Publications by authors named "Jonathan M Davis"

120 Publications

The impact of antenatal cannabis use on the neonate: Time for open engagement?

Pediatr Res 2021 Jun 11. Epub 2021 Jun 11.

Department of Pediatrics, Tufts Children's Hospital, The Tufts Clinical and Translational Research Institute, Tufts University School of Medicine, Boston, MA, USA.

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http://dx.doi.org/10.1038/s41390-021-01591-7DOI Listing
June 2021

Escaping the Finnegan - Is it time?

Semin Fetal Neonatal Med 2021 Jun 25;26(3):101218. Epub 2021 Feb 25.

Division of Newborn Medicine, Tufts Children's Hospital, Boston, MA, 02111, USA; The Tufts Clinical and Translational Science Institute, Tufts University, Boston, MA, USA. Electronic address:

Neonatal Abstinence Syndrome (NAS) has significantly increased worldwide secondary to a marked increase in the incidence of opioid use disorders (OUD) in women of childbearing age. Since first described in 1975, the Finnegan Neonatal Abstinence Scoring Tool (FNAST) remains the mainstay of monitoring NAS severity and its clinical management. The complexity of the tool (21 independent variables), the need for external validation, excessive subjectivity, poor inter-rater reliability, and uncertainty regarding the clinical relevance of some items has resulted in the need to develop an alternate scoring tool. A validated, simple, clinically relevant, and universally accepted approach to assessing opioid exposed neonates would facilitate high quality clinical care while assisting in the generation of generalizable data from future research studies conducted in this vulnerable population.
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http://dx.doi.org/10.1016/j.siny.2021.101218DOI Listing
June 2021

Novel Variant Findings and Challenges Associated With the Clinical Integration of Genomic Testing: An Interim Report of the Genomic Medicine for Ill Neonates and Infants (GEMINI) Study.

JAMA Pediatr 2021 May 3;175(5):e205906. Epub 2021 May 3.

Department of Pediatrics, The Floating Hospital for Children at Tufts Medical Center, Boston, Massachusetts.

Importance: A targeted genomic sequencing platform focused on diseases presenting in the first year of life may minimize financial and ethical challenges associated with rapid whole-genomic sequencing.

Objective: To report interim variants and associated interpretations of an ongoing study comparing rapid whole-genomic sequencing with a novel targeted genomic platform composed of 1722 actionable genes targeting disorders presenting in infancy.

Design, Setting, And Participants: The Genomic Medicine in Ill Neonates and Infants (GEMINI) study is a prospective, multicenter clinical trial with projected enrollment of 400 patients. The study is being conducted at 6 US hospitals. Hospitalized infants younger than 1 year of age suspected of having a genetic disorder are eligible. Results of the first 113 patients enrolled are reported here. Patient recruitment began in July 2019, and the interim analysis of enrolled patients occurred from March to June 2020.

Interventions: Patient (proband) and parents (trios, when available) were tested simultaneously on both genomic platforms. Each laboratory performed its own phenotypically driven interpretation and was blinded to other results.

Main Outcomes And Measures: Variants were classified according to the American College of Medical Genetics and Genomics standards of pathogenic (P), likely pathogenic (LP), or variants of unknown significance (VUS). Chromosomal and structural variations were reported by rapid whole-genomic sequencing.

Results: Gestational age of 113 patients ranged from 23 to 40 weeks and postmenstrual age from 27 to 83 weeks. Sixty-seven patients (59%) were male. Diagnostic and/or VUS were returned for 51 patients (45%), while 62 (55%) had negative results. Results were concordant between platforms in 83 patients (73%). Thirty-seven patients (33%) were found to have a P/LP variant by 2 or both platforms and 14 (12%) had a VUS possibly related to phenotype. The median day of life at diagnosis was 22 days (range, 3-313 days). Significant alterations in clinical care occurred in 29 infants (78%) with a P/LP variant. Incidental findings were reported in 7 trios. Of 51 positive cases, 34 (67%) differed in the reported result because of technical limitations of the targeted platform, interpretation of the variant, filtering discrepancies, or multiple causes.

Conclusions And Relevance: As comprehensive genetic testing becomes more routine, these data highlight the critically important variant detection capabilities of existing genomic sequencing technologies and the significant limitations that must be better understood.
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http://dx.doi.org/10.1001/jamapediatrics.2020.5906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885094PMC
May 2021

Racial and ethnic disparities in adult COVID-19 and the future impact on child health.

