Publications by authors named "Joan Smith"

89 Publications

Co-Therapy of Pegylated G-CSF and Ghrelin for Enhancing Survival After Exposure to Lethal Radiation.

Front Pharmacol 2021 2;12:628018. Epub 2021 Feb 2.

Radiation Combined Injury Program, Armed Forces Radiobiology Research Institute, Bethesda, MD, United States.

Exposure to ionizing radiation (radiation injury, RI) in nuclear-related episode is evident to be life-threatening. RI occurs at levels of organs, tissues, cytosols, or nucleus. Their mechanisms are still not fully understood. FDA approves pegylated granulocyte colony-stimulating factor (Neulasta™, Peg-G-CSF) for acute hematopoietic syndrome and has been shown to save lives after lethal RI. We aimed to test whether Ghrelin enhanced Peg-G-CSF's efficacy to save more lives after lethal RI. B6D2F1/J female mice were used for the study. They received 9.5 Gy (LD50/30 at 0.4 Gy/min) emitted from the Co-γ-photon radiation facility. Peg-G-CSF was injected subcutaneously at 1 mg/kg once on days 1, 8, and 15 after irradiation. Ghrelin contains 28 amino acid and is a hunger peptide that has been shown to stimulate food intake, promote intestinal epithelial cell proliferation, elevates immunity, inhibits brain hemorrhage, and increases stress-coping. Ghrelin was injected subcutaneously at 113 μg/kg once on days 1, 2, and 3 after irradiation. Survival, body weight, water consumption, hematology, spleen weight, splenocytes, bone marrow cells, and histology of bone marrow and ileum were performed. We observed that radiation resulted in 30-days survival by 30%. RI decreased their body weights and water consumption volumes. On the 30th day post-RI, platelets and WBCs such as basophils, eosinophils, monocytes, lymphocytes, neutrophils and leukocytes were still significantly decreased in surviving mice. Likewise, their RBC, hemoglobin, hematocrit, and splenocytes remained low; splenomegaly was found in these mice. Bone marrow in surviving RI animals maintained low cellularity with high counts of fat cells and low counts of megakaryocytes. Meanwhile, ileum histology displayed injury. However, mice co-treated with both drugs 24 h after RI resulted in 30-days survival by 45% above the vehicle group. Additionally, the body-weight loss was mitigated, the acute radiation syndrome was reduced. This co-therapy significantly increased neutrophils, eosinophils, leukocytes, and platelets in circulation, inhibited splenomegaly, and increased bone marrow cells. Histopathological analysis showed significant improvement on bone marrow cellularity and ileum morphology. In conclusion, the results provide a proof of concept and suggest that the co-therapy of Peg-G-CSF and Ghrelin is efficacious to ameliorate RI.
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http://dx.doi.org/10.3389/fphar.2021.628018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884820PMC
February 2021

Neonatal feeding performance is related to feeding outcomes in childhood.

Early Hum Dev 2020 12 10;151:105202. Epub 2020 Oct 10.

Program in Occupational Therapy, Washington University School of Medicine, St. Louis, MO, USA; University of Southern California, Chan Division of Occupational Science and Occupational Therapy, Los Angeles, CA, USA; Keck School of Medicine, Department of Pediatrics, Los Angeles, CA, USA. Electronic address:

Aim: Define relationships of early feeding performance with feeding outcomes in childhood, while assessing the predictive validity of the Neonatal Eating Outcome Assessment.

Study Design: Ninety-one infants (44 preterm infants born ≤32 weeks at term-equivalent age and 47 full-term infants within 4 days of life) had feeding evaluated using the Neonatal Eating Outcome Assessment and the Neonatal Oral Motor Assessment Scale (NOMAS). At 4 years of age, 39 of these infants (22 preterm infants and 17 full-term infants; 43% follow-up rate) had parent-report measures of feeding conducted using the Behavioral Pediatrics Feeding Assessment Scale (BPFAS) and Pediatric Eating Assessment Tool (PediEAT).

Results: Lower Neonatal Eating Outcome Assessment scores were related to higher PediEAT scores (p = 0.01; r = -0.44), but were not related to BPFAS scores (p = 0.17; r = -0.23). Relationships were not detected between the NOMAS and BPFAS (p = 0.35; r = 0.17), and relationships between the NOMAS and PediEAT failed to reach significance (p = 0.06; r = 0.34). There was a relationship between the BPFAS and PediEAT scores at 4 years (p < 0.001; r = 0.66). Preterm infants performed poorer than full-term infants on the Neonatal Eating Outcome Assessment (p < 0.001) and NOMAS (p < 0.001), but no differences were detected in preterm compared to full-term performance on the BPFAS (p = 0.87) and PediEAT scores (p = 0.27).

Discussion: Neonatal feeding performance is an important predictor of feeding outcomes at 4 years of age. The Neonatal Eating Outcome Assessment has predictive validity, and the Pediatric Eating Assessment Tool has concurrent validity with relationships to another childhood feeding tool.
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http://dx.doi.org/10.1016/j.earlhumdev.2020.105202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732130PMC
December 2020

Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity.

bioRxiv 2020 Aug 5. Epub 2020 Aug 5.

