Publications by authors named "Shannon Kelly"

122 Publications

Rare genetic variants explain missing heritability in smoking.

Nat Hum Behav 2022 Aug 4. Epub 2022 Aug 4.

Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

Common genetic variants explain less variation in complex phenotypes than inferred from family-based studies, and there is a debate on the source of this 'missing heritability'. We investigated the contribution of rare genetic variants to tobacco use with whole-genome sequences from up to 26,257 unrelated individuals of European ancestries and 11,743 individuals of African ancestries. Across four smoking traits, single-nucleotide-polymorphism-based heritability ([Formula: see text]) was estimated from 0.13 to 0.28 (s.e., 0.10-0.13) in European ancestries, with 35-74% of it attributable to rare variants with minor allele frequencies between 0.01% and 1%. These heritability estimates are 1.5-4 times higher than past estimates based on common variants alone and accounted for 60% to 100% of our pedigree-based estimates of narrow-sense heritability ([Formula: see text], 0.18-0.34). In the African ancestry samples, [Formula: see text] was estimated from 0.03 to 0.33 (s.e., 0.09-0.14) across the four smoking traits. These results suggest that rare variants are important contributors to the heritability of smoking.
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http://dx.doi.org/10.1038/s41562-022-01408-5DOI Listing
August 2022

Paper 4: a review of reporting and disseminating approaches for rapid reviews in health policy and systems research.

Syst Rev 2022 Jul 30;11(1):152. Epub 2022 Jul 30.

Li Ka Shing Knowledge Institute of St. Michael's - Unity Health Toronto, 38 Shuter St, ON, M5B 1A6, Toronto, Canada.

Background: Transparent reporting of rapid reviews enables appropriate use of research findings and dissemination strategies can strengthen uptake and impact for the targeted knowledge users, including policy-makers and health system managers. The aim of this literature review was to understand reporting and dissemination approaches for rapid reviews and provide an overview in the context of health policy and systems research.

Methods: A literature review and descriptive summary of the reporting and disseminating approaches for rapid reviews was conducted, focusing on available guidance and methods, considerations for engagement with knowledge users, and optimizing dissemination. MEDLINE, PubMed, Google scholar, as well as relevant websites and reference lists were searched from January 2017 to March 2021 to identify the relevant literature with no language restrictions. Content was abstracted and charted.

Results: The literature review found limited guidance specific to rapid reviews. Building on the barriers and facilitators to systematic review use, we provide practical recommendations on different approaches and methods for reporting and disseminating expedited knowledge synthesis considering the needs of health policy and systems knowledge users. Reporting should balance comprehensive accounting of the research process and findings with what is "good enough" or sufficient to meet the requirements of the knowledge users, while considering the time and resources available to conduct a review. Typical approaches may be used when planning the dissemination of rapid review findings; such as peer-reviewed publications or symposia and clear and ongoing engagement with knowledge users in crafting the messages is essential so they are appropriately tailored to the target audience. Consideration should be given to providing different products for different audiences. Dissemination measures and bibliometrics are also useful to gauge impact and reach.

Conclusions: Limited guidance specific to the reporting and dissemination of rapid reviews is available. Although approaches to expedited synthesis for health policy and systems research vary, considerations for the reporting and dissemination of findings are pertinent to all.
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http://dx.doi.org/10.1186/s13643-022-01897-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9338534PMC
July 2022

Is Severity Score Associated With Indication for Hematopoietic Stem Cell Transplantation in Individuals With Sickle Cell Anemia?

Transplant Cell Ther 2022 Jul 3. Epub 2022 Jul 3.

Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Instituto da Criança, São Paulo, Brazil.

Manifestations of sickle cell disease (SCD) begin early in childhood and cause morbidity and decreased life expectancy. Hematopoietic stem cell transplantation (HSCT) is curative but associated with risk of mortality attributable to the transplant. This risk should be counterbalanced with SCD morbidity and mortality. A severity score using a Bayesian network model was previously validated to predict the risk of death in adult individuals with SCD. The objective of this study is to calculate the severity scores of participants in a multicenter cohort of Brazilians with SCD, using a previously published Bayesian network-derived score, associated with risk of death and then compare the severity scores between participants with and without an indication for HSCT as defined by the Brazilian Ministry of Health (MoH) criteria. This is an observational, retrospective study. We analyzed 2063 individuals with sickle cell anemia from the Recipient Epidemiology and Donor Evaluation Study-III Brazil SCD cohort and applied a Bayesian network-derived score to compare candidates and non-candidates for HSCT according to the Brazilian MoH transplant criteria. Classical statistical methods were used to analyze data and make comparisons. We compared severity scores between cohort members with (n = 431) and without (n = 1632) HSCT indications according to Brazilian MoH. Scores were not different in adult participants with ≥1 HSCT indication when compared to those with no indication (mean 0.342 versus 0.292; median 0.194 versus 0.183, P = .354) and receiver operating characteristic curves did not demonstrate an obvious threshold to differentiate participants with or without HSCT indications. Severity score may predict risk of death but does not differentiate HSCT candidates. Current indications should be evaluated to ensure that patients with more severe disease who might benefit from HSCT are appropriately identified.
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http://dx.doi.org/10.1016/j.jtct.2022.06.024DOI Listing
July 2022

Distribution of cardiomyocyte-selective adeno-associated virus serotype 9 vectors in swine following intracoronary and intravenous infusion.

Physiol Genomics 2022 Jul 1;54(7):261-272. Epub 2022 Jun 1.

Department of Ophthalmology, Stanford University, Palo Alto, California.