Pediatr Res 2021 04 9;89(5):1052-1054. Epub 2021 Feb 9.

Department of Neonatology, Beth Israel Deaconess Medical Center, Boston, MA, USA.

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http://dx.doi.org/10.1038/s41390-021-01377-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871017PMC
April 2021

Definitions of neonatal abstinence syndrome in clinical studies of mothers and infants: an expert literature review.

J Perinatol 2021 Jun 29;41(6):1364-1371. Epub 2021 Jan 29.

Division of Newborn Medicine, Tufts Children's Hospital, Boston, MA, USA.

Neonatal abstinence syndrome (NAS) results from discontinuation of in utero exposures to opioids/substances. The rising incidence of NAS has prompted an increased need for accurate research and public health data. To examine how NAS has been defined in clinical studies of opioid-exposed mothers and infants, a review process was developed based on the RAND/UCLA Appropriateness Method, yielding 888 abstracts. Per inclusion criteria, 57 abstracts underwent full-text review. To define NAS, studies cited using modified versions of the Finnegan NAS scoring tool (n = 21; 37%), ICD-9/10 coding (n = 17; 30%), original Finnegan tool (n = 16; 28%), Eat Sleep Console (n = 3; 5%), and Lipsitz (n = 3; 5%) tools, (3 cited 2+ tools). Most studies utilized subjective NAS scoring/assessment algorithms and neonatal coding as key elements defining NAS. While most cited opioid exposure as integral to their inclusion criteria, 26% did not. These approaches highlight the need for a more refined and standardized definition of NAS.
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http://dx.doi.org/10.1038/s41372-020-00893-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225507PMC
June 2021

Effect of Pacifier Design on Nonnutritive Suck Maturation and Weight Gain in Preterm Infants: A Pilot Study.

Curr Ther Res Clin Exp 2020 17;93:100617. Epub 2020 Nov 17.

Department of Pediatrics, Tufts Children's Hospital, Boston, Massachusetts.

Background: Pacifiers are effective in promoting oral feeding by increasing the maturation of nonnutritive sucking to nutritive suck in preterm neonates. It is unclear whether pacifier design can influence suck dynamics and weight loss during the first week of life.

Objectives: This pilot study examined the feasibility of studying the effect of pacifier design on suck maturation and weight loss in preterm neonates.

Methods: Twenty-five preterm neonates (mean [SD] birth weight 1791 [344.9] grams, mean [SD] gestational age 33.1 [1.2] weeks) were studied in a single newborn intensive care unit. Neonates were assigned to either an orthodontic pacifier (n = 13) or a bulb-shaped pacifier (n = 12) immediately after birth. Suck dynamics (cycles per minute, total compressions per minute, cycle bursts, and amplitude) were assessed with an NTrainer (Innara Health, Olathe, Kansas). Weight was recorded during the first week of life on day 1.2 (±2.5 days) and day 6.0 (±2.1 days). Descriptive statistics were applied to analyze data.

Results: No significant differences were seen between groups with respect to birth weight and gestational age. Reproducible nonnutritive sucking measurements could be obtained with the NTrainer, with both types of pacifiers. No differences were detected in nonnutritive sucking dynamics or weight loss over time within each group or between groups.

Conclusions: Data indicate that it is feasible to measure nonnutritive sucking dynamics and associated weight loss in relation to pacifier design in preterm neonates. Larger trials over longer time periods are needed to determine whether pacifier design influences suck dynamics and maturation, oromotor function, feeding/weight loss, and dental formation in preterm neonates. ( 2020; 81:XXX-XXX).
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http://dx.doi.org/10.1016/j.curtheres.2020.100617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720017PMC
November 2020

Neonatal Abstinence Syndrome Severity Index Predicts 18-Month Neurodevelopmental Outcome in Neonates Randomized to Morphine or Methadone.

J Pediatr 2020 12 14;227:101-107.e1. Epub 2020 Aug 14.

Brown Center for the Study of Children at Risk and Women and Infants Hospital, Providence, RI; Department of Pediatrics, Warren Alpert Medical School of Brown University and Women and Infants Hospital, Providence, RI; Department of Psychiatry and Human Behavior, Warren Alpert Medical School of Brown University, Providence, RI. Electronic address:

Objective: To develop an index to determine which opioid-exposed neonates have the most severe neonatal abstinence syndrome (NAS).