Antiviral therapy is urgently needed to combat the coronavirus disease 2019 (COVID-19) pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The protease inhibitor camostat mesylate inhibits SARS-CoV-2 infection of lung cells by blocking the virus-activating host cell protease TMPRSS2. Camostat mesylate has been approved for treatment of pancreatitis in Japan and is currently being repurposed for COVID-19 treatment. However, potential mechanisms of viral resistance as well as camostat mesylate metabolization and antiviral activity of metabolites are unclear. Here, we show that SARS-CoV-2 can employ TMPRSS2-related host cell proteases for activation and that several of them are expressed in viral target cells. However, entry mediated by these proteases was blocked by camostat mesylate. The camostat metabolite GBPA inhibited the activity of recombinant TMPRSS2 with reduced efficiency as compared to camostat mesylate and was rapidly generated in the presence of serum. Importantly, the infection experiments in which camostat mesylate was identified as a SARS-CoV-2 inhibitor involved preincubation of target cells with camostat mesylate in the presence of serum for 2 h and thus allowed conversion of camostat mesylate into GBPA. Indeed, when the antiviral activities of GBPA and camostat mesylate were compared in this setting, no major differences were identified. Our results indicate that use of TMPRSS2-related proteases for entry into target cells will not render SARS-CoV-2 camostat mesylate resistant. Moreover, the present and previous findings suggest that the peak concentrations of GBPA established after the clinically approved camostat mesylate dose (600 mg/day) will result in antiviral activity.
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http://dx.doi.org/10.1101/2020.08.05.237651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418737PMC
August 2020

The Baby Bridge program: A sustainable program that can improve therapy service delivery for preterm infants following NICU discharge.

PLoS One 2020 29;15(5):e0233411. Epub 2020 May 29.

Center for Health Economics and Policy, Institute for Public Health, Brown School, Washington University, St Louis, Missouri, United States of America.

Objective: The aim of this project was to determine revenues and costs over time to assess the sustainability of the Baby Bridge program.

Methods: The Baby Bridge program was developed to promote timely, consistent and high quality early therapy services for high-risk infants following neonatal intensive care unit (NICU) discharge. Key features of the Baby Bridge program were defined as: 1) having the therapist establish rapport with the family while in the NICU, 2) scheduling the first home visit within one week of discharge and continuing weekly visits until other services commence, 3) conducting comprehensive assessments to inform targeted interventions by a skilled, single provider, and 4) using a comprehensive therapeutic approach while collaborating with the NICU medical team and community therapy providers. The Baby Bridge program was implemented with infants hospitalized in an urban Level IV NICU from January 2016 to January 2018. The number of infants enrolled increased gradually over the first several months to reach the case-load capacity associated with one full-time therapist by mid-2017. Costs of the therapists delivering Baby Bridge services, travel, and equipment were tracked and compared with claim records of participants. The operational cost of Baby Bridge programming at capacity was estimated based on the completed and anticipated claims and reimbursement of therapy services as a means to inform possible scale-ups of the program.

Results: In 2016, the first year of programming, the Baby Bridge program experienced a loss of $26,460, with revenue to the program totaling $11,138 and expenses totaling $37,598. In 2017, the Baby Bridge program experienced a net positive income of $2,969, with revenues to the program totaling $53,989 and expenses totaling $51,020. By Spring 2017, 16 months after initiating Baby Bridge programming, program revenue began to exceed cost. It is projected that cumulative revenue would have exceeded cumulative costs by January 2019, 3 years following implementation. Net annual program income, once scaled up to capacity, would be approximately $16,308.

Discussion: There were initial losses during phase-in of Baby Bridge programming associated with operating far below capacity, yet the program achieved sustainability within 16 months of implementation. These costs related to implementation do not consider the potential cost reduction due to mitigated health burden for the community and families, particularly due to earlier receipt of therapy services, which is an important area for further inquiry.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0233411PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7259591PMC
August 2020

Ghrelin, a novel therapy, corrects cytokine and NF-κB-AKT-MAPK network and mitigates intestinal injury induced by combined radiation and skin-wound trauma.

Cell Biosci 2020 12;10:63. Epub 2020 May 12.

1Scientific Research Department, Armed Forces Radiobiology Research Institute, Bethesda, MD 20814 USA.

Background: Compared to radiation injury alone (RI), radiation injury combined wound (CI) further enhances acute radiation syndrome and subsequently mortality. We previously reported that therapy with Ghrelin, the 28-amino-acid-peptide secreted from the stomach, significantly increased 30-day survival and mitigated hematopoietic death by enhancing and sustaining granulocyte-colony stimulating factor (G-CSF) and keratinocyte chemoattractant (KC) in the blood and bone marrow; increasing circulating white blood cell depletion; inhibiting splenocytopenia; and accelerating skin-wound healing on day 30 after CI. Herein, we aimed to study the efficacy of Ghrelin on intestinal injury at early time points after CI.

Methods: B6D2F1/J female mice were exposed to Co-γ-photon radiation (9.5 Gy, 0.4 Gy/min, bilateral), followed by 15% total-body-surface-area skin wounds. Several endpoints were measured: at 4-5 h and on days 1, 3, 7, and 15.

Results: Ghrelin therapy mitigated CI-induced increases in IL-1β, IL-6, IL-17A, IL-18, KC, and TNF-α in serum but sustained G-CSF, KC and MIP-1α increases in ileum. Histological analysis of ileum on day 15 showed that Ghrelin treatment mitigated ileum injury by increasing villus height, crypt depth and counts, as well as decreasing villus width and mucosal injury score. Ghrelin therapy increased AKT activation and ERK activation; suppressed JNK activation and caspase-3 activation in ileum; and reduced NF-κB, iNOS, BAX and Bcl-2 in ileum. This therapy recovered the tight junction protein and mitigated bacterial translocation and lipopolysaccharides levels. The results suggest that the capacity of Ghrelin therapy to reduce CI-induced ileum injury is mediated by a balanced NF-κB-AKT-MAPK network that leads to homeostasis of pro-inflammatory and anti-inflammatory cytokines.

Conclusions: Our novel results are the first to suggest that Ghrelin therapy effectively decreases intestinal injury after CI.
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http://dx.doi.org/10.1186/s13578-020-00425-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216502PMC
May 2020

Cigarette Smoke Exposure and Inflammatory Signaling Increase the Expression of the SARS-CoV-2 Receptor ACE2 in the Respiratory Tract.