Limited reports exist regarding adeno-associated virus (AAV) biodistribution in swine. This study assessed biodistribution following antegrade intracoronary and intravenous delivery of two self-complementary serotype 9 AAV (AAV9sc) biologics designed to target signaling in the cardiomyocyte considered important for the development of heart failure. Under the control of a cardiomyocyte-specific promoter, AAV9sc.shmAKAP and AAV9sc.RBD express a small hairpin RNA for the perinuclear scaffold protein muscle A-kinase anchoring protein β (mAKAPβ) and an anchoring disruptor peptide for p90 ribosomal S6 kinase type 3 (RSK3), respectively. Quantitative PCR was used to assess viral genome (vg) delivery and transcript expression in Ossabaw and Yorkshire swine tissues. Myocardial viral delivery was 2-5 × 10 vg/µg genomic DNA (gDNA) for both infusion techniques at a dose ∼10 vg/kg body wt, demonstrating delivery of ∼1-3 viral particles per cardiac diploid genome. Myocardial RNA levels for each expressed transgene were generally proportional to dose and genomic delivery, and comparable with levels for moderately expressed endogenous genes. Despite significant AAV9sc delivery to other tissues, including the liver, neither biologic induced toxic effects as assessed using functional, structural, and circulating cardiac and systemic markers. These results indicate successful targeted delivery of cardiomyocyte-selective viral vectors in swine without negative side effects, an important step in establishing efficacy in a preclinical experimental setting.
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http://dx.doi.org/10.1152/physiolgenomics.00032.2022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9236866PMC
July 2022

Cerebellar Volumes and Sensorimotor Behavior in Autism Spectrum Disorder.

Front Integr Neurosci 2022 3;16:821109. Epub 2022 May 3.

Schiefelbusch Institute for Life Span Studies and Kansas Center for Autism Research and Training (K-CART), University of Kansas, Lawrence, KS, United States.

Background: Sensorimotor issues are common in autism spectrum disorder (ASD), though their neural bases are not well understood. The cerebellum is vital to sensorimotor control and reduced cerebellar volumes in ASD have been documented. Our study examined the extent to which cerebellar volumes are associated with multiple sensorimotor behaviors in ASD.

Materials And Methods: Fifty-eight participants with ASD and 34 typically developing (TD) controls (8-30 years) completed a structural MRI scan and precision grip testing, oculomotor testing, or both. Force variability during precision gripping as well as absolute error and trial-to-trial error variability of visually guided saccades were examined. Volumes of cerebellar lobules, vermis, and white matter were quantified. The relationships between each cerebellar region of interest (ROI) and force variability, saccade error, and saccade error variability were examined.

Results: Relative to TD controls, individuals with ASD showed increased force variability. Individuals with ASD showed a reduced volume of cerebellar vermis VI-VII relative to TD controls. Relative to TD females, females with ASD showed a reduced volume of bilateral cerebellar Crus II/lobule VIIB. Increased volume of Crus I was associated with increased force variability. Increased volume of vermal lobules VI-VII was associated with reduced saccade error for TD controls but not individuals with ASD. Increased right lobule VIII and cerebellar white matter volumes as well as reduced right lobule VI and right lobule X volumes were associated with greater ASD symptom severity. Reduced volumes of right Crus II/lobule VIIB were associated with greater ASD symptom severity in only males, while reduced volumes of right Crus I were associated with more severe restricted and repetitive behaviors only in females.

Conclusion: Our finding that increased force variability in ASD is associated with greater cerebellar Crus I volumes indicates that disruption of sensory feedback processing supported by Crus I may contribute to skeletomotor differences in ASD. Results showing that volumes of vermal lobules VI-VII are associated with saccade precision in TD but not ASD implicates atypical organization of the brain systems supporting oculomotor control in ASD. Associations between volumes of cerebellar subregions and ASD symptom severity suggest cerebellar pathological processes may contribute to multiple developmental challenges in ASD.
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http://dx.doi.org/10.3389/fnint.2022.821109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9113114PMC
May 2022

Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed.

Cell Genom 2022 Jan 13;2(1). Epub 2022 Jan 13.

Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.

Genetic studies on telomere length are important for understanding age-related diseases. Prior GWAS for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally-diverse individuals (European, African, Asian and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n=109,122 individuals. We identified 59 sentinel variants (p-value <5×10) in 36 loci associated with telomere length, including 20 newly associated loci (13 were replicated in external datasets). There was little evidence of effect size heterogeneity across populations. Fine-mapping at indicated the independent signals colocalized with cell-type specific eQTLs for (). Using a multi-variant gene-based approach, we identified two genes newly implicated in telomere length, () and . In PheWAS, we demonstrated our TL polygenic trait scores (PTS) were associated with increased risk of cancer-related phenotypes.
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http://dx.doi.org/10.1016/j.xgen.2021.100084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9075703PMC
January 2022

The Recipient Epidemiology and Donor Evaluation Study-IV-Pediatric (REDS-IV-P): A research program striving to improve blood donor safety and optimize transfusion outcomes across the lifespan.

Transfusion 2022 05 19;62(5):982-999. Epub 2022 Apr 19.

Department of Pathology and Laboratory Medicine, University of British Columbia, Victoria, British Columbia, Canada.

Background: The Recipient Epidemiology and Donor Evaluation Study-IV-Pediatric (REDS-IV-P) is a new iteration of prior National Heart, Lung, and Blood Institute (NHLBI) REDS programs that focus on improving transfusion recipient outcomes across the lifespan as well as the safety and availability of the blood supply.

Study Design And Methods: The US program includes blood centers and hospitals (22 including 6 free-standing Children's hospitals) in four geographic regions. The Brazilian program has 5 participating hemocenters. A Center for Transfusion Laboratory Studies (CTLS) and a Data Coordinating Center (DCC) support synergistic studies and activities over the 7-year REDS-IV-P program.

Results: The US is building a centralized, vein-to-vein (V2V) database, linking information collected from blood donors, their donations, the resulting manufactured components, and data extracts from hospital electronic medical records of transfused and non-transfused patients. Simultaneously, the Brazilian program is building a donor, donation, and component database. The databases will serve as the backbone for retrospective and prospective observational studies in transfusion epidemiology, transfusion recipient outcomes, blood component quality, and emerging blood safety issues. Special focus will be on preterm infants, patients with sickle cell disease, thalassemia or cancer, and the effect of donor biologic variability and component manufacturing on recipient outcomes. A rapid response capability to emerging safety threats has resulted in timely studies related to Severe Acute Respiratory Syndrome Corona Virus-2 (SARS-CoV-2).