Study Design: Full-term neonates with NAS (n = 116) from mothers maintained on methadone or buprenorphine were enrolled from 8 sites into a randomized clinical trial of morphine vs methadone. Ninety-nine (85%) were evaluated at hospital discharge using the NICU Network Neurobehavioral Scale (NNNS). At 18 months, 83 of 99 (83.8%) were evaluated with the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III), and 77 of 99 (77.7%) were evaluated with the Child Behavior Checklist (CBCL).

Results: Cluster analysis was used to define high (n = 21) and low (n = 77) NAS severity. Compared with infants in the low NAS severity cluster, infants in the high NAS severity cluster had a longer length of stay (P < .001), longer length of stay due to NAS (P < .001), longer duration of treatment due to NAS (P < .001), and higher total dose of the study drug (P < .001) and were more likely to have received phenobarbital (P < .001), to have been treated with morphine (P = .020), and to have an atypical NNNS profile (P = .005). The 2 groups did not differ in terms of maximum Finnegan score. At 18 months, in unadjusted analyses, compared with the high-severity cluster, the low-severity cluster had higher scores on the Bayley-III Cognitive (P = .013), Language (P < .001), and Motor (P = .041) composites and less total behavior problems on the CBCL (P = .028). In adjusted analyses, the difference in the Bayley-III Language composite remained (P = .013).

Conclusions: Presumptive measures of NAS severity can be aggregated to develop an index that predicts developmental outcomes at age 18 months.
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http://dx.doi.org/10.1016/j.jpeds.2020.08.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731918PMC
December 2020

Difficult to Diagnose: An Unusual Cause of Cavitary Lung Lesion.

Am J Case Rep 2020 May 25;21:e921274. Epub 2020 May 25.

Department of Pulmonary and Critical Care Medicine, University of Tennessee Health Science Center, Memphis, TN, USA.

BACKGROUND Cavitary lung lesions are commonly identified on thoracic imaging, but typically require further workup for definitive diagnosis. CASE REPORT Here, we present the case of a 40-year-old Middle Eastern male who presented with an unusual cause of cavitary lung lesion with associated pleural mass and pleural thickening. He underwent bronchoscopic biopsy and computer tomography (CT)-guided core needle biopsy, both of which were non-diagnostic. Surgical biopsy subsequently revealed hyalinized necrotizing granulomatous tissue, consistent with histoplasmosis, and the patient was treated with itraconazole, which he responded well to. CONCLUSIONS This case demonstrates the importance of identifying unusual causes of cavitary lung lesions and emphasizes the role of using proper tissue sampling for diagnosis.
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http://dx.doi.org/10.12659/AJCR.921274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274497PMC
May 2020

Key clinical research priorities for the pediatric community during the COVID-19 pandemic.

Pediatr Res 2021 03 15;89(4):730-732. Epub 2020 May 15.

Institute for Advanced Clinical Trials for Children, Rockville, MD, USA.

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http://dx.doi.org/10.1038/s41390-020-0962-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049863PMC
March 2021

Association of a Simplified Finnegan Neonatal Abstinence Scoring Tool With the Need for Pharmacologic Treatment for Neonatal Abstinence Syndrome.

JAMA Netw Open 2020 04 1;3(4):e202275. Epub 2020 Apr 1.

Tufts Clinical and Translational Science Institute, Boston, Massachusetts.

Importance: Observer-rated scales, such as the Finnegan Neonatal Abstinence Scoring Tool (FNAST), are used to quantify the severity of neonatal abstinence syndrome (NAS) and guide pharmacologic therapy. The FNAST, a comprehensive 21-item assessment tool, was developed for research and subsequently integrated into clinical practice; a simpler tool, designed to account for clinically meaningful outcomes, is urgently needed to standardize assessment.

Objectives: To identify FNAST items independently associated with the decision to use pharmacologic therapy and to simplify the FNAST while minimizing loss of information for the treatment decision.

Design, Setting, And Participants: This multisite cohort study included 424 neonates with opioid exposure who had a gestational age of at least 36 weeks with follow-up from birth to hospital discharge in the derivation cohort and 109 neonates with opioid exposure from the Maternal Opioid Treatment: Human Experimental Research Study in the validation cohort. Neonates in the derivation cohort were included in a medical record review at the Universities of Louisville and Kentucky or in a randomized clinical trial and observational study conducted at Tufts University (2014-2018); the Maternal Opioid Treatment: Human Experimental Research was conducted from 2005 to 2008. Data analysis was conducted from May 2017 to August 2019.