Dev Cell 2020 06 16;53(5):514-529.e3. Epub 2020 May 16.

Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. Electronic address:

The factors mediating fatal SARS-CoV-2 infections are poorly understood. Here, we show that cigarette smoke causes a dose-dependent upregulation of angiotensin converting enzyme 2 (ACE2), the SARS-CoV-2 receptor, in rodent and human lungs. Using single-cell sequencing data, we demonstrate that ACE2 is expressed in a subset of secretory cells in the respiratory tract. Chronic smoke exposure triggers the expansion of this cell population and a concomitant increase in ACE2 expression. In contrast, quitting smoking decreases the abundance of these secretory cells and reduces ACE2 levels. Finally, we demonstrate that ACE2 expression is responsive to inflammatory signaling and can be upregulated by viral infections or interferon treatment. Taken together, these results may partially explain why smokers are particularly susceptible to severe SARS-CoV-2 infections. Furthermore, our work identifies ACE2 as an interferon-stimulated gene in lung cells, suggesting that SARS-CoV-2 infections could create positive feedback loops that increase ACE2 levels and facilitate viral dissemination.
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http://dx.doi.org/10.1016/j.devcel.2020.05.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229915PMC
June 2020

STEPP IN: Working Together to Keep Infants Warm in the Perioperative Period.

Pediatrics 2020 04 19;145(4). Epub 2020 Mar 19.

Department of Pediatrics, Children's Mercy Kansas City, Kansas City, Missouri.

Objectives: Reduce postoperative hypothermia by up to 50% over a 12-month period in children's hospital NICUs and identify specific clinical practices that impact success.

Methods: Literature review, expert opinion, and benchmarking were used to develop clinical practice recommendations for maintaining perioperative euthermia that included the following: established euthermia before transport to the operating room (OR), standardized practice for maintaining euthermia on transport to and from the OR, and standardized practice to prevent intraoperative heat loss. Process measures were focused on maintaining euthermia during these time points. The outcome measure was the proportion of patients with postoperative hypothermia (temperature ≤36°C within 30 minutes of a return to the NICU or at the completion of a procedure in the NICU). Balancing measures were the proportion of patients with postoperative temperature >38°C or the presence of thermal burns. Multivariable logistic regression was used to identify key practices that improved outcome.

Results: Postoperative hypothermia decreased by 48%, from a baseline of 20.3% (January 2011 to September 2013) to 10.5% by June 2015. Strategies associated with decreased hypothermia include >90% compliance with patient euthermia (36.1-37.9°C) at times of OR arrival (odds ratio: 0.58; 95% confidence interval [CI]: 0.43-0.79; < .001) and OR departure (odds ratio: 0.0.73; 95% CI: 0.56-0.95; = .017) and prewarming the OR ambient temperature to >74°F (odds ratio: 0.78; 95% CI: 0.62-0.999; = .05). Hyperthermia increased from a baseline of 1.1% to 2.2% during the project. No thermal burns were reported.

Conclusions: Reducing postoperative hypothermia is possible. Key practices include prewarming the OR and compliance with strategies to maintain euthermia at select time points throughout the perioperative period.
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http://dx.doi.org/10.1542/peds.2019-1121DOI Listing
April 2020

A pilot study demonstrating the impact of the supporting and enhancing NICU sensory experiences (SENSE) program on the mother and infant.

Early Hum Dev 2020 05 6;144:105000. Epub 2020 Mar 6.

St. Louis Children's Hospital, Department of Quality, Safety, and Practice Excellence, St Louis, MO, United States of America.

Aim: To explore differences in maternal mental health and infant neurobehavioral outcome among infants who received and did not receive the Supporting and Enhancing NICU Sensory Experiences (SENSE) program.

Study Design: Eighty preterm infants (50 receiving standard-of-care and 30 receiving the SENSE program) born ≤32 weeks gestation were enrolled within the first week of life in a prospective quasi-experimental design, using a historical control group for comparison. Standard-of-care consisted of tactile (skin-to-skin, touch, holding) and olfactory (scent cloth, close maternal contact) interventions as determined to be appropriate by health care professionals and parents. The SENSE group received specific doses of tactile (skin-to-skin care, holding, massage, touch), auditory (human speech, music), olfactory (scent cloth, close maternal contact), kinesthetic/vestibular (movement, rocking/transfers), and visual (dim or cycled light) exposures, based on the infant's postmenstrual age and tailored to medical status and infant cues according to the SENSE program. The SENSE program includes the intentional delivery of positive, age-appropriate sensory exposures by parents (or a sensory support team, when parents are unavailable) each day of NICU hospitalization. Infant neurobehavioral outcome, as well as maternal mental health and confidence, were assessed prior to NICU discharge, using standardized measures.

Results: Seventy-three infants were included in the final analysis. Mothers whose infants received the SENSE program demonstrated higher scores on the Maternal Confidence Questionnaire (p = 0.01). Infants who received the SENSE program demonstrated less asymmetry on the NICU Network Neurobehavioral Scale (p = 0.02; mean difference 0.9) and higher scores on the Hammersmith Neonatal Neurological Evaluation (p < 0.001; mean difference 4.8).

Discussion: Preliminary evidence demonstrates improvements in maternal confidence and infant neurobehavioral performance following SENSE implementation.
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http://dx.doi.org/10.1016/j.earlhumdev.2020.105000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282956PMC
May 2020

Single-Chromosomal Gains Can Function as Metastasis Suppressors and Promoters in Colon Cancer.