Conclusions: The REDS-IV-P program endeavors to improve donor-recipient-linked research with a focus on children and special populations while also maintaining the flexibility to address emerging blood safety issues.
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http://dx.doi.org/10.1111/trf.16869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9353062PMC
May 2022

Mendelian randomization supports bidirectional causality between telomere length and clonal hematopoiesis of indeterminate potential.

Sci Adv 2022 Apr 6;8(14):eabl6579. Epub 2022 Apr 6.

Department of Biostatistics, School of Public Health, University of Alabama, Birmingham, AL, USA.

Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in the Trans-Omics for Precision Medicine (TOPMed) program ( = 63,302) and UK Biobank ( = 47,080). Bidirectional Mendelian randomization studies were consistent with longer genetically imputed LTL increasing propensity to develop CHIP, but CHIP then, in turn, hastens to shorten measured LTL (mLTL). We also demonstrated evidence of modest mediation between CHIP and CAD by mLTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD.
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http://dx.doi.org/10.1126/sciadv.abl6579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8986098PMC
April 2022

The influence of reinforcement schedule on experience-dependent changes in motivation.

J Exp Anal Behav 2022 05 28;117(3):320-330. Epub 2022 Mar 28.

Department of Pharmacology, Vanderbilt University.

The progressive ratio procedure is used across fields to assess motivation for different reinforcers, define the effects of experimental interventions on motivation, and determine experience-dependent changes in motivation. However, less is known about how operant training schedules affect performance on this widely utilized task. Here we designed an experiment to examine the effect of variable ratio versus fixed ratio training schedules of reinforcement on progressive ratio performance while holding other performance variables constant between groups. We found a robust increase in maximum ratio completed between the pretest and posttraining test highlighting a robust training effect on progressive ratio performance. However, it did not matter if the training was under a fixed or variable ratio schedule. Additionally, we show that neither individual rates during training nor extinction responding correlated with maximum ratio achieved during the sessions. Finally, we show that rates during the training sessions do correlate with extinction performance, suggesting that these variables measure a different aspect of performance that does not predict motivation.
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http://dx.doi.org/10.1002/jeab.755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9090977PMC
May 2022

Mechanism-Driven Modeling to Aid Non-invasive Monitoring of Cardiac Function Ballistocardiography.

Front Med Technol 2022 16;4:788264. Epub 2022 Feb 16.

Electrical Engineering and Computer Science, College of Engineering, University of Missouri, Columbia, MO, United States.

Left ventricular (LV) catheterization provides LV pressure-volume (P-V) loops and it represents the gold standard for cardiac function monitoring. This technique, however, is invasive and this limits its applicability in clinical and in-home settings. Ballistocardiography (BCG) is a good candidate for non-invasive cardiac monitoring, as it is based on capturing non-invasively the body motion that results from the blood flowing through the cardiovascular system. This work aims at building a mechanistic connection between changes in the BCG signal, changes in the P-V loops and changes in cardiac function. A mechanism-driven model based on cardiovascular physiology has been used as a virtual laboratory to predict how changes in cardiac function will manifest in the BCG waveform. Specifically, model simulations indicate that a decline in LV contractility results in an increase of the relative timing between the ECG and BCG signal and a decrease in BCG amplitude. The predicted changes have subsequently been observed in measurements on three swine serving as pre-clinical models for pre- and post-myocardial infarction conditions. The reproducibility of BCG measurements has been assessed on repeated, consecutive sessions of data acquisitions on three additional swine. Overall, this study provides experimental evidence supporting the utilization of mechanism-driven mathematical modeling as a guide to interpret changes in the BCG signal on the basis of cardiovascular physiology, thereby advancing the BCG technique as an effective method for non-invasive monitoring of cardiac function.
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http://dx.doi.org/10.3389/fmedt.2022.788264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8888976PMC
February 2022

Managing unmanageable loads of evidence: are living reviews the answer?

JBI Evid Synth 2022 01;20(1):1-2

Li Ka Shing Knowledge Institute, St. Michael's Hospital, Unity Health Toronto, Toronto, ON, Canada.

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http://dx.doi.org/10.11124/JBIES-21-00458DOI Listing
January 2022

Clonal hematopoiesis in sickle cell disease.

J Clin Invest 2022 02;132(4)

Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.

BACKGROUNDCurative gene therapies for sickle cell disease (SCD) are currently undergoing clinical evaluation. The occurrence of myeloid malignancies in these trials has prompted safety concerns. Individuals with SCD are predisposed to myeloid malignancies, but the underlying causes remain undefined. Clonal hematopoiesis (CH) is a premalignant condition that also confers significant predisposition to myeloid cancers. While it has been speculated that CH may play a role in SCD-associated cancer predisposition, limited data addressing this issue have been reported.METHODSHere, we leveraged 74,190 whole-genome sequences to robustly study CH in SCD. Somatic mutation calling methods were used to assess CH in all samples and comparisons between individuals with and without SCD were performed.RESULTSWhile we had sufficient power to detect a greater than 2-fold increased rate of CH, we found no detectable variation in rate or clone properties between individuals affected by SCD and controls. The rate of CH in individuals with SCD was unaltered by hydroxyurea use.CONCLUSIONSWe did not observe an increased risk for acquiring detectable CH in SCD, at least as measured by whole-genome sequencing. These results should help guide ongoing efforts and further studies that seek to better define the risk factors underlying myeloid malignancy predisposition in SCD and help ensure that curative therapies can be more safely applied.FUNDINGNew York Stem Cell Foundation and the NIH.
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http://dx.doi.org/10.1172/JCI156060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8843701PMC
February 2022

Comparative efficacy and safety of antihyperglycemic drug classes for patients with type 2 diabetes following failure with metformin monotherapy: A systematic review and network meta-analysis of randomized controlled trials.

