. 2) The genetic homogenization between the populations of the arid Andes is not only due to migrations during the Inca Empire or the subsequent colonial period. It started at least during the earlier expansion of the Wari Empire (600 to 1,000 years before present). 3) This demographic history allowed for cases of positive natural selection in the high and arid Andes vs. the low Amazon tropical forest: in the Andes, a putative enhancer in (heart and neural crest derivatives expressed 2 antisense RNA1, a noncoding gene related to cardiovascular function) and rs269868-C/Ser1067 in (dual oxidase 2, related to thyroid function and innate immunity) genes and, in the Amazon, the gene encoding for the CD45 protein, essential for antigen recognition by T and B lymphocytes in viral-host interaction.
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http://dx.doi.org/10.1073/pnas.2013773117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768732PMC
December 2020

Integrative molecular characterisation of gallbladder cancer reveals micro-environment-associated subtypes.

J Hepatol 2021 05 1;74(5):1132-1144. Epub 2020 Dec 1.

Division of Cancer Epidemiology and Genetics, NIH, Rockville, MD, USA. Electronic address:

Background & Aims: Gallbladder cancer (GBC) is the most common type of biliary tract cancer, but the molecular mechanisms involved in gallbladder carcinogenesis remain poorly understood. In this study, we applied integrative genomics approaches to characterise GBC and explore molecular subtypes associated with patient survival.

Methods: We profiled the mutational landscape of GBC tumours (whole-exome sequencing on 92, targeted sequencing on 98, in total 190 patients). In a subset (n = 45), we interrogated the matched transcriptomes, DNA methylomes, and somatic copy number alterations. We explored molecular subtypes identified through clustering tumours by genes whose expression was associated with survival in 47 tumours and validated subtypes on 34 publicly available GBC cases.

Results: Exome analysis revealed TP53 was the most mutated gene. The overall mutation rate was low (median 0.82 Mut/Mb). APOBEC-mediated mutational signatures were more common in tumours with higher mutational burden. Aflatoxin-related signatures tended to be highly clonal (present in ≥50% of cancer cells). Transcriptome-wide survival association analysis revealed a 95-gene signature that stratified all GBC patients into 3 subtypes that suggested an association with overall survival post-resection. The 2 poor-survival subtypes were associated with adverse clinicopathologic features (advanced stage, pN1, pM1), immunosuppressive micro-environments (myeloid-derived suppressor cell accumulation, extensive desmoplasia, hypoxia) and T cell dysfunction, whereas the good-survival subtype showed the opposite features.

Conclusion: These data suggest that the tumour micro-environment and immune profiles could play an important role in gallbladder carcinogenesis and should be evaluated in future clinical studies, along with mutational profiles.

Lay Summary: Gallbladder cancer is highly fatal, and its causes are poorly understood. We evaluated gallbladder tumours to see if there were differences between tumours in genetic information such as DNA and RNA. We found evidence of aflatoxin exposure in these tumours, and immune cells surrounding the tumours were associated with survival.
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http://dx.doi.org/10.1016/j.jhep.2020.11.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058239PMC
May 2021

Association between Age, Weight, and Dose and Clinical Response to Probiotics in Children with Acute Gastroenteritis.

J Nutr 2021 01;151(1):65-72

Sections of Pediatric Emergency Medicine and Gastroenterology, Department of Pediatrics, Alberta Children's Hospital, Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.

Background: Gastroenteritis is a common and impactful disease in childhood. Probiotics are often used to treat acute gastroenteritis (AGE); however, in a large multicenter randomized controlled trial (RCT) in 971 children, Lactobacillus rhamnosus GG (LGG) was no better than placebo in improving patient outcomes.

Objectives: We sought to determine whether the effect of LGG is associated with age, weight z score and weight percentile adjusted for age and sex, or dose per kilogram administered.

Methods: This was a preplanned secondary analysis of a multicenter double-blind RCT of LGG 1 × 1010 CFU twice daily for 5 d or placebo in children 3-48 mo of age with AGE. Our primary outcome was moderate to severe gastroenteritis. Secondary outcomes included diarrhea and vomiting frequency and duration, chronic diarrhea, and side effects. We used multivariable linear and nonlinear models testing for interaction effects to assess outcomes by age, weight z score and weight percentile adjusted for age and sex, and dose per kilogram of LGG received.

Results: A total of 813 children (84%) were included in the analysis; 413 received placebo and 400 LGG. Baseline characteristics were similar between treatment groups. There were no differential interaction effects across ranges of age (P-interaction = 0.32), adjusted weight z score (P-interaction = 0.43), adjusted weight percentile (P-interaction = 0.45), or dose per kilogram of LGG received (P-interaction = 0.28) for the primary outcome. Whereas we found a statistical association favoring placebo at the extremes of adjusted weight z scores for the number of vomiting episodes (P-interaction = 0.02) and vomiting duration (P-interaction = 0.0475), there were no statistically significant differences in other secondary outcome measures (all P-interactions > 0.05).