Dev Cell 2020 02;52(4):413-428.e6

Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. Electronic address:

High levels of cancer aneuploidy are frequently associated with poor prognosis. To examine the relationship between aneuploidy and cancer progression, we analyzed a series of congenic cell lines that harbor single extra chromosomes. We found that across 13 different trisomic cell lines, 12 trisomies suppressed invasiveness or were largely neutral, while a single trisomy increased metastatic behavior by triggering a partial epithelial-mesenchymal transition. In contrast, we discovered that chromosomal instability activates cGAS/STING signaling but strongly suppresses invasiveness. By analyzing patient copy-number data, we demonstrate that specific aneuploidies are associated with distinct outcomes, and the acquisition of certain aneuploidies is in fact linked with a favorable prognosis. Thus, aneuploidy is not a uniform driver of malignancy, and different aneuploidies can uniquely influence tumor progression. At the same time, the gain of a single chromosome is capable of inducing a profound cell state transition, thereby linking genomic plasticity, phenotypic plasticity, and metastasis.
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http://dx.doi.org/10.1016/j.devcel.2020.01.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354079PMC
February 2020

Preterm infant feeding performance at term equivalent age differs from that of full-term infants.

J Perinatol 2020 04 17;40(4):646-654. Epub 2020 Feb 17.

Department of Quality, Safety, and Practice Excellence, Saint Louis Children's Hospital, St. Louis, MO, USA.

Objective: To identify differences in feeding skill performance among preterm infants at term equivalent age compared with full-term infants.

Study Design: Ninety-two infants (44 preterm infants born ≤32 weeks gestation at term equivalent age and 48 full-term infants within 4 days of birth) had a standardized oral feeding assessment.

Result: Preterm infants at term equivalent age had lower Neonatal Eating Outcome Assessment scores (67.8 ± 13.6 compared with 82.2 ± 8.1; p < 0.001) and were more likely to have poor arousal (p = 0.04), poor tongue positioning (p = 0.04), suck-swallow-breathe discoordination (p < 0.001), inadequate sucking bursts (p = 0.01), tonal abnormalities (p < 0.001), discoordination of the jaw and tongue during sucking (p < 0.001), lack of positive engagement with the feeder and/or discomfort (p < 0.001), signs of aspiration (p < 0.001), difficulty regulating breathing (p < 0.001), and have an inability to maintain an appropriate state (p < 0.001), and complete the feeding (<0.001).

Conclusion: A broad range of feeding-related difficulties appear to remain evident in preterm infants at term equivalent age.
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http://dx.doi.org/10.1038/s41372-020-0616-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7117861PMC
April 2020

Auditory exposure of high-risk infants discharged from the NICU and the impact of social factors.

Acta Paediatr 2020 10 10;109(10):2049-2056. Epub 2020 Mar 10.

Washington University Program in Occupational Therapy, St. Louis, Missouri.

Aim: To (a) define the early home auditory environment of high-risk infants within one month of neonatal intensive care unit (NICU) discharge, (b) compare auditory exposures in the home environment to the NICU environment,  and (c) define relationships between maternal/infant factors and auditory exposures within the home.

Methods: Seventy-three high-risk infants (48 high-risk infants in the NICU at term-equivalent age and 25 high-risk infants in the home following NICU discharge) had auditory exposures measured.

Results: An average of 1.3 hours more noise (P ≤ .001) and 2 hours less silence (P = .01) were observed in the NICU compared with the home, but differences varied based on whether comparing to an open ward or private room. Infants with public insurance, lower household income and mothers without a college education were exposed to an average of 2.8, 3.0 and 2.3 hours more TV/electronic sounds respectively (P < .05). An average of 1744 fewer adult words (P = .03) were spoken in households with public insurance. There was an average of 3.1 hours less silence and 4.5 dB louder stimuli among households with lower income (P < .05).

Conclusion: Elucidating differences across environments can lead to interventions to foster appropriate auditory exposures to improve language development of high-risk infants.
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http://dx.doi.org/10.1111/apa.15209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398846PMC
October 2020

Maternal Milk and Relationships to Early Neurobehavioral Outcome in Preterm Infants.

J Perinat Neonatal Nurs 2020 Jan/Mar;34(1):72-79

Program in Occupational Therapy (Dr Pineda and Ms Muñoz) and Department of Pediatrics (Dr Pineda), Washington University School of Medicine, Saint Louis, Missouri; Spotsylvania Regional Medical Center, Fredericksburg, Virginia (Dr Chrzastowski); Children's Hospital of Wisconsin, Madison (Dr Dunsirn-Baillie); Division of Biostatistics, Washington University, Saint Louis, Missouri (Dr Wallendorf); and Department of Quality, Safety, and Practice Excellence, St Louis Children's Hospital, St Louis, Missouri (Dr Smith).

The purpose of this study was to (1) define medical and sociodemographic factors related to maternal milk feedings and (2) explore relationships between maternal milk feeding and early neurobehavioral outcome. Ninety-two preterm infants born ≤ 32 weeks gestation had maternal milk feeding and breastfeeding tracked in this retrospective analysis. At 34 to 41 weeks postmenstrual age (PMA), neurobehavior was assessed with the NICU Network Neurobehavioral Scale. Maternal milk feeding was often delayed by the use of total parenteral nutrition, administered for a median of 11 (7-26) days, impacting the timing of gastric feeding initiation. Seventy-nine (86%) infants received some maternal milk during neonatal intensive care unit (NICU) hospitalization. Twenty-one (27%) infants continued to receive maternal milk at 34 to 41 weeks PMA, with 10 (48%) of those receiving maternal milk exclusively. Among mothers who initiated maternal milk feeds, 20 (25%) put their infants directly at the breast at least once during hospitalization. Mothers who were younger (P = .02), non-Caucasian (P < .001), or on public insurance (P < .001) were less likely to provide exclusive maternal milk feedings by 34 to 41 weeks PMA. Infants who received maternal milk at 34 to 41 weeks PMA demonstrated better orientation (P = .03), indicating they had better visual and auditory attention to people and objects in the environment. Our findings demonstrate a relationship between maternal milk feedings and better neurobehavior, which is evident before the infant is discharged home from the NICU.
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http://dx.doi.org/10.1097/JPN.0000000000000460DOI Listing
November 2020

Preventable Harm Reduction: A Balancing Act to Zero Harm.