Diabetes Metab Res Rev 2022 05 8;38(4):e3515. Epub 2022 Jan 8.

School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada.

Aims: To compare the efficacy and safety of antihyperglycemic agents, taken in combination with metformin, for the treatment of type 2 diabetes mellitus (T2DM).

Methods: A previous 2016 comprehensive search of Ovid MEDLINE, PubMed, and Cochrane CENTRAL was updated to October 2018, and a systematic review and network meta-analysis (NMA) was conducted. Randomized controlled trials (RCTs) of patients with T2DM taking an antihyperglycemic agent in combination with metformin were included. Bayesian NMA was performed to assess the relative efficacy and safety of the antihyperglycemic classes.

Results: In total, 204 RCTs were included, which assessed the efficacy and safety of eight antihyperglycemic drug classes (i.e., sulfonylureas, meglitinides, alpha-glucosidase inhibitors, thiazolidinediones, basal and biphasic insulin, dipeptidyl peptidase 4 inhibitors, glucagon-like-peptide-1 receptor agonists and sodium-glucose cotransport-2 inhibitors). All drug classes significantly reduced haemoglobin A1c (HbA1c) compared to metformin monotherapy (mean reduction from 0.50 to 0.92). The drug classes varied in their relative effects on hypoglycemia, body weight, body mass index, systolic and diastolic blood pressure, total cholesterol, high and low density lipoprotein cholesterol, and the classes had differing safety profiles on total adverse events, urogenital adverse events, heart failure, serious adverse events, and withdraw due to adverse events.

Conclusions: All eight antihyperglycemic drug classes, taken in combination with metformin, reduced HbA1c levels; however, the effects of the agents on other outcomes varied among the classes.
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http://dx.doi.org/10.1002/dmrr.3515DOI Listing
May 2022

Guidance for using artificial intelligence for title and abstract screening while conducting knowledge syntheses.

BMC Med Res Methodol 2021 12 20;21(1):285. Epub 2021 Dec 20.

Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.

Background: Systematic reviews are the cornerstone of evidence-based medicine. However, systematic reviews are time consuming and there is growing demand to produce evidence more quickly, while maintaining robust methods. In recent years, artificial intelligence and active-machine learning (AML) have been implemented into several SR software applications. As some of the barriers to adoption of new technologies are the challenges in set-up and how best to use these technologies, we have provided different situations and considerations for knowledge synthesis teams to consider when using artificial intelligence and AML for title and abstract screening.

Methods: We retrospectively evaluated the implementation and performance of AML across a set of ten historically completed systematic reviews. Based upon the findings from this work and in consideration of the barriers we have encountered and navigated during the past 24 months in using these tools prospectively in our research, we discussed and developed a series of practical recommendations for research teams to consider in seeking to implement AML tools for citation screening into their workflow.

Results: We developed a seven-step framework and provide guidance for when and how to integrate artificial intelligence and AML into the title and abstract screening process. Steps include: (1) Consulting with Knowledge user/Expert Panel; (2) Developing the search strategy; (3) Preparing your review team; (4) Preparing your database; (5) Building the initial training set; (6) Ongoing screening; and (7) Truncating screening. During Step 6 and/or 7, you may also choose to optimize your team, by shifting some members to other review stages (e.g., full-text screening, data extraction).

Conclusion: Artificial intelligence and, more specifically, AML are well-developed tools for title and abstract screening and can be integrated into the screening process in several ways. Regardless of the method chosen, transparent reporting of these methods is critical for future studies evaluating artificial intelligence and AML.
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http://dx.doi.org/10.1186/s12874-021-01451-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8686081PMC
December 2021

NUQUEST-NUtrition QUality Evaluation Strengthening Tools: development of tools for the evaluation of risk of bias in nutrition studies.

Am J Clin Nutr 2022 01;115(1):256-271

Bureau of Nutritional Sciences, Health Canada, Ottawa, Ontario, Canada.

Background: Dietary exposure assessments are a critical issue in evaluating human nutrition studies; however, nutrition-specific criteria are not consistently included in existing bias assessment tools.

Objectives: Our objective was to develop a set of risk of bias (RoB) tools that integrated nutrition-specific criteria into validated generic assessment tools to address RoB issues, including those specific to dietary exposure assessment.

Methods: The Nutrition QUality Evaluation Strengthening Tools (NUQUEST) development and validation process included 8 steps. The first steps identified 1) a development strategy; 2) generic assessment tools with demonstrated validity; and 3) nutrition-specific appraisal issues. This was followed by 4) generation of nutrition-specific items and 5) development of guidance to aid users of NUQUEST. The final steps used established ratings of selected studies and feedback from independent raters to 6) assess reliability and validity; 7) assess formatting and usability; and 8) finalize NUQUEST.

Results: NUQUEST is based on the Scottish Intercollegiate Guidelines Network checklists for randomized controlled trials, cohort studies, and case-control studies. Using a purposive sample of 45 studies representing the 3 study designs, interrater reliability was high (Cohen's κ: 0.73; 95% CI: 0.52, 0.93) across all tools and at least moderate for individual tools (range: 0.57-1.00). The use of a worksheet improved usability and consistency of overall interrater agreement across all study designs (40% without worksheet, 80%-100% with worksheet). When compared to published ratings, NUQUEST ratings for evaluated studies demonstrated high concurrent validity (93% perfect or near-perfect agreement). Where there was disagreement, the nutrition-specific component was a contributing factor in discerning exposure methodological issues.

Conclusions: NUQUEST integrates nutrition-specific criteria with generic criteria from assessment tools with demonstrated reliability and validity. NUQUEST represents a consistent and transparent approach for evaluating RoB issues related to dietary exposure assessment commonly encountered in human nutrition studies.
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http://dx.doi.org/10.1093/ajcn/nqab335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8755056PMC
January 2022

Dopamine release in the nucleus accumbens core signals perceived saliency.