Conclusions: LGG does not improve outcomes in children with AGE regardless of the age, adjusted weight z score, and adjusted weight percentile of participants, or the probiotic dose per kilogram received. These results further strengthen the conclusions of low risk of bias clinical trials which demonstrate that LGG provides no clinical benefit in children with AGE.This trial was registered at clinicaltrials.gov as NCT01773967.
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http://dx.doi.org/10.1093/jn/nxaa313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779240PMC
January 2021

Health-Related Quality of Life After Community-Acquired Septic Shock in Children With Preexisting Severe Developmental Disabilities.

Pediatr Crit Care Med 2021 05;22(5):e302-e313

Department of Pediatrics, Seattle Children's Hospital, Seattle Research Institute, University of Washington School of Medicine, Seattle, WA.

Objectives: To serially evaluate health-related quality of life during the first year after community-acquired septic shock in children with preexisting severe developmental disabilities and explore factors associated with health-related quality of life changes in these children.

Design: Secondary analysis of the Life after Pediatric Sepsis Evaluation investigation.

Setting: Twelve academic PICU in the United States.

Patients: Children greater than or equal to 1 month and less than 18 years old identified by their family caregiver (e.g., parent/guardian) as having severe developmental disability prior to septic shock.

Interventions: Family caregivers completed the Stein-Jessop Functional Status II-R Short Form as a measure of their child's health-related quality of life at baseline (reflecting preadmission status), day 7, and months 1, 3, 6, and 12 following PICU admission. Stein-Jessop Functional Status II-R Short Form scores were linearly transformed to a 0-100 scale, with higher scores indicating better health-related quality of life.

Measurements And Main Results: Of 392 Life after Pediatric Sepsis Evaluation participants, 137 were identified by their caregiver as having a severe developmental disability. Sixteen children (11.6%) with severe disability died during the 12 months following septic shock. Among 121 survivors, Stein-Jessop Functional Status II-R Short Form scores declined from preadmission baseline to day 7 (70.7 ± 16.1 vs 55.6 ± 19.2; p < 0.001). Stein-Jessop Functional Status II-R Short Form scores remained below baseline through month 12 (59.1 ± 21.0, p < 0.001 vs baseline). After adjusting for baseline Stein-Jessop Functional Status II-R Short Form, the caregiver being a single parent/guardian was associated with lower month 3 Stein-Jessop Functional Status II-R Short Form scores (p = 0.041). No other baseline child or caregiver characteristic, or critical illness-related factors were significantly associated with month 3 Stein-Jessop Functional Status II-R Short Form scores.

Conclusions: Health-related quality of life among children with severe developmental disability remains, on average, below baseline during the first year following community-acquired septic shock. Children with severe disability and septic shock that are in single parent families are at increased risk. Clinical awareness of the potential for decline in health-related quality of life among disabled children is essential to prevent this adverse outcome from being missed.
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http://dx.doi.org/10.1097/PCC.0000000000002606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099927PMC
May 2021

Metastatic and recurrent adrenocortical cancer is not defined by its genomic landscape.

BMC Med Genomics 2020 11 4;13(1):165. Epub 2020 Nov 4.

Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, 20892, USA.

Background: Adrenocortical carcinoma (ACC) is a rare, often-aggressive neoplasm of the adrenal cortex, with a 14-17 month median overall survival. We asked whether tumors from patients with advanced or metastatic ACC would offer clues as to putative genes that might have critical roles in disease progression or in more aggressive disease biology.

Methods: We conducted comprehensive genomic and expression analyses of ACCs from 43 patients, 30 female, and 42 from metastatic sites, including deep sequencing, copy number analysis, mRNA expression and microRNA arrays.

Results: Copy number gains and losses were similar to that previously reported for ACC. We identified a median mutation rate of 3.38 per megabase (Mb). The mutational signature was characterized by a predominance of C > T, C > A and T > C transitions. Only cancer genes TP53 (26%) and beta-catenin (CTNNB1, 14%) were mutated in more than 10% of samples. The TCGA-identified putative cancer genes MEN1 and PRKAR1A were found in low frequency-4.7 and 2.3%, respectively. The majority of the mutations were in genes not implicated in the etiology or maintenance of cancer. Specifically, amongst the 38 genes that were mutated in more than 9% of samples, only four were represented in Tier 1 of the 576 COSMIC Cancer Gene Census (CCGC). Thus, 82% of genes found to have mutations likely have no role in the etiology or biology of ACC; while the role of the other 18%, if any, remains to be proven. Finally, the transcript length for the 38 most frequently mutated genes in ACC is statistically longer than the average of all coding genes, raising the question of whether transcript length in part determined mutation probability.