Authors:
Joan R Smith

J Perinat Neonatal Nurs 2019 Oct/Dec;33(4):283-284

St Louis Children's Hospital St Louis, Missouri.

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http://dx.doi.org/10.1097/JPN.0000000000000447DOI Listing
May 2020

Differences in early auditory exposure across neonatal environments.

Early Hum Dev 2019 09 9;136:27-32. Epub 2019 Jul 9.

Program in Occupational Therapy, Washington University School of Medicine, St. Louis, MO, United States of America; Department of Pediatrics, Washington University School of Medicine in St. Louis, MO, United States of America. Electronic address:

Background: To date, no study has compared preterm and full term auditory environments.

Aim: To define differences in auditory exposure for preterm infants at term equivalent age in the neonatal intensive care unit (NICU) compared to auditory exposure in hospital rooms on a labor and delivery ward after full term birth.

Study Design: Ninety-eight infants (48 preterm infants born 28 weeks gestation in the NICU at term equivalent age and 50 full term infants in a hospital room on the labor and delivery ward within 4 days of birth) had auditory exposure measured over a single 16-hour period using the Language Environment Acquisition (LENA) device.

Results: More language (p < 0.001) was observed on the labor and delivery ward than in the NICU, with an average of 3.3 h more language in a 16-hour period and an average of 14,110 more words spoken around infants in a 16-hour period on the labor and delivery ward (p < 0.001). More electronic sounds were observed in the NICU, with an average of 2.3 h more in the 16-hour period (p < 0.001). The average decibel level in the NICU was lower than in the hospital rooms on the labor and delivery ward (57.16 ± 2.30 dB, compared to 63.31 ± 2.22 dB; p < 0.001).

Conclusion: The NICU auditory environment for preterm infants is different than the auditory environment for full term infants, with less language, more electronic sounds, and quieter stimuli. This understanding can aid in developing appropriate interventions that enhance positive forms of auditory exposures.
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http://dx.doi.org/10.1016/j.earlhumdev.2019.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689434PMC
September 2019

Supporting and enhancing NICU sensory experiences (SENSE): Defining developmentally-appropriate sensory exposures for high-risk infants.

Early Hum Dev 2019 06 1;133:29-35. Epub 2019 May 1.

St. Louis Children's Hospital, St Louis, MO, United States of America.

Introduction: There is evidence to support the use of positive sensory exposures (music, touch, skin-to-skin) with preterm infants in the neonatal intensive care unit (NICU), but strategies to improve their consistent use are lacking. The Supporting and Enhancing NICU Sensory Experiences (SENSE) program was developed to promote consistent, age-appropriate, responsive, and evidence-based positive sensory exposures for the preterm infant every day of NICU hospitalization.

Methods: A systematic and rigorous process of development of the SENSE program included an integrative review of evidence on sensory exposures in the NICU, stakeholder feedback, expert opinion, and focus groups.

Results: SENSE implementation materials consist of parent education materials, tailored doses of sensory exposures for each postmenstrual age, an infant assessment of tolerance, bedside logs and implementation considerations for integrating the SENSE program into the NICU.

Discussion: Research is needed to evaluate the SENSE program as an implementation strategy and to assess its impact on parent and infant outcomes.
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http://dx.doi.org/10.1016/j.earlhumdev.2019.04.012DOI Listing
June 2019

Disparate Care in the NICU: An Opportunity for Improvement.

Authors:
Joan R Smith

J Perinat Neonatal Nurs 2019 Apr/Jun;33(2):103-104

St Louis Children's Hospital St Louis, Missouri.

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http://dx.doi.org/10.1097/JPN.0000000000000408DOI Listing
December 2019

Neonatal Nurses Transforming Care Through Innovation.

Authors:
Joan R Smith

J Perinat Neonatal Nurs 2019 Jan/Mar;33(1):7-8

St Louis Children's Hospital St Louis, Missouri.

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http://dx.doi.org/10.1097/JPN.0000000000000388DOI Listing
December 2019

Health Care Professionals' Perceptions about Sensory-Based Interventions in the NICU.

Am J Perinatol 2019 10 21;36(12):1229-1236. Epub 2018 Dec 21.

Department of Quality, Safety and Practice Excellence, Saint Louis Children's Hospital, St. Louis, Missouri.

Objective: The main objective of this article is to define perceptions of health care professionals regarding current use of sensory-based interventions in the neonatal intensive care unit (NICU).

Study Design: A multidisciplinary group of NICU health care professionals ( = 108) defined the types of sensory-based interventions used in their NICU, the postmenstrual age (PMA) sensory-based interventions are administered, conditions under which sensory-based interventions are used, and personnel who administer sensory-based interventions.

Results: The most commonly reported tactile intervention was infant holding (88% of respondents), the most common auditory intervention was recorded music/singing (69% of respondents), the most common kinesthetic intervention was occupational and physical therapy (85% of respondents), and the most common vestibular intervention was infant swings (86% of respondents). Tactile interventions were initiated most often at 24 to 26 weeks PMA (74% of respondents), auditory interventions at 30 to 32 weeks (60% of respondents), kinesthetic interventions at 30 to 32 weeks (76% of respondents), vestibular interventions at 33 to 34 weeks (86% of respondents), and visual interventions at 32 to 36 weeks (72% of respondents). Conditions under which sensory-based interventions were administered, and personnel who provided them, varied across settings.