Curr Biol 2021 11 15;31(21):4748-4761.e8. Epub 2021 Sep 15.

Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Addiction Research, Vanderbilt University, Nashville, TN 37232, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA; Department of Psychiatry and Behavioral Sciences, Vanderbilt University, Nashville, TN 37232, USA. Electronic address:

A large body of work has aimed to define the precise information encoded by dopaminergic projections innervating the nucleus accumbens (NAc). Prevailing models are based on reward prediction error (RPE) theory, in which dopamine updates associations between rewards and predictive cues by encoding perceived errors between predictions and outcomes. However, RPE cannot describe multiple phenomena to which dopamine is inextricably linked, such as behavior driven by aversive and neutral stimuli. We combined a series of behavioral tasks with direct, subsecond dopamine monitoring in the NAc of mice, machine learning, computational modeling, and optogenetic manipulations to describe behavior and related dopamine release patterns across multiple contingencies reinforced by differentially valenced outcomes. We show that dopamine release only conforms to RPE predictions in a subset of learning scenarios but fits valence-independent perceived saliency encoding across conditions. Here, we provide an extended, comprehensive framework for accumbal dopamine release in behavioral control.
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http://dx.doi.org/10.1016/j.cub.2021.08.052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9084920PMC
November 2021

Cocaine self-administration induces sex-dependent protein expression in the nucleus accumbens.

Commun Biol 2021 07 16;4(1):883. Epub 2021 Jul 16.

Department of Pharmacology, Vanderbilt University, Nashville, TN, USA.

Substance use disorder (SUD) is a chronic neuropsychiatric condition characterized by long-lasting alterations in the neural circuitry regulating reward and motivation. Substantial work has focused on characterizing the molecular substrates that underlie these persistent changes in neural function and behavior. However, this work has overwhelmingly focused on male subjects, despite mounting clinical and preclinical evidence that females demonstrate dissimilar progression to SUD and responsivity to stimulant drugs of abuse, such as cocaine. Here, we show that sex is a critical biological variable that defines drug-induced plasticity in the nucleus accumbens (NAc). Using quantitative mass spectrometry, we assessed the protein expression patterns induced by cocaine self-administration and demonstrated unique molecular profiles between males and females. We show that 1. Cocaine self-administration induces non-overlapping protein expression patterns in significantly regulated proteins in males and females and 2. Critically, cocaine-induced protein regulation differentially interacts with sex to eliminate basal sexual dimorphisms in the proteome. Finally, eliminating these baseline differences in the proteome is concomitant with the elimination of sex differences in behavior for non-drug rewards. Together, these data suggest that cocaine administration is capable of rewriting basal proteomic function and reward-associated behaviors.
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http://dx.doi.org/10.1038/s42003-021-02358-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285523PMC
July 2021

Remote Monitoring of Cardiovascular Implantable Electronic Devices in Canada: Survey of Patients and Device Health Care Professionals.

CJC Open 2021 Apr 20;3(4):391-399. Epub 2020 Nov 20.

Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.

Background: Remote monitoring is used to supplement in-clinic follow-up for patients with cardiac implantable electronic devices (CIEDs) every 6-12 months. There is a need to optimize remote management for CIEDs because of the consistent increases in CIED implants over the past decade. The objective of this study was to investigate real and perceived barriers to the use of remote patient management strategies in Canada and to better understand how remote models of care can be optimized.

Methods: We surveyed 512 CIED patients and practitioners in 22 device clinics in Canada.

Results: Device clinic surveys highlighted significant variation and inconsistency in follow-up care for in-clinic and remote visits across and within clinics. This survey showed that funding policies and management of additional workflow are barriers to optimal use and uptake. Despite this, device clinics perceive remote follow-up as a valuable resource and an efficient way to manage patient follow-up. Patients were broadly satisfied with their CIED follow-up care but identified barriers related to coordination of care, visit logistics, and information needs. Views varied as a function of clinical or sociodemographic characteristics. Most patients (n = 228; 91%) expressed a desire to receive a phone call from their device clinic after a remote transmission has been received.

Conclusions: Lack of a unified, guideline-supported approach to follow-up after CIED implant, and discrepant funding policies across jurisdictions, are significant barriers to the use of remote patient management strategies in Canada. Efforts to increase or expand use of remote follow-up must recognize these barriers and the needs of specific subgroups of patients.
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http://dx.doi.org/10.1016/j.cjco.2020.11.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129436PMC
April 2021

A System for Phenotype Harmonization in the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine (TOPMed) Program.

Am J Epidemiol 2021 10;190(10):1977-1992

Genotype-phenotype association studies often combine phenotype data from multiple studies to increase statistical power. Harmonization of the data usually requires substantial effort due to heterogeneity in phenotype definitions, study design, data collection procedures, and data-set organization. Here we describe a centralized system for phenotype harmonization that includes input from phenotype domain and study experts, quality control, documentation, reproducible results, and data-sharing mechanisms. This system was developed for the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine (TOPMed) program, which is generating genomic and other -omics data for more than 80 studies with extensive phenotype data. To date, 63 phenotypes have been harmonized across thousands of participants (recruited in 1948-2012) from up to 17 studies per phenotype. Here we discuss challenges in this undertaking and how they were addressed. The harmonized phenotype data and associated documentation have been submitted to National Institutes of Health data repositories for controlled access by the scientific community. We also provide materials to facilitate future harmonization efforts by the community, which include 1) the software code used to generate the 63 harmonized phenotypes, enabling others to reproduce, modify, or extend these harmonizations to additional studies, and 2) the results of labeling thousands of phenotype variables with controlled vocabulary terms.
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http://dx.doi.org/10.1093/aje/kwab115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8485147PMC
October 2021

A randomized, placebo-controlled, double-blinded clinical trial of colchicine to improve vascular health in people living with HIV.