Exposures: Prenatal opioid exposure.

Main Outcomes And Measures: All FNAST items were dichotomized as present or not present, and logistic regression was used to identify binary items independently associated with pharmacologic treatment. The final model was validated with an independent cohort of neonates with opioid exposure.

Results: Among 424 neonates (gestational age, ≥36 weeks; 217 [51%] female infants), convulsions were not observed, and high-pitched cry and hyperactive Moro reflex had extremely different frequencies across cohorts. Therefore, these 3 FNAST items were removed from further analysis. The 2 tremor items were combined, and 8 of the remaining 17 items were independently associated with pharmacologic treatment, with an area under the curve of 0.86 (95% CI, 0.82-0.89) compared with 0.90 (95% CI, 0.87-0.94) for the 21-item FNAST. External validation of the 8 items resulted in an area under the curve of 0.86 (95% CI, 0.79-0.93). Thresholds of 4 and 5 on the simplified scale yielded the closest agreement with FNAST thresholds of 8 and 12 (weighted κ = 0.55; 95% CI, 0.48-0.61).

Conclusions And Relevance: The findings of this study suggest that 8 signs of NAS may be sufficient to assess whether a neonate meets criteria for pharmacologic therapy. A focus on these signs could simplify the FNAST tool and may enhance its clinical utility.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.2275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7142377PMC
April 2020

Neurodevelopmental Outcomes of Neonates Randomized to Morphine or Methadone for Treatment of Neonatal Abstinence Syndrome.

J Pediatr 2020 04 24;219:146-151.e1. Epub 2020 Jan 24.

Department of Pediatrics, Warren Alpert Medical School of Brown University and Women and Infants Hospital, Providence, RI; Brown Center for the Study of Children at Risk and Women and Infants Hospital, Providence, RI.

Objective: To evaluate the effects of pharmacologic treatment of neonatal abstinence syndrome on neurodevelopmental outcome from a randomized, controlled trial.

Study Design: Eight sites enrolled 116 full-term newborn infants with neonatal abstinence syndrome born to mothers maintained on methadone or buprenorphine into a randomized trial of morphine vs methadone. Ninety-nine infants (85%) were evaluated at hospital discharge using the NICU Network Neurobehavioral Scale. At 18 months, 83 of 99 infants (83.8%) were evaluated with the Bayley Scales of Infant and Toddler Development-Third Edition and 77 of 99 (77.7%) with the Child Behavior Checklist (CBCL).

Results: Primary analyses showed no significant differences between treatment groups on the NICU Network Neurobehavioral Scale, Bayley Scales of Infant and Toddler Development-Third Edition, or CBCL. However in post hoc analyses, we found differences by atypical NICU Network Neurobehavioral Scale profile on the CBCL. Infants receiving adjunctive phenobarbital had lower Bayley Scales of Infant and Toddler Development-Third Edition scores and more behavior problems on the CBCL. In adjusted analyses, internalizing and total behavior problems were associated with use of phenobarbital (P = .03; P = .04), maternal psychological distress (measured by the Brief Symptom Inventory) (both P < .01), and infant medical problems (both P = .02). Externalizing problems were associated with maternal psychological distress (P < .01) and continued maternal substance use (P < .01).

Conclusions: Infants treated with either morphine or methadone had similar short-term and longer term neurobehavioral outcomes. Neurodevelopmental outcome may be related to the need for phenobarbital, overall health of the infant, and postnatal caregiving environment.

Trial Registration: ClinicalTrials.gov: NCT01958476.
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http://dx.doi.org/10.1016/j.jpeds.2019.12.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7161698PMC
April 2020

How to introduce MSC-based therapy for the developing lung safely into clinical care?

Pediatr Res 2020 09 13;88(3):365-368. Epub 2020 Jan 13.

Department of Pediatrics, Division of Neonatology, Children's Hospital of Eastern Ontario (CHEO) and CHEO Research Institute, Sinclair Center for Regenerative Medicine, Ottawa Hospital Research Institute, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.