Conclusion: Varied use of sensory-based interventions in the NICU were reported. While this study was limited by biased sampling and the identification of health care professionals' perceptions but not real-world practice, this information can be used to build a comprehensive approach to positive sensory exposures in the NICU.
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http://dx.doi.org/10.1055/s-0038-1676536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635089PMC
October 2019

Systematic identification of mutations and copy number alterations associated with cancer patient prognosis.

Elife 2018 12 11;7. Epub 2018 Dec 11.

Cold Spring Harbor Laboratory, Cold Spring Harbor, United States.

Successful treatment decisions in cancer depend on the accurate assessment of patient risk. To improve our understanding of the molecular alterations that underlie deadly malignancies, we analyzed the genomic profiles of 17,879 tumors from patients with known outcomes. We find that mutations in almost all cancer driver genes contain remarkably little information on patient prognosis. However, CNAs in these same driver genes harbor significant prognostic power. Focal CNAs are associated with worse outcomes than broad alterations, and CNAs in many driver genes remain prognostic when controlling for stage, grade, status, and total aneuploidy. By performing a meta-analysis across independent patient cohorts, we identify robust prognostic biomarkers in specific cancer types, and we demonstrate that a subset of these alterations also confer specific therapeutic vulnerabilities. In total, our analysis establishes a comprehensive resource for cancer biomarker identification and underscores the importance of gene copy number profiling in assessing clinical risk.
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http://dx.doi.org/10.7554/eLife.39217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6289580PMC
December 2018

Resiliency: A Core Competency in Today's NICU Nurse Leader.

J Perinat Neonatal Nurs 2018 Oct/Dec;32(4):295-296

St Louis Children's Hospital St Louis, Missouri.

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http://dx.doi.org/10.1097/JPN.0000000000000370DOI Listing
September 2019

Effects of Low-to-Moderate Doses of Gamma Radiation on Mouse Hematopoietic System.

Radiat Res 2018 12 12;190(6):612-622. Epub 2018 Oct 12.

a   Radiation Countermeasures Program, Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, Maryland.

In this study, we investigated the effects of low-to-moderate doses of radiation in mice, given our limited understanding of the health risks associated with these exposures. Here, we demonstrate the different responses of the CD2F1 mouse hematopoietic system to low-to-moderate (0.5, 1, 3 or 5 Gy) doses of gamma radiation. After 3 and 5 Gy of Co total-body irradiation (TBI), mouse blood cell counts were decreased and maintained below baseline up to 28-42 days. In contrast, after 0.5 Gy TBI, lymphocyte and monocyte counts increased, and peaked from day 3 to day 14. Radiation doses at 0.5 and 1 Gy did not cause cell death or T-cell subpopulation changes in spleen and thymus, whereas the clonogenicity of mouse bone marrow (BM) progenitor cells was significantly suppressed on the first day after 0.5-5 Gy TBI, and these low levels were maintained up to 42 days. Although a transient recovery in total colony forming units (CFUs) was shown in mouse BM at days 14 and 21 after 0.5 Gy TBI, the early-stage multipotential progenitor colonies (CFU-GEMM) remained at a significantly low level compared to those of the sham-irradiated (0 Gy) controls. Consistently, the level of stem cell factor (SCF) in BM cells was decreased after low-to-moderate TBI. Serum from individual mice was collected after irradiation and 23 cytokines/chemokines were measured; massive releases of cytokines and chemokines were observed at day 3 postirradiation in a dose-dependent manner. When human hematopoietic CD34 cells were cultured with the serum collected from mice irradiated at different doses, a significant decrease of CFU-GEMM colonies in the CD34 cells was observed. Our data suggest that low-to-moderate doses of radiation induced cellular responses that are cell type-dependent. The early stage multipotential progenitor cells in mouse BM were the most sensitive cells even to low-dose irradiation compared to spleen and thymic cells, and 0.5 Gy TBI induced hematopoietic cell injury from day 1 to the end of our experiment, day 42 postirradiation. Radiation-induced decrease of SCF in mouse BM and increase in circulating pro-inflammatory factors may be responsible for the enhanced sensitivity of hematopoietic progenitor cells to radiation.
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http://dx.doi.org/10.1667/RR15087.1DOI Listing
December 2018

Non-Nutritive Sucking in the Preterm Infant.

Am J Perinatol 2019 02 6;36(3):268-276. Epub 2018 Aug 6.

Department of Quality, Safety, and Practice Excellence, St. Louis Children's Hospital, St. Louis, Missouri.

Objective: To identify the progression of non-nutritive sucking (NNS) across postmenstrual age (PMA) and to investigate the relationship of NNS with medical and social factors and oral feeding.

Study Design: Fifty preterm infants born at ≤32 weeks gestation had NNS assessed weekly starting at 32 weeks PMA with the NTrainer System. Oral feeding was assessed at 38 weeks PMA.

Results: There were increases in NNS bursts per minute ( = 0.005), NNS per minute ( < 0.0001), NNS per burst ( < 0.001), and peak pressure ( = 0.0003) with advancing PMA. Level of immaturity and medical complications were related to NNS measures ( < 0.05). NNS measures were not related to Neonatal Oral Motor Assessment Scale scores. Smaller weekly change in NNS peak pressure ( = 0.03;  = -1.4) was related to feeding success at 38 weeks PMA.

Conclusion: Infants demonstrated NNS early in gestation. Variability in NNS scores could reflect medical complications and immaturity. More stable sucking pressure across time was related to feeding success at 38 weeks PMA.
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http://dx.doi.org/10.1055/s-0038-1667289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561102PMC
February 2019

An Innovative ECMO Staffing Model to Reduce Harm.

J Perinat Neonatal Nurs 2018 Jul/Sep;32(3):204-205

St Louis Children's Hospital St Louis, Missouri.

