Publications by authors named "Bryan A Comstock"

79 Publications

Antibiotics versus Appendectomy for Acute Appendicitis - Longer-Term Outcomes.

N Engl J Med 2021 Oct 25. Epub 2021 Oct 25.

From University of Washington Medical Center-UW Medicine (G.H.D., D.R.F., E.F., D.C.L., B.B., S.O.L., F.F., L.G.K.), University of Washington (S.E.M., E.C.V., P.J.H., B.A.C.), Swedish Medical Center (K.A.M.), and Harborview Medical Center-UW Medicine (J.C., H.L.E.), Seattle, and Providence Regional Medical Center, Everett (J.G.) - all in Washington; McGovern Medical School, University of Texas Health Science Center (L.S.K.), Lyndon B. Johnson General Hospital, University of Texas (J.H., M.K.L.), and HCA Healthcare Kingwood, University of Houston (M.K.L.) - all in Houston; BC Academic Science Health Network, Vancouver, BC, Canada (D.C.L.); Olive View-UCLA Medical Center (A.K., D.S., G.J.M., D.A.T.), Harbor-UCLA Medical Center (A.H.K., D.A.D.), and UCLA Ronald Reagan Medical Center (D.A.T.), Los Angeles, and the University of California, San Francisco (J.C.) - all in California; Weill Cornell Medical Center (R.J.W.), Tisch Hospital, NYU Langone Medical Center (P.A.-C., W.C., J.V.), Bellevue Hospital Center, NYU School of Medicine (W.C.), and Columbia University Medical Center (N.C., K.F.) - all in New York; Vanderbilt University Medical Center, Nashville (W.H.S., C.M.T.); University of Utah, Salt Lake City (C.M.T.); University of Michigan Medical Center, Ann Arbor (P.K.P., H.B.A.), and Henry Ford Health System, Detroit (J.J., J.H.P.) - both in Michigan; UCHealth, University of Colorado Hospital, Denver (M.S., L.F.); Rush University Medical Center, Chicago (T.P.P., N.S.); Morehouse School of Medicine, Atlanta (P.A.-C.); Maine Medical Center, Portland (B.C., D.W.C.); University of Mississippi Medical Center, Jackson (M.E.K., A.J.); University of Iowa Hospitals and Clinics, Iowa City (B.A.F.); Medical University of South Carolina, Charleston (H.L.E.); and Boston University Medical Center (F.T.D., S.E.S.) and Beth Israel Deaconess Medical Center (C.P., S.R.O.) - both in Boston.

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http://dx.doi.org/10.1056/NEJMc2116018DOI Listing
October 2021

Diffusion Tensor Imaging Changes Do Not Affect Long-Term Neurodevelopment following Early Erythropoietin among Extremely Preterm Infants in the Preterm Erythropoietin Neuroprotection Trial.

Brain Sci 2021 Oct 16;11(10). Epub 2021 Oct 16.

Division of Neonatology, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.

We aimed to evaluate diffusion tensor imaging (DTI) in infants born extremely preterm, to determine the effect of erythropoietin (Epo) on DTI, and to correlate DTI with neurodevelopmental outcomes at 2 years of age for infants in the Preterm Erythropoietin Neuroprotection (PENUT) Trial. Infants who underwent MRI with DTI at 36 weeks postmenstrual age were included. Neurodevelopmental outcomes were evaluated by Bayley Scales of Infant and Toddler Development (BSID-III). Generalized linear models were used to assess the association between DTI parameters and treatment group, and then with neurodevelopmental outcomes. A total of 101 placebo- and 93 Epo-treated infants underwent MRI. DTI white matter mean diffusivity (MD) was lower in placebo- compared to Epo-treated infants in the cingulate and occipital regions, and occipital white matter fractional isotropy (FA) was lower in infants born at 24-25 weeks vs. 26-27 weeks. These values were not associated with lower BSID-III scores. Certain decreases in clustering coefficients tended to have lower BSID-III scores. Consistent with the PENUT Trial findings, there was no effect on long-term neurodevelopment in Epo-treated infants even in the presence of microstructural changes identified by DTI.
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http://dx.doi.org/10.3390/brainsci11101360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8533828PMC
October 2021

Do Extremely Low Gestational Age Neonates Regulate Iron Absorption via Hepcidin?