Extreme prematurity is associated with an increased risk to develop bronchopulmonary dysplasia (BPD). Severe BPD is associated with a significant long-term burden for the affected infant, families and society. Currently there are limited prevention and treatment options. Regenerative approaches using mesenchymal stromal cells (MSC) are associated with promising benefits in animal experiments. First clinical studies, using MSC in humans, suggest safety. To accelerate the process of bench to bed-side development of MSC-based therapies, a global and collaborative approach is needed that includes all key stakeholders. Results of a workshop that was held during the Pediatric Academic Societies meeting in 2019 are summarized. A roadmap is provided discussing next steps of bringing MSC-based interventions into clinical practice.
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http://dx.doi.org/10.1038/s41390-020-0758-0DOI Listing
September 2020

Preventing long-term respiratory morbidity in preterm neonates: is there a path forward?

Pediatr Res 2020 01 7;87(1):9-10. Epub 2019 Nov 7.

Department of Neonatology, Beth Israel Deaconess Medical Center, Department of Pediatrics, Harvard Medical School, Boston, MA, USA.

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http://dx.doi.org/10.1038/s41390-019-0641-zDOI Listing
January 2020

Assessment of long-term neurodevelopmental outcome following trials of medicinal products in newborn infants.

Pediatr Res 2019 11 9;86(5):567-572. Epub 2019 Aug 9.

Institute of Translational Medicine, University of Liverpool, Liverpool, UK.

There is significant uncertainty over the role of assessment of long-term neurodevelopmental outcome (LTO) in neonatal clinical trials. A multidisciplinary working group was established to identify key issues in this area and to make recommendations about optimal approaches to evaluate LTO in therapeutic trials in newborns, which can be developed by sponsors and investigators with other key stakeholders. A key consideration for neonatal trials is the potential for the investigational product to cause widespread effects and drives the need to assess outcome in multiple organs. Thus investigators must assess whether the product has an impact on the brain and the potential for it to cause potential effects on LTO. Critically, is assessment of LTO an important direct therapeutic target or a safety outcome? Such decisions and outcomes need to be specific to the product being studied and use published data, only considering expert opinion when prior evidence does not exist. In designing the trial, the balance of benefits, costs, and burdens of assessments to the researcher and families need to be considered. Families and parent advocates should be involved in design and execution of the study. A framework is presented for use by all key stakeholders to determine the need, nature, and duration of LTO assessments in regulatory trials involving newborn infants.
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http://dx.doi.org/10.1038/s41390-019-0526-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6848023PMC
November 2019

Cognitive and Behavioral Impact on Children Exposed to Opioids During Pregnancy.

Pediatrics 2019 08 18;144(2). Epub 2019 Jul 18.

College of Medicine, University of Kentucky, Lexington, Kentucky.

The developmental impact of opioid use during pregnancy is a subject of ongoing debate. Short-term neonatal outcomes, such as lower birth weight and neonatal abstinence syndrome, are the most well-recognized outcomes. However, knowledge gaps exist regarding longer-term neurocognitive and mental health outcomes. In this article, we summarize an expert panel discussion that was held in April 2018 by the Substance Abuse and Mental Health Services Administration and attended by national experts in the field of perinatal opioid exposure and its impact on child development. Despite the challenges with research in this area, there is emerging literature revealing an association between neonates exposed to opioids in utero and longer-term adverse neurocognitive, behavioral, and developmental outcomes. Although adverse sequalae may not be apparent in the neonatal period, they may become more salient as children develop and reach preschool and school age. Multiple variables (genetic, environmental, and biological) result in a highly complex picture. The next steps and strategies to support families impacted by opioid use disorder are explored. Model programs are also considered, including integrated care for the child and mother, parenting supports, and augmentations to home visiting.
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http://dx.doi.org/10.1542/peds.2019-0514DOI Listing
August 2019

Comparative effectiveness of opioid replacement agents for neonatal opioid withdrawal syndrome: a systematic review and meta-analysis.

J Perinatol 2019 11 17;39(11):1535-1545. Epub 2019 Jul 17.

Department of Anesthesiology, Columbia University Medical Center, New York, NY, USA.

Objective(s): To compare short-term treatment outcomes of opioid pharmacotherapy for neonatal opioid withdrawal syndrome (NOWS).

Study Design: PubMed/MEDLINE, Embase, PsycINFO, and The Cochrane Library were searched from inception through September 30, 2018. Primary outcome was treatment duration (LOT). Secondary outcomes included hospitalization duration (LOS) and rate of adjunct drug needed (RAD).