Conclusions: We conclude that the mutational and expression profiles of advanced and metastatic tumors are very similar to those from newly diagnosed patients-with very little in the way of genomic aberration to explain differences in biology. With relatively low mutation rates, few major oncogenic drivers, and loss of function mutations in several epigenetic regulators, an epigenetic basis for ACC may be postulated and serve as the basis for future studies.
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http://dx.doi.org/10.1186/s12920-020-00809-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7640690PMC
November 2020

Embryonic liver developmental trajectory revealed by single-cell RNA sequencing in the Foxa2 mouse.

Commun Biol 2020 11 3;3(1):642. Epub 2020 Nov 3.

BGI-Shenzhen, 518033, Shenzhen, China.

The liver and gallbladder are among the most important internal organs derived from the endoderm, yet the development of the liver and gallbladder in the early embryonic stages is not fully understood. Using a transgenic Foxa2 reporter mouse line, we performed single-cell full-length mRNA sequencing on endodermal and hepatic cells isolated from ten embryonic stages, ranging from E7.5 to E15.5. We identified the embryonic liver developmental trajectory from gut endoderm to hepatoblasts and characterized the transcriptome of the hepatic lineage. More importantly, we identified liver primordium as the nascent hepatic progenitors with both gut and liver features and documented dynamic gene expression during the epithelial-hepatic transition (EHT) at the stage of liver specification during E9.5-11.5. We found six groups of genes switched on or off in the EHT process, including diverse transcripitional regulators that had not been previously known to be expressed during EHT. Moreover, we identified and revealed transcriptional profiling of gallbladder primordium at E9.5. The present data provides a high-resolution resource and critical insights for understanding the liver and gallbladder development.
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http://dx.doi.org/10.1038/s42003-020-01364-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642341PMC
November 2020

Risk Factors for Mortality in Refractory Pediatric Septic Shock Supported with Extracorporeal Life Support.

ASAIO J 2020 Nov/Dec;66(10):1152-1160

Division of Critical Care, Department of Pediatrics, Children's Hospital of Michigan/Wayne State University, Detroit, Michigan.

Risk factors for mortality in children with refractory pediatric septic shock who are supported with extracorporeal life support (ECLS) are largely unknown. Therefore, we performed univariable and multivariable analyses to determine risk factors for mortality among children (<19 years) who underwent an ECLS run between January 2012 and September 2014 at eight tertiary pediatric hospitals, and who had septic shock based on 2005 International Consensus Criteria. Of the 514 children treated with ECLS during the study period, 70 were identified with septic shock. The mortality rate was similar between those with (54.3%) and without septic shock (43.7%). Among those with septic shock, significant risk factors for mortality included cardiac failure or extracorporeal cardiopulmonary resuscitation (ECPR) as indication for ECLS cannulation compared with respiratory failure (P = 0.003), having a new neurologic event following cannulation (P = 0.032), acquiring a new infection following cannulation (P = 0.005), inability to normalize pH in the 48 hours following ECLS cannulation (P = 0.010), and requiring higher daily volume of platelet transfusions (P = 0.005). These findings can be used to help guide clinical decision making for children with septic shock that is refractory to medical management.
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http://dx.doi.org/10.1097/MAT.0000000000001147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773130PMC
March 2021

A Core Outcome Set for Pediatric Critical Care.

Crit Care Med 2020 12;48(12):1819-1828

Children and Young People Health Research, School of Health Sciences, University of Nottingham and Nottingham Children's Hospital, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom.

Objectives: More children are surviving critical illness but are at risk of residual or new health conditions. An evidence-informed and stakeholder-recommended core outcome set is lacking for pediatric critical care outcomes. Our objective was to create a multinational, multistakeholder-recommended pediatric critical care core outcome set for inclusion in clinical and research programs.

Design: A two-round modified Delphi electronic survey was conducted with 333 invited research, clinical, and family/advocate stakeholders. Stakeholders completing the first round were invited to participate in the second. Outcomes scoring greater than 69% "critical" and less than 15% "not important" advanced to round 2 with write-in outcomes considered. The Steering Committee held a virtual consensus conference to determine the final components.

Setting: Multinational survey.

Patients: Stakeholder participants from six continents representing clinicians, researchers, and family/advocates.