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http://dx.doi.org/10.1097/JPN.0000000000000355DOI Listing
September 2019

Manual Expression of Breast Milk: A Strategy to Aid in Breastfeeding Success.

J Perinat Neonatal Nurs 2018 Apr/Jun;32(2):102-103

St Louis Children's Hospital St Louis, Missouri.

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http://dx.doi.org/10.1097/JPN.0000000000000328DOI Listing
September 2019

Circulating Cytokine/Chemokine Concentrations Respond to Ionizing Radiation Doses but not Radiation Dose Rates: Granulocyte-Colony Stimulating Factor and Interleukin-18.

Radiat Res 2018 06 13;189(6):634-643. Epub 2018 Apr 13.

c   Biodosimetry Program, Armed Forces Radiobiology Research Institute, Bethesda, Maryland.

Exposure to ionizing radiation is a crucial life-threatening factor in nuclear and radiological incidents. It is known that ionizing radiation affects cytokine/chemokine concentrations in the blood of B6D2F1 mice. It is not clear whether radiation dose rates would vary the physiological response. Therefore, in this study we utilized data from two experiments using B6D2F1 female mice exposed to six different dose rates ranging from low to high rates. In one experiment, mice received a total dose of 8 Gy (LD) of Co gamma radiation at four dose rates: 0.04, 0.15, 0.30 and 0.47 Gy/min. Blood samples from mice were collected at 24 and 48 h postirradiation for cytokine/chemokine measurements, including interleukin (IL)-1β, IL-6, IL-10, keratinocyte cytokine (KC), IL-12p70, IL-15, IL-17A, IL-18, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage (GM)-CSF, macrophage (M)-CSF, monokine induced by gamma interferon (MIG), tumor necrosis factor (TNF)-α, fibroblast growth factor (FGF)-basic, vascular endothelial growth factor (VEGF) and platelet-derived growth factor basic (PDGF-bb). At 24 h after ionizing irradiation at dose rate of 0.04 Gy/min, significant increases were observed only in G-CSF and M-CSF ( P < 0.05). At 0.15 Gy/min, IL-10, IL-17A, G-CSF and GM-CSF concentrations were increased. At 0.3 Gy/min, IL-15, IL-18, G-CSF, GM-CSF, M-CSF, MCP-1, MIP-2, MIG, FGF-basic, VEGF and PDGF-bb were significantly elevated ( P < 0.05). At 0.47 Gy/min, IL-6, KC, IL-10, MCP-1, G-CSF, GM-CSF and M-CSF were significantly increased. At 48 h postirradiation, all cytokines/chemokines except MCP-1 returned to or were below their baselines, suggesting these increases are transient at LD irradiation. Of note, there is a limitation on day 2 because cytokines/chemokines are either at or below their baselines. Other parameters such as fms-like tyrosine kinase receptor-3 ligand (Flt-3 ligand) concentrations and lymphocyte counts, which have proven to be unaffected by radiation dose rates, can be used instead for assessing the radiation dose. However, in a separate radiation dose and time-course experiment, increases in IL-18 and G-CSF depended on the radiation doses but showed no significant differences between 0.58 and 1.94 Gy/min ( P > 0.05) at 3 and 6 Gy but not 12 Gy. G-CSF continued to increase up to day 7, whereas IL-18 increased on day 4 and remained above baseline level on day 7. Therefore, time after irradiation at different doses should be taken into consideration. To our knowledge, these results are the first to suggest that ionizing radiation, even at a very low-dose-rate (0.04 Gy/min), induces circulating G-CSF increases but not others for selected time points; radiation-induced increases in IL-18 at radiation dose rates between 0.15 and 1.94 Gy/min are also not in a radiation dose-rate-dependent manner. C-CSF, lymphocyte counts and circulating Flt-3 ligand should be explored further as possible biomarkers of radiation exposure at early time points. IL-18 is also worthy of further study as a potential biomarker at later time points.
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http://dx.doi.org/10.1667/RR14966.1DOI Listing
June 2018

Ghrelin therapy mitigates bone marrow injury and splenocytopenia by sustaining circulating G-CSF and KC increases after irradiation combined with wound.

Cell Biosci 2018 5;8:27. Epub 2018 Apr 5.

1Radiation Combined Injury Program, Armed Forces Radiobiology Research Institute, Bethesda, MD 20889 USA.

Background: Radiation injury combined wound (CI) enhances acute radiation syndrome and subsequently mortality as compared to radiation injury alone (RI). We previously reported that ghrelin (a 28-amino-acid-peptide secreted from the stomach) treatment significantly increased a 30-day survival, mitigated hematopoietic death, circulating white blood cell (WBC) depletion and splenocytopenia and accelerated skin-wound healing on day 30 after CI. Herein, we aimed to study the ghrelin efficacy at early time points after CI.

Methods: B6D2F1/J female mice were exposed to Co-γ-photon radiation at 9.5 Gy (LD) followed by a 15% total-body-surface-area skin wound. Several endpoints were measured at 4-5 h, days 1, 3, 7 and 15.

Results: Histological analysis of sternums on day 15 showed that CI induced more adipocytes and less megakaryocytes than RI. Bone marrow cell counts from femurs also indicated CI resulted in lower bone marrow cell counts on days 1, 7 and 15 than RI. Ghrelin treatment mitigated these CI-induced adverse effects. RI and CI decreased WBCs within 4-5 h and continued to decrease to day 15. Ghrelin treatment mitigated decreases in CI mice, mainly from all types of WBCs, but not RBCs, hemoglobin levels and hematocrit values. Ghrelin mitigated the CI-induced thrombocytopenia and splenocytopenia. CI increased granulocyte-colony stimulating factor (G-CSF) and keratinocyte chemoattractant (KC) in blood and bone marrow. Ghrelin therapy was able to enhance and sustain the increases in serum on day 15, probably contributed by spleen and ileum, suggesting the correlation between G-CSF and KC increases and the neutropenia mitigation. Activated caspase-3 levels in bone marrow cells were significantly mitigated by ghrelin therapy on days 3 and 15.