Results: Of 753 publications, 11 studies met inclusion criteria. There was no difference in LOT (WMD -1.39 [-5.79 to -3.01] days, I 82%) or LOS (WMD -1.48 [-5.75 to -2.79] days, I 92%) between morphine and methadone. RAD with morphine was higher (RR 1.51 [1.35-1.69], I 0%). Buprenorphine was associated with shorter LOT (WMD 7.70 [0.88-14.53] days, I 76%) and LOS (WMD 5.61 [-0.01 to -11.24] days, I 60%) compared with morphine, in addition to methadone according to two cohort studies.

Conclusions: Methadone had superior primary treatment success compared with morphine. Buprenorphine was associated with the shortest overall durations of treatment and hospitalization.
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http://dx.doi.org/10.1038/s41372-019-0437-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784556PMC
November 2019

Protecting Pregnant Women With Substance Use Disorders and Their Neonates Participating in Research.

JAMA 2019 Aug;322(7):609-610

Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

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http://dx.doi.org/10.1001/jama.2019.9002DOI Listing
August 2019

Necrotizing Enterocolitis: Using Regulatory Science and Drug Development to Improve Outcomes.

J Pediatr 2019 09 22;212:208-215.e1. Epub 2019 Jun 22.

Department of Pediatrics, The Floating Hospital for Children at Tufts Medical Center, Boston, MA; The Tufts Clinical and Translational Research Institute, Boston, MA.

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http://dx.doi.org/10.1016/j.jpeds.2019.05.032DOI Listing
September 2019

Cell-based therapies in neonates: the emerging role of regulatory science.

Pediatr Res 2019 08 26;86(2):145-146. Epub 2019 May 26.

Department of Neonatology, Beth Israel Deaconess Medical Center, Department of Pediatrics, Harvard Medical School, Boston, MA, USA.

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http://dx.doi.org/10.1038/s41390-019-0442-4DOI Listing
August 2019

Paired involvement of human-specific Olduvai domains and NOTCH2NL genes in human brain evolution.

Hum Genet 2019 Jul 13;138(7):715-721. Epub 2019 May 13.

Department of Biochemistry and Molecular Genetics, Human Medical Genetics and Genomics Program and Neuroscience Program, University of Colorado School of Medicine, Aurora, CO, 80045, USA.

Sequences encoding Olduvai (DUF1220) protein domains show the largest human-specific increase in copy number of any coding region in the genome and have been linked to human brain evolution. Most human-specific copies of Olduvai (119/165) are encoded by three NBPF genes that are adjacent to three human-specific NOTCH2NL genes that have been shown to promote cortical neurogenesis. Here, employing genomic, phylogenetic, and transcriptomic evidence, we show that these NOTCH2NL/NBPF gene pairs evolved jointly, as two-gene units, very recently in human evolution, and are likely co-regulated. Remarkably, while three NOTCH2NL paralogs were added, adjacent Olduvai sequences hyper-amplified, adding 119 human-specific copies. The data suggest that human-specific Olduvai domains and adjacent NOTCH2NL genes may function in a coordinated, complementary fashion to promote neurogenesis and human brain expansion in a dosage-related manner.
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http://dx.doi.org/10.1007/s00439-019-02018-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611739PMC
July 2019

The role of recombinant human CC10 in the prevention of chronic pulmonary insufficiency of prematurity.

Pediatr Res 2019 08 13;86(2):254-260. Epub 2019 May 13.

Department of Pediatric Newborn Medicine, Brigham and Women's Hospital, Boston, MA, USA.

Background: Preterm neonates can develop chronic pulmonary insufficiency of prematurity (CPIP) later in infancy. Recombinant human CC10 protein (rhCC10) is an anti-inflammatory agent that could potentially prevent CPIP.

Methods: The safety and efficacy of a single intratracheal dose of rhCC10 in reducing CPIP at 12 months corrected gestational age (CGA) was evaluated in a Phase II double-blind, randomized, placebo-controlled, multisite clinical trial. Eighty-eight neonates were randomized: 22 to placebo and 22 to 1.5 mg/kg rhCC10 in the first cohort and 21 to placebo and 23 to 5 mg/kg rhCC10 in the second cohort. Neonates were followed to 12 months CGA.

Results: With CPIP defined as signs/symptoms, medical visits, hospital readmissions, and use of medications for respiratory complications at 12 months CGA, no significant differences were observed between rhCC10 or placebo groups. Only 5% of neonates had no evidence of CPIP at 12 months CGA.