AIDS 2021 06;35(7):1041-1050

Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine.

Objectives: People living with HIV (PWH) experience an increased burden of coronary artery disease (CAD) believed to be related, in part, to an interplay of chronically increased inflammation and traditional risk factors. Recent trials suggest cardiovascular benefits of the anti-inflammatory, colchicine, in HIV-seronegative CAD patients. However, the impact of colchicine on impaired vascular health, as measured by coronary endothelial function (CEF), an independent contributor to CAD, has not been studied in PWH. We tested the hypothesis that colchicine improves vascular health in PWH.

Design: This was a randomized, placebo-controlled, double-blinded trial in 81 PWH to test whether low-dose colchicine (0.6 mg daily) improves CEF over 8-24 weeks.

Methods: Coronary and systemic endothelial function and serum inflammatory markers were measured at baseline, and at 8 and 24 weeks. The primary endpoint was CEF, measured as the change in coronary blood flow from rest to that during an isometric handgrip exercise, an endothelial-dependent stressor, measured with non-invasive MRI at 8 weeks.

Results: Colchicine was well tolerated and not associated with increased adverse events. However, there were no significant improvements in coronary or systemic endothelial function or reductions in serum inflammatory markers at 8 or 24 weeks with colchicine as compared to placebo.

Conclusions: In PWH with no history of CAD, low-dose colchicine was well tolerated but did not improve impaired coronary endothelial function, a predictor of cardiovascular events. These findings suggest that this anti-inflammatory approach using colchicine in PWH does not improve vascular health, the central, early driver of coronary atherosclerosis.
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http://dx.doi.org/10.1097/QAD.0000000000002845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8916096PMC
June 2021

Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program.

Nature 2021 02 10;590(7845):290-299. Epub 2021 Feb 10.

The Broad Institute of MIT and Harvard, Cambridge, MA, USA.

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes). In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.
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http://dx.doi.org/10.1038/s41586-021-03205-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875770PMC
February 2021

The right ventricular transcriptome signature in Ossabaw swine with cardiometabolic heart failure: implications for the coronary vasculature.

Physiol Genomics 2021 03 25;53(3):99-115. Epub 2021 Jan 25.

Department of Biomedical Sciences, University of Missouri, Columbia, Missouri.

Heart failure (HF) patients with deteriorating right ventricular (RV) structure and function have a nearly twofold increased risk of death compared with those without. Despite the well-established clinical risk, few studies have examined the molecular signature associated with this HF condition. The purpose of this study was to integrate morphological, molecular, and functional data with the transcriptome data set in the RV of a preclinical model of cardiometabolic HF. Ossabaw swine were fed either normal diet without surgery (lean control, = 5) or Western diet and aortic-banding (WD-AB; = 4). Postmortem RV weight was increased and positively correlated with lung weight in the WD-AB group compared with CON. Total RNA-seq was performed and gene expression profiles were compared and analyzed using principal component analysis, weighted gene co-expression network analysis, module enrichment analysis, and ingenuity pathway analysis. Gene networks specifically associated with RV hypertrophic remodeling identified a hub gene in MAPK8 (or JNK1) that was associated with the selective induction of the extracellular matrix (ECM) component fibronectin. JNK1 and fibronectin protein were increased in the right coronary artery (RCA) of WD-AB animals and associated with a decrease in matrix metalloproteinase 14 protein, which specifically degrades fibronectin. RCA fibronectin content was correlated with increased vascular stiffness evident as a decreased elastin elastic modulus in WD-AB animals. In conclusion, this study establishes a molecular and transcriptome signature in the RV using Ossabaw swine with cardiometabolic HF. This signature was associated with altered ECM regulation and increased vascular stiffness in the RCA, with selective dysregulation of fibronectin.
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http://dx.doi.org/10.1152/physiolgenomics.00093.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988741PMC
March 2021

Scoliosis Screening.

J Am Acad Orthop Surg 2021 May;29(9):370-379

From the Division of Orthopaedic Surgery and Sports Medicine, Children's National Hospital, Washington, DC (Oetgen, Kelly), and the Orthopaedic Surgery Department, George Washington University Hospital, Washington, DC (Heyer).

The national recommendations for school screening programs for scoliosis in the United States have undergone a shift in perspective over the past two decades. In 2004, the United States Preventive Services Task Force recommended against screening programs but changed its recommendation to be inconclusive in 2018. Early diagnosis of scoliosis can allow for close monitoring of the deformity and early initiation of bracing treatment when appropriate, with the goal of preventing costly and invasive surgical intervention. Several different diagnostic tools are available, including Adam's forward bending test alone, Adam's forward bending test with scoliometry, the humpometer, and Moiré topography, each with varying degrees of sensitivity and specificity. Controversy prevails over the cost efficacy of screening programs and possible unnecessary exposure of adolescents to radiation for confirmatory radiographs after a positive screening test. However, the recent definitive evidence of bracing treatment efficacy in slowing the progression of scoliotic curves and preventing the need for surgery indicates that school screening programs may still have a role in allowing early diagnosis.
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http://dx.doi.org/10.5435/JAAOS-D-20-00356DOI Listing
May 2021

Sex differences in dopamine release regulation in the striatum.

Neuropsychopharmacology 2021 02 14;46(3):491-499. Epub 2020 Dec 14.

Department of Pharmacology, Vanderbilt University, Nashville, TN, 37232, USA.