Conclusions: Our novel results are the first to suggest that ghrelin therapy effectively decreases hematopoietic death and splenocytopenia by sustaining circulating G-CSF and KC increases after CI. These results demonstrate efficacy of ghrelin as a radio-mitigator/therapy agent for CI.
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http://dx.doi.org/10.1186/s13578-018-0225-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5887249PMC
April 2018

MELK expression correlates with tumor mitotic activity but is not required for cancer growth.

Elife 2018 02 8;7. Epub 2018 Feb 8.

Cold Spring Harbor Laboratory, Cold Spring Harbor, United States.

The Maternal Embryonic Leucine Zipper Kinase (MELK) has been identified as a promising therapeutic target in multiple cancer types. MELK over-expression is associated with aggressive disease, and MELK has been implicated in numerous cancer-related processes, including chemotherapy resistance, stem cell renewal, and tumor growth. Previously, we established that triple-negative breast cancer cell lines harboring CRISPR/Cas9-induced null mutations in MELK proliferate at wild-type levels in vitro (Lin et al., 2017). Here, we generate several additional knockout clones of MELK and demonstrate that across cancer types, cells lacking MELK exhibit wild-type growth in vitro, under environmental stress, in the presence of cytotoxic chemotherapies, and in vivo. By combining our MELK-knockout clones with a recently described, highly specific MELK inhibitor, we further demonstrate that the acute inhibition of MELK results in no specific anti-proliferative phenotype. Analysis of gene expression data from cohorts of cancer patients identifies MELK expression as a correlate of tumor mitotic activity, explaining its association with poor clinical prognosis. In total, our results demonstrate the power of CRISPR/Cas9-based genetic approaches to investigate cancer drug targets, and call into question the rationale for treating patients with anti-MELK monotherapies.
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http://dx.doi.org/10.7554/eLife.32838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5805410PMC
February 2018

Pacifier use in newborns: related to socioeconomic status but not to early feeding performance.

Acta Paediatr 2018 05 8;107(5):806-810. Epub 2018 Mar 8.

St. Louis Children's Hospital, St. Louis, MO, USA.

Aim: Mothers are often advised not to use pacifiers until breastfeeding has been well-established. This study determined the infant and social factors that were related to pacifier use during the first few days of life and whether it led to alterations in feeding performance.

Methods: We enroled 51 full-term infants and their mothers at Barnes-Jewish Hospital in urban St. Louis, USA, in 2015. Before they were discharged the mothers completed a questionnaire, and infant feeding was assessed using a standardised assessment.

Results: There were 24 (47%) infants who used a pacifier during the first few days of life and seven (29%) of these were exclusively breastfed. Pacifier use was less common among mothers who exclusively breastfed (p = 0.04). Pacifier use was more common among mothers whose income was less than 25 000 US dollars (p = 0.02), who were single (p = 0.002) and who did not have a college education (p = 0.03). No associations between pacifier use and feeding performance were observed.

Conclusion: While lower socioeconomic status was related to pacifier use, feeding performance in the first few days of life was no different between those infants who did and did not use pacifiers after a full-term birth.
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http://dx.doi.org/10.1111/apa.14253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5902635PMC
May 2018

The Art of Skillful Disclosure.

J Perinat Neonatal Nurs 2018 Jan/Mar;32(1):12-14

St Louis Children's Hospital, St Louis, Missouri.

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http://dx.doi.org/10.1097/JPN.0000000000000313DOI Listing
September 2019

Parent participation in the neonatal intensive care unit: Predictors and relationships to neurobehavior and developmental outcomes.

Early Hum Dev 2018 02 21;117:32-38. Epub 2017 Dec 21.

St. Louis Children's Hospital, St. Louis, MO, USA.

Objective: To 1) define predictors of parent presence, any holding, holding in arms, and skin-to-skin care in the NICU and 2) investigate the relationships between parent participation and a) early neurobehavior and b) developmental outcomes at age 4 to 5years among preterm infants.

Methods: Eighty-one preterm infants born ≤32weeks estimated gestational age were prospectively enrolled within one week of life in a level III-IV NICU. Parent (maternal and paternal) presence and holding (including holding in arms and skin-to-skin care) were tracked throughout NICU hospitalization. Neurobehavior at term equivalent age and development at 4 to 5years were determined using standardized assessments.

Results: The median number of days per week parents were documented to be present over NICU hospitalization was 4.0 (IQR=2.4-5.8) days; days held per week 2.8 (IQR=1.4-4.3) days [holding in arms days per week was 2.2 (IQR=1.2-3.2) days and parent skin-to-skin care days per week was 0.2 (IQR=0.0-0.7) days]. More parent presence was observed among mothers who were Caucasian, married, older, or employed and among those who had fewer children, familial support and provided breast milk (p<0.05). More holding was observed in infants with fewer medical interventions (p<0.05) and among those who were Caucasian, had a father who was employed, had fewer children and family support (p<0.05). More parent holding in the NICU was related to better reflex development at term age (p=0.02). More parent skin-to-skin care was related to better infant reflexes (p=0.03) and less asymmetry (p=0.04) at term and better gross motor development (p=0.02) at 4-5years.

Discussion: Social and medical factors appear to impact parent presence, holding, and skin-to-skin care in the NICU. Parent holding is related to better developmental outcomes, which highlights the importance of engaging families in the NICU.
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http://dx.doi.org/10.1016/j.earlhumdev.2017.12.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5856604PMC
February 2018