J Pediatr 2021 Oct 7. Epub 2021 Oct 7.

Department of Pediatrics, University of Washington, Seattle, WA.

Objectives: To evaluate whether extremely preterm infants regulate iron status via hepcidin.

Study Design: In this retrospective analysis of infants from the Preterm Epo Neuroprotection (PENUT) Trial, urine hepcidin (Uhep) normalized to creatinine (Uhep/UCr) was evaluated among infants randomized to erythropoietin (Epo) or placebo.

Results: The correlation (r) between Uhep/UCr and serum markers of iron status (ferritin and zinc protoporphyrin-to-heme ratio [ZnPP/H]) and iron dose was assessed. A total of 243 urine samples from 76 infants born at 24-27 weeks gestation were analyzed. The median Uhep/UCr concentration was 0.3, 1.3, 0.4, and 0.1 ng/mg at baseline, 2 weeks, 4 weeks, and 12 weeks, respectively, in placebo-treated infants. The median Uhep/UCr value in Epo-treated infants were not significantly different, with the exception of the value at the 2-week time point (median Uhep/UCr, 0.1 ng/mg; P < .001). A significant association was seen between Uhep/UCr and ferritin at 2 weeks (r = 0.63; P < .001) and at 4 weeks (r = 0.41; P = .01) and between Uhep/UCr and ZnPP/H at 2 weeks (r = -0.49; P = .002).

Conclusions: Uhep/UCr values correlate with serum iron markers. Uhep/UCr values vary over time and are affected by treatment with Epo, suggesting that extremely preterm neonates can regulate hepcidin and therefore their iron status. Uhep is suppressed in extremely preterm neonates, particularly those treated with Epo.
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http://dx.doi.org/10.1016/j.jpeds.2021.09.059DOI Listing
October 2021

Early Biomarkers of Hypoxia and Inflammation and Two-Year Neurodevelopmental Outcomes in the Preterm Erythropoietin Neuroprotection (PENUT) Trial.

EBioMedicine 2021 Oct 4;72:103605. Epub 2021 Oct 4.

Division of Neonatology, Department of Pediatrics, University of Washington, Seattle, WA. Electronic address:

Background: In the Preterm Erythropoietin (Epo) NeUroproTection (PENUT) Trial, potential biomarkers of neurological injury were measured to determine their association with outcomes at two years of age and whether Epo treatment decreased markers of inflammation in extremely preterm (<28 weeks' gestation) infants.

Methods: Plasma Epo was measured (n=391 Epo, n=384 placebo) within 24h after birth (baseline), 30min after study drug administration (day 7), 30min before study drug (day 9), and on day 14. A subset of infants (n=113 Epo, n=107 placebo) had interferon-gamma (IFN-γ), Interleukin (IL)-6, IL-8, IL-10, Tau, and tumour necrosis factor-α (TNF-α) levels evaluated at baseline, day 7 and 14. Infants were then evaluated at 2 years using the Bayley Scales of Infant and Toddler Development, 3rd Edition (BSID-III).

Findings: Elevated baseline Epo was associated with increased risk of death or severe disability (BSID-III Motor and Cognitive subscales <70 or severe cerebral palsy). No difference in other biomarkers were seen between treatment groups at any time, though Epo appeared to mitigate the association between elevated baseline IL-6 and lower BSID-III scores in survivors. Elevated baseline, day 7 and 14 Tau concentrations were associated with worse BSID-III Cognitive, Motor, and Language skills at two years.

Interpretation: Elevated Epo at baseline and elevated Tau in the first two weeks after birth predict poor outcomes in infants born extremely preterm. However, no clear prognostic cut-off values are apparent, and further work is required before these biomarkers can be widely implemented in clinical practice.

Funding: PENUT was funded by the National Institute of Neurological Disorders and Stroke (U01NS077955 and U01NS077953).
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http://dx.doi.org/10.1016/j.ebiom.2021.103605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8498235PMC
October 2021

Association between Term Equivalent Brain Magnetic Resonance Imaging and 2-Year Outcomes in Extremely Preterm Infants: A Report from the Preterm Erythropoietin Neuroprotection Trial Cohort.

J Pediatr 2021 Dec 26;239:117-125.e6. Epub 2021 Aug 26.