The mesolimbic dopamine system-which originates in the ventral tegmental area and projects to the striatum-has been shown to be involved in the expression of sex-specific behavior and is thought to be a critical mediator of many psychiatric diseases. While substantial work has focused on sex differences in the anatomy of dopamine neurons and relative dopamine levels between males and females, an important characteristic of dopamine release from axon terminals in the striatum is that it is rapidly modulated by local regulatory mechanisms independent of somatic activity. These processes can occur via homosynaptic mechanisms-such as presynaptic dopamine autoreceptors and dopamine transporters-as well as heterosynaptic mechanisms, such as retrograde signaling from postsynaptic cholinergic and GABAergic systems, among others. These regulators serve as potential targets for the expression of sex differences in dopamine regulation in both ovarian hormone-dependent and independent fashions. This review describes how sex differences in microcircuit regulatory mechanisms can alter dopamine dynamics between males and females. We then describe what is known about the hormonal mechanisms controlling/regulating these processes. Finally, we highlight the missing gaps in our knowledge of these systems in females. Together, a more comprehensive and mechanistic understanding of how sex differences in dopamine function manifest will be particularly important in developing evidence-based therapeutics that target this system and show efficacy in both sexes.
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http://dx.doi.org/10.1038/s41386-020-00915-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027008PMC
February 2021

How Ancestry Influences the Chances of Finding Unrelated Donors: An Investigation in Admixed Brazilians.

Front Immunol 2020 6;11:584950. Epub 2020 Nov 6.

Laboratory of Evolutionary Genetics, Institute of Biosciences, University of São Paulo, São Paulo, Brazil.

A match of HLA loci between patients and donors is critical for successful hematopoietic stem cell transplantation. However, the extreme polymorphism of HLA loci - an outcome of millions of years of natural selection - reduces the chances that two individuals will carry identical combinations of multilocus HLA genotypes. Further, HLA variability is not homogeneously distributed throughout the world: African populations on average have greater variability than non-Africans, reducing the chances that two unrelated African individuals are HLA identical. Here, we explore how self-identification (often equated with "ethnicity" or "race") and genetic ancestry are related to the chances of finding HLA compatible donors in a large sample from Brazil, a highly admixed country. We query REDOME, Brazil's Bone Marrow Registry, and investigate how different criteria for identifying ancestry influence the chances of finding a match. We find that individuals who self-identify as "Black" and "Mixed" on average have lower chances of finding matches than those who self-identify as "White" (up to 57% reduction). We next show that an individual's African genetic ancestry, estimated using molecular markers and quantified as the proportion of an individual's genome that traces its ancestry to Africa, is strongly associated with reduced chances of finding a match (up to 60% reduction). Finally, we document that the strongest reduction in chances of finding a match is associated with having an MHC region of exclusively African ancestry (up to 75% reduction). We apply our findings to a specific condition, for which there is a clinical indication for transplantation: sickle-cell disease. We show that the increased African ancestry in patients with this disease leads to reduced chances of finding a match, when compared to the remainder of the sample, without the condition. Our results underscore the influence of ancestry on chances of finding compatible HLA matches, and indicate that efforts guided to increasing the African component of registries are necessary.
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http://dx.doi.org/10.3389/fimmu.2020.584950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677137PMC
June 2021

Diversity of variant alleles encoding Kidd, Duffy, and Kell antigens in individuals with sickle cell disease using whole genome sequencing data from the NHLBI TOPMed Program.

Transfusion 2021 02 24;61(2):603-616. Epub 2020 Nov 24.

Institute of Tropical Medicine, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.

Background: Genetic variants in the SLC14A1, ACKR1, and KEL genes, which encode Kidd, Duffy, and Kell red blood cell antigens, respectively, may result in weakened expression of antigens or a null phenotype. These variants are of particular interest to individuals with sickle cell disease (SCD), who frequently undergo chronic transfusion therapy with antigen-matched units. The goal was to describe the diversity and the frequency of variants in SLC14A1, ACKR1, and KEL genes among individuals with SCD using whole genome sequencing (WGS) data.

Study Design And Methods: Two large SCD cohorts were studied: the Recipient Epidemiology and Donor Evaluation Study III (REDS-III) (n = 2634) and the Outcome Modifying Gene in SCD (OMG) (n = 640). Most of the studied individuals were of mixed origin. WGS was performed as part of the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine (TOPMed) program.

Results: In SLC14A1, variants included four encoding a weak Jk phenotype and five null alleles (JK ). JKA*01N.09 was the most common JK . One possible JK mutation was novel: c.812G>T. In ACKR1, identified variants included two that predicted Fy (FY*X) and one corresponding to the c.-67T>C GATA mutation. The c.-67T>C mutation was associated with FY*A (FY*01N.01) in four participants. FY*X was identified in 49 individuals. In KEL, identified variants included three null alleles (KEL*02N.17, KEL*02N.26, and KEL*02N.04) and one allele predicting K phenotype, all in heterozygosity.

Conclusions: We described the diversity and distribution of SLC14A1, ACKR1, and KEL variants in two large SCD cohorts, comprising mostly individuals of mixed ancestry. This information may be useful for planning the transfusion support of patients with SCD.
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http://dx.doi.org/10.1111/trf.16204DOI Listing
February 2021

Reduced Proactive Control Processes Associated With Behavioral Response Inhibition Deficits in Autism Spectrum Disorder.

Autism Res 2021 02 27;14(2):389-399. Epub 2020 Oct 27.

Clinical Child Psychology Program, University of Kansas, Lawrence, Kansas, USA.