Conclusions: A single dose of rhCC10 was not effective in reducing CPIP at 12 CGA. Since most neonates had evidence of CPIP using these exploratory endpoints, it is essential to develop more robust outcome measures for clinical trials of respiratory medications in high-risk premature neonates.
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http://dx.doi.org/10.1038/s41390-019-0419-3DOI Listing
August 2019

Current Understanding of Medication Use in Pregnancy/Lactation and Neonates: What Are the Key Knowledge Gaps?

Clin Perinatol 2019 06 1;46(2):xvii-xviii. Epub 2019 Apr 1.

Tufts University School of Medicine, Department of Obstetrics & Gynecology, Tufts Medical Center, 800 Washington Street, Boston, MA 02111, USA. Electronic address:

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http://dx.doi.org/10.1016/j.clp.2019.03.001DOI Listing
June 2019

Impact of Regulatory Incentive Programs on the Future of Pediatric Drug Development.

Ther Innov Regul Sci 2019 09 14;53(5):609-614. Epub 2019 Apr 14.

3 The Tufts Center for the Study of Drug Development, Boston, MA, USA.

Surveys evaluating industry experience with performing pediatric studies under the Best Pharmaceutical for Children Act (BPCA) and Pediatric Research Equity Act (PREA) regulatory regime were conducted by Tufts Center for the Study of Drug Development (Tufts CSDD) in 2000, 2006, and 2016. These survey results are being used to assess the future impact of regulatory incentive programs on generating pediatric specific labeling information and development of age-appropriate drug formulations. A second perspective will be provided through the experience and expertise of neonatal/pediatric clinicians and researchers with a focus on the urgent need for the study of new and existing drugs in this vulnerable population (especially with 90% of drugs in neonates still being used off-label). This group will also address the impact of existing regulations and the likely trajectory of future pediatric drug development efforts after nearly 2 decades of regulatory incentives (both mandatory and voluntary). Finally, this review will provide input on approaches that are needed to continue to advance pediatric drug development with an emphasis on rare diseases.
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http://dx.doi.org/10.1177/2168479019837522DOI Listing
September 2019

A Third Linear Association Between Olduvai (DUF1220) Copy Number and Severity of the Classic Symptoms of Inherited Autism.

Am J Psychiatry 2019 08 15;176(8):643-650. Epub 2019 Feb 15.

The Department of Biochemistry and Molecular Genetics, Human Medical Genetics and Genomics Program and Neuroscience Program, University of Colorado School of Medicine, Aurora (Davis, Heft, Sikela); the McLaughlin Centre and the Department of Molecular Genetics, University of Toronto, and the Centre for Applied Genomics and Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto (Scherer).

Objective: The authors previously reported that the copy number of sequences encoding an Olduvai protein domain subtype (CON1) shows a linear association with the severity of social deficits and communication impairment in individuals with autism. In this study, using an improved measurement method, the authors replicated this association in an independent population.

Method: The authors obtained whole genome sequence (WGS) data and phenotype data on 215 individuals from the Autism Speaks MSSNG project. They derived copy number from WGS data using a modified sequence read-depth technique. A linear mixed-effects model was used to test the association between Olduvai CON1 copy number and symptom severity as measured by the Autism Diagnostic Interview-Revised. The authors then combined data from previous studies (N=524) for final analyses.

Results: A significant linear association was observed between CON1 copy number and social diagnostic score (SDS) (β=0.24) and communicative diagnostic score (CDS) (β=0.23). Using the combined data, the authors present strong significant associations of CON1 dosage with SDS (β=0.18) and CDS (β=0.13). The authors also implicate Olduvai subtypes found in two genes, and (R=6.2%). Associations were preferentially found in multiplex versus simplex families.

Conclusions: The finding of a third dose-dependent association between Olduvai sequences and autism severity, preferentially in multiplex families, provides strong evidence that this highly duplicated and underexamined protein domain family plays an important role in inherited autism.
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http://dx.doi.org/10.1176/appi.ajp.2018.18080993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6675654PMC
August 2019

The contributions of genetics to premature birth.

Pediatr Res 2019 03 15;85(4):416-417. Epub 2019 Jan 15.

Department of Pediatrics and the Clinical and Translational Science Institute, Tufts University School of Medicine, Boston, MA, USA.

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http://dx.doi.org/10.1038/s41390-019-0292-0DOI Listing
March 2019

Recommendations for the design of therapeutic trials for neonatal seizures.

Pediatr Res 2019 06 24;85(7):943-954. Epub 2018 Dec 24.