Division of Neonatology, Department of Pediatrics, University of Washington, Seattle, WA.

Objectives: To compare the term equivalent brain magnetic resonance imaging (MRI) findings between erythropoietin (Epo) treated and placebo control groups in infants 24-27 weeks of gestational age and to assess the associations between MRI findings and neurodevelopmental outcomes at 2 years corrected age.

Study Design: The association between brain abnormality scores and Bayley Scales of Infant Development, Third Edition at 2 years corrected age was explored in a subset of infants enrolled in the Preterm Erythropoietin Neuroprotection Trial. Potential risk factors for neurodevelopmental outcomes such as treatment assignment, recruitment site, gestational age, inpatient complications, and treatments were examined using generalized estimating equation models.

Results: One hundred ten infants were assigned to Epo and 110 to placebo groups. 27% of MRI scans were rated as normal, and 60%, 10%, and 2% were rated as having mild, moderate, or severe abnormality. Brain abnormality scores did not significantly differ between the treatment groups. Factors that increased the risk of higher brain injury scores included intubation; bronchopulmonary dysplasia; retinopathy of prematurity; opioid, benzodiazepine, or antibiotic treatment >7 days; and periventricular leukomalacia or severe intraventricular hemorrhage diagnosed on cranial ultrasound. Increased global brain abnormality and white matter injury scores at term equivalent were associated with reductions in cognitive, motor, and language abilities at 2 years of corrected age.

Conclusions: Evidence of brain injury on brain MRIs obtained at term equivalent correlated with adverse neurodevelopmental outcomes as assessed by the Bayley Scales of Infant and Toddler Development, Third Edition at 2 years corrected age. Early Epo treatment had no effect on the MRI brain injury scores compared with the placebo group.
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http://dx.doi.org/10.1016/j.jpeds.2021.08.040DOI Listing
December 2021

Enteral Iron Supplementation in Infants Born Extremely Preterm and its Positive Correlation with Neurodevelopment; Post Hoc Analysis of the Preterm Erythropoietin Neuroprotection Trial Randomized Controlled Trial.

J Pediatr 2021 11 27;238:102-109.e8. Epub 2021 Jul 27.

Department of Pediatrics, University of Washington, Seattle, WA.

Objectives: To test whether an increased iron dose is associated with improved neurodevelopment as assessed by the Bayley Scales of Infant Development, third edition (BSID-III) among infants enrolled in the Preterm Erythropoietin (Epo) Neuroprotection Trial (PENUT).

Study Design: This is a post hoc analysis of a randomized trial that enrolled infants born at 24-28 completed weeks of gestation. All infants in PENUT who were assessed with BSID-III at 2 years were included in this study. The associations between enteral iron dose at 60 and 90 days and BSID-III component scores were evaluated using generalized estimating equations models adjusted for potential confounders.

Results: In total, 692 infants were analyzed (355 placebo, 337 Epo). Enteral iron supplementation ranged from 0 to 14.7 mg/kg/d (IQR 2.1-5.8 mg/kg/d) at day 60, with a mean of 3.6 mg/kg/d in infants treated with placebo and 4.8 mg/kg/d in infants treated with Epo. A significant positive association was seen between BSID-III cognitive scores and iron dose at 60 days, with an effect size of 0.77 BSID points per 50 mg/kg increase in cumulative iron dose (P = .03). Greater iron doses were associated with greater motor and language scores but did not reach statistical significance. Results at 90 days were not significant. The effect size in the infants treated with Epo compared with placebo was consistently greater.

Conclusions: A positive association was seen between iron dose at 60 days and cognitive outcomes. Our results suggest that increased iron supplementation in infants born preterm, at the doses administered in the PENUT Trial, may have positive neurodevelopmental effects, particularly in infants treated with Epo.

Trial Registration: Clinicaltrials.gov: NCT01378273.
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http://dx.doi.org/10.1016/j.jpeds.2021.07.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8629150PMC
November 2021

Assessment of 2-Year Neurodevelopmental Outcomes in Extremely Preterm Infants Receiving Opioids and Benzodiazepines.

JAMA Netw Open 2021 Jul 1;4(7):e2115998. Epub 2021 Jul 1.

Division of Neonatology, Department of Pediatrics, University of Washington, Seattle.