Impairments in inhibitory control are common in individuals with autism spectrum disorder (ASD) and associated with multiple clinical issues. Proactive (i.e., delaying response onset) and reactive control mechanisms (i.e., stopping quickly) contribute to successful inhibitory control in typically developing individuals and may be compromised in ASD. We assessed inhibitory control in 58 individuals with ASD and 63 typically developing controls aged 5-29 years using an oculomotor stop-signal task during which participants made rapid eye movements (i.e., saccades) toward peripheral targets (i.e., GO trials) or inhibited saccades (i.e., STOP trials). Individuals with ASD exhibited reduced ability to inhibit saccades, reduced reaction time slowing (GO RT slowing), and faster stop-signal reaction times (SSRT) compared to controls. Across participants, stopping accuracy was positively related to GO RT slowing, and increased age was associated with higher stopping accuracy and GO RT slowing. Our results indicate that failures to proactively delay prepotent responses in ASD underpin deficits of inhibitory control and may contribute to difficulties modifying their behavior according to changes in contextual demands. These findings implicate frontostriatal brain networks in inhibitory control and core symptoms of ASD. LAY SUMMARY: Difficulties stopping actions are common in individuals with autism spectrum disorder (ASD) and are related to repetitive behaviors. This study compared the ability to stop eye movements in individuals with ASD and healthy peers. We found that individuals with ASD were less able to stop eye movements and that this difficulty was related to a reduced ability to delay their eye movements before seeing the cue to stop, not their ability to react quickly to this cue.
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http://dx.doi.org/10.1002/aur.2415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878417PMC
February 2021

Pharmacologic treatment of attention deficit hyperactivity disorder in adults: A systematic review and network meta-analysis.

PLoS One 2020 21;15(10):e0240584. Epub 2020 Oct 21.

Cardiovascular Research Methods Centre, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.

Background: Attention deficit hyperactivity disorder (ADHD) affects approximately 3% of adults globally. Many pharmacologic treatments options exist, yet the comparative benefits and harms of individual treatments are largely unknown. We performed a systematic review and network meta-analysis to assess the relative effects of individual pharmacologic treatments for adults with ADHD.

Methods: We searched English-language published and grey literature sources for randomized clinical trials (RCTs) involving pharmacologic treatment of ADHD in adults (December 2018). The primary outcome was clinical response; secondary outcomes were quality of life, executive function, driving behaviour, withdrawals due to adverse events, treatment discontinuation, serious adverse events, hospitalization, cardiovascular adverse events, and emergency department visits. Data were pooled via pair-wise meta-analyses and Bayesian network meta-analyses. Risk of bias was assessed by use of Cochrane's Risk of Bias tool, and the certainty of the evidence was assessed by use of the GRADE framework.

Results: Eighty-one unique trials that reported at least one outcome of interest were included, most of which were at high or unclear risk of at least one important source of bias. Notably, only 5 RCTs were deemed at overall low risk of bias. Included pharmacotherapies were methylphenidate, atomoxetine, dexamfetamine, lisdexamfetamine, guanfacine, bupropion, mixed amphetamine salts, and modafinil. As a class, ADHD pharmacotherapy improved patient- and clinician-reported clinical response compared with placebo (range: 4 to 15 RCTs per outcome); however, these findings were not conserved when the analyses were restricted to studies at low risk of bias, and the certainty of the finding is very low. There were few differences among individual medications, although atomoxetine was associated with improved patient-reported clinical response and quality of life compared with placebo. There was no significant difference in the risk of serious adverse events or treatment discontinuation between ADHD pharmacotherapies and placebo; however, the proportion of participants who withdrew due to adverse events was significantly higher among participants who received any ADHD pharmacotherapy. Few RCTs reported on the occurrence of adverse events over a long treatment duration.

Conclusions: Overall, despite a class effect of improving clinical response relative to placebo, there were few differences among the individual ADHD pharmacotherapies, and most studies were at risk of at least one important source of bias. Furthermore, the certainty of the evidence was very low to low for all outcomes, and there was limited reporting of long-term adverse events. As such, the choice between ADHD pharmacotherapies may depend on individual patient considerations, and future studies should assess the long-term effects of individual pharmacotherapies on patient-important outcomes, including quality of life, in robust blinded RCTs.

Registration: PROSPERO no. CRD 42015026049.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240584PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577505PMC
December 2020

The MDM2 inhibitor CGM097 combined with the BET inhibitor OTX015 induces cell death and inhibits tumor growth in models of neuroblastoma.

Cancer Med 2020 11 9;9(21):8144-8158. Epub 2020 Oct 9.

Pediatric Oncology Translational Research Program, Helen DeVos Children's Hospital, Grand Rapids, MI, USA.

Background: Neuroblastoma (NB) is the most common extracranial solid tumor in infants and children, with amplification of the oncogene MYCN being a hallmark of high-risk disease and poor prognosis. Although less frequent, overexpression of MYC is similarly an indicator of poor prognosis. Most NB tumors initially respond to chemotherapy, however, most will relapse, resulting in chemoresistant disease. After relapse, there is growing evidence of p53 inactivation. MYC/MYCN and MDM2 have been shown to interact and contribute to NB growth and disease progression. MDM2 inhibitors and Bromodomain and Extra-Terminal domain (BET) inhibitors have both shown promise in treating NB by increasing the expression of p53 and decreasing MYC/MYCN expression, respectively. Our study focuses on the combined treatment of a MDM2 inhibitor (CGM097) with a BET inhibitor (OTX015) in neuroblastoma.

Methods: Two p53 wild-type and two p53 mutant established neuroblastoma cells lines were used to test this combination. Ray design assays were used to test whether this combination was synergistically cytotoxic to NB cells. Western blots were performed to check signaling pathways of interest after drug treatment. IncuCyte imaging and flow cytometry were utilized to quantify the apoptotic and cytostatic effects of these drugs on NB cells. In vivo studies were carried out to test the antitumor effect of this combination in a living host.

Results: The combination of CGM097 and OTX015 resulted in p53 activation, decreased expression of MYC family proteins and a subsequent synergistic increase in NB cell death.

Conclusion: This study warrants further investigation into the combination of MDM2 inhibitors and BET inhibitors for the treatment in NB.
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http://dx.doi.org/10.1002/cam4.3407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643634PMC
November 2020

Implementation and expansion of a preoperative COVID-19 testing process for pediatric surgical patients.

Paediatr Anaesth 2020 08;30(8):952-953

Division of Anesthesiology, Pain and Perioperative Medicine, Children's National Hospital, The George Washington University, Washington, DC, USA.

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http://dx.doi.org/10.1111/pan.13963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537163PMC
August 2020
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