The Floating Hospital for Children at Tufts Medical Center and the Tufts Clinical and Translational Science Institute, Boston, MA, USA.

Although seizures have a higher incidence in neonates than any other age group and are associated with significant mortality and neurodevelopmental disability, treatment is largely guided by physician preference and tradition, due to a lack of data from well-designed clinical trials. There is increasing interest in conducting trials of novel drugs to treat neonatal seizures, but the unique characteristics of this disorder and patient population require special consideration with regard to trial design. The Critical Path Institute formed a global working group of experts and key stakeholders from academia, the pharmaceutical industry, regulatory agencies, neonatal nurse associations, and patient advocacy groups to develop consensus recommendations for design of clinical trials to treat neonatal seizures. The broad expertise and perspectives of this group were invaluable in developing recommendations addressing: (1) use of neonate-specific adaptive trial designs, (2) inclusion/exclusion criteria, (3) stratification and randomization, (4) statistical analysis, (5) safety monitoring, and (6) definitions of important outcomes. The guidelines are based on available literature and expert consensus, pharmacokinetic analyses, ethical considerations, and parental concerns. These recommendations will ultimately facilitate development of a Master Protocol and design of efficient and successful drug trials to improve the treatment and outcome for this highly vulnerable population.
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http://dx.doi.org/10.1038/s41390-018-0242-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760680PMC
June 2019

Development of a Retinopathy of Prematurity Activity Scale and Clinical Outcome Measures for Use in Clinical Trials.

JAMA Ophthalmol 2019 03;137(3):305-311

The Floating Hospital for Children, Tufts Medical Center, Boston, Massachusetts.

Importance: To facilitate drug and device development for neonates, the International Neonatal Consortium brings together key stakeholders, including pharmaceutical companies, practitioners, regulators, funding agencies, scientists, and families, to address the need for objective, standardized clinical trial outcome measurements to fulfill regulatory requirements. Retinopathy of prematurity (ROP) is a disease that affects preterm neonates. The current International Classification of Retinopathy of Prematurity does not take into account all of the characteristics of ROP and does not adequately discriminate small changes in disease after treatment. These factors are critical for evaluating outcomes in clinical trials.

Observations: There is need for an updated ROP acute disease activity and structure scale as well as end-stage structure and ophthalmologic outcome measures designed for use at different ages. The scale and measures, based on current diagnostic methods and treatments, could be used as a guideline for clinical intervention trials. The scale is intended to be validated against retrospective data and revised for use in future trials. An iterative revision process can be accomplished if new measures are added to clinical trials and evaluated at the end of each trial for prognostic value. The new measures would then be incorporated into a new version of the activity scale and the outcome measures revised.

Conclusions And Relevance: An ROP activity scale and outcome measures to obtain the most robust and discriminatory data for clinical trials are needed. The scales should be dynamic and modified as knowledge and imaging modalities improve and then validated using data from well-documented clinical trials. This approach is relevant to improving clinical trial data quality.
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http://dx.doi.org/10.1001/jamaophthalmol.2018.5984DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6565513PMC
March 2019

Pharmacologic treatment of infants with neonatal abstinence syndrome in community hospitals compared to academic medical centers.

J Perinatol 2018 12 20;38(12):1651-1656. Epub 2018 Sep 20.

Division of Newborn Medicine, Tufts Medical Center, Boston, MA, USA.

Objective: To compare length of hospital stay (LOS), LOS due to neonatal abstinence syndrome (NAS), and duration of pharmacologic treatment in community or academic settings.

Study Design: One hundred-two infants exposed to opioids in utero at two community hospitals were compared to 256 from eight academic centers. All infants were managed with non-pharmacologic care followed by similar pharmacologic treatment options.

Results: Two hundred-twelve infants received pharmacologic treatment for NAS. Mean LOS (24.7 ± 8.5 vs. 24.5 ± 11.3 days), LOS due to NAS (24.0 ± 8.2 vs. 23.3 ± 9.2 days), and duration of NAS treatment (19.3 ± 8.0 vs. 18.9 ± 9.2 days) were similar in community compared to academic medical centers.

Conclusions: No significant differences were found in infants managed in the community compared to academic care settings. These findings support caring for opioid-exposed infants in both community and academic settings with the use of standardized care protocols.
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http://dx.doi.org/10.1038/s41372-018-0230-8DOI Listing
December 2018
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