Measurements And Main Results: Overall response rates were 75% and 82% for each round. Participants voted on seven Global Domains and 45 Specific Outcomes in round 1, and six Global Domains and 30 Specific Outcomes in round 2. Using overall (three stakeholder groups combined) results, consensus was defined as outcomes scoring greater than 90% "critical" and less than 15% "not important" and were included in the final PICU core outcome set: four Global Domains (Cognitive, Emotional, Physical, and Overall Health) and four Specific Outcomes (Child Health-Related Quality of Life, Pain, Survival, and Communication). Families (n = 21) suggested additional critically important outcomes that did not meet consensus, which were included in the PICU core outcome set-extended.

Conclusions: The PICU core outcome set and PICU core outcome set-extended are multistakeholder-recommended resources for clinical and research programs that seek to improve outcomes for children with critical illness and their families.
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http://dx.doi.org/10.1097/CCM.0000000000004660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785252PMC
December 2020

Therapeutic Alliance Between Bereaved Parents and Physicians in the PICU.

Pediatr Crit Care Med 2021 04;22(4):e243-e252

Department of Pediatrics, Children's Hospital of Michigan, Detroit, MI.

Objectives: Therapeutic alliance is the collaborative bond that develops between patients/families and healthcare providers. Our objective is to determine the extent of therapeutic alliance bereaved parents perceive to have occurred with their child's physicians during their child's PICU stay, and associated factors.

Design: Multicenter observational study.

Setting: Eight children's hospitals affiliated with the Collaborative Pediatric Critical Care Research Network.

Patients: Parents greater than or equal to 18 years old whose child died in a PICU (including cardiac ICU).

Interventions: Bereaved parents completed the Human Connection Scale, a 16-item measure of therapeutic alliance, 6 months after their child's death. Human Connection Scale scores range from 16 to 64 with higher scores indicating greater alliance. Parents provided sociodemographic data, and medical records were reviewed for the child's clinical characteristics.

Measurements And Main Results: Two-hundred and thirty-three parents of 157 deceased children responded to the Human Connection Scale with greater than or equal to 80% item completion. Among parents, 146 (62.7%) were female, 155 (66.5%) were White and 46 (19.7%) were Black, 175 (75.1%) were married, and 209 (89.7%) had at least a high-school education. Among children, median age at the time of death was 5.9 years (interquartile range, 0.64-13.9 yr) and 114 (72.6%) died after limitation or withdrawal of life support. Mean Human Connection Scale score was 51.4 ± 11.1 for all parents, 52.6 ± 9.0 for White parents, and 47.0 ± 13.7 for Black parents. In multivariable modeling predicting Human Connection Scale scores, race was the only parent or child characteristic in the final model. Human Connection Scale scores were significantly different (-4.56; 95% CI, -8.53 to -0.6; p = 0.025) between the Black and White parents with items about trust, care, and honest communication showing the greatest mean difference.

Conclusions: Among parents bereaved in the PICU, therapeutic alliance with physicians is moderately high. Future research should identify strategies to strengthen therapeutic alliance with Black parents and examine the role of alliance on bereaved parents' health outcomes.
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http://dx.doi.org/10.1097/PCC.0000000000002585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016694PMC
April 2021

Temporal airway microbiome changes related to ventilator-associated pneumonia in children.

Eur Respir J 2021 03 18;57(3). Epub 2021 Mar 18.

Biostatistics and Informatics, University of Colorado, Colorado School of Public Health, Aurora, CO, USA.

We sought to determine whether temporal changes in the lower airway microbiome are associated with ventilator-associated pneumonia (VAP) in children.Using a multicentre prospective study of children aged 31 days to 18 years requiring mechanical ventilation support for >72 h, daily tracheal aspirates were collected and analysed by sequencing of the 16S rRNA gene. VAP was assessed using 2008 Centers for Disease Control and Prevention paediatric criteria. The association between microbial factors and VAP was evaluated using joint longitudinal time-to-event modelling, matched case-control comparisons and unsupervised clustering.Out of 366 eligible subjects, 66 (15%) developed VAP at a median of 5 (interquartile range 3-5) days post intubation. At intubation, there was no difference in total bacterial load (TBL), but Shannon diversity and the relative abundance of , Lactobacillales and were lower for VAP subjects non-VAP subjects. However, higher TBL on each sequential day was associated with a lower hazard (hazard ratio 0.39, 95% CI 0.23-0.64) for developing VAP, but sequential values of diversity were not associated with VAP. Similar findings were observed from the matched analysis and unsupervised clustering. The most common dominant VAP pathogens included species (19%), (14%) and / (10%). and were also identified as dominant organisms in several subjects.In mechanically ventilated children, changes over time in microbial factors were marginally associated with VAP risk, although these changes were not suitable for predicting VAP in individual patients. These findings suggest that focusing exclusively on pathogen burden may not adequately inform VAP diagnosis.
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http://dx.doi.org/10.1183/13993003.01829-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979474PMC
March 2021
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