Importance: Extremely preterm (EP) infants frequently receive opioids and/or benzodiazepines, but these drugs' association with neurodevelopmental outcomes is poorly understood.

Objectives: To describe the use of opioids and benzodiazepines in EP infants during neonatal intensive care unit (NICU) hospitalization and to explore these drugs' association with neurodevelopmental outcomes at 2 years' corrected age.

Design, Setting, And Participants: This cohort study was a secondary analysis of data from the Preterm Erythropoietin Neuroprotection (PENUT) Trial, which was conducted among infants born between gestational ages of 24 weeks, 0 days, and 27 weeks, 6 days. Infants received care at 19 sites in the United States, and data were collected from December 2013 to September 2016. Data analysis for this study was conducted from March to December 2020.

Exposures: Short (ie, ≤7 days) and prolonged (ie, >7 days) exposure to opioids and/or benzodiazepines during NICU stay.

Main Outcomes And Measures: Cognitive, language, and motor development scores were assessed using the Bayley Scales of Infant Development-Third Edition (BSID-III).

Results: There were 936 EP infants (448 [48%] female infants; 611 [65%] White infants; mean [SD] gestational age, 181 [8] days) included in the study, and 692 (74%) had neurodevelopmental outcome data available. Overall, 158 infants (17%) were not exposed to any drugs of interest, 297 (32%) received either opioids or benzodiazepines, and 481 (51%) received both. Infants exposed to both had adjusted odds ratios of 9.7 (95% CI, 2.9 to 32.2) for necrotizing enterocolitis and 1.7 (95% CI, 1.1 to 2.7) for severe bronchopulmonary dysplasia; they also had a longer estimated adjusted mean difference in length of stay of 34.2 (95% CI, 26.2 to 42.2) days compared with those who received neither drug. After adjusting for site and propensity scores derived for each exposure category, infants exposed to opioids and benzodiazepines had lower BSID-III cognitive, motor, and language scores compared with infants with no exposure (eg, estimated difference in mean scores on cognitive scale: -5.72; 95% CI, -8.88 to -2.57). Prolonged exposure to morphine, fentanyl, midazolam, or lorazepam was associated with lower BSID-III scores compared with infants without exposure (median [interquartile range] motor score, 85 [73-97] vs 97 [91-107]). In contrast, BSID-III scores for infants with short exposure to both opioids and benzodiazepines were not different than those of infants without exposure.

Conclusions And Relevance: In this study, prolonged combined use of opioids and benzodiazepines was associated with a risk of poorer neurodevelopmental outcomes as measured by BSID-III at 2 years' corrected age.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.15998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264640PMC
July 2021

Intracranial Hemorrhage and 2-Year Neurodevelopmental Outcomes in Infants Born Extremely Preterm.

J Pediatr 2021 Nov 2;238:124-134.e10. Epub 2021 Jul 2.

Division of Neonatology, Department of Pediatrics, University of Washington, Seattle, WA.

Objectives: To determine the incidence, timing, progression, and risk factors for intracranial hemorrhage (ICH) in infants 24 to 27 weeks of gestational age and to characterize the association between ICH and death or neurodevelopmental impairment (NDI) at 2 years of corrected age.

Study Design: Infants enrolled in the Preterm Erythropoietin Neuroprotection Trial had serial cranial ultrasound scans performed on day 1, day 7-9, and 36 weeks of postmenstrual age to evaluate ICH. Potential risk factors for development of ICH were examined. Outcomes included death or severe NDI as well as Bayley Scales of Infant and Toddler Development, 3rd Edition, at 2 years of corrected age.

Results: ICH was identified in 38% (n = 339) of 883 enrolled infants. Multiple gestation and cesarean delivery reduced the risk of any ICH on day 1. Risk factors for development of bilateral Grade 2, Grade 3, or Grade 4 ICH at day 7-9 included any ICH at day 1; 2 or more doses of prenatal steroids decreased risk. Bilateral Grade 2, Grade 3, or Grade 4 ICH at 36 weeks were associated with previous ICH at day 7-9. Bilateral Grade 2, any Grade 3, and any Grade 4 ICH at 7-9 days or 36 weeks of postmenstrual age were associated with increased risk of death or severe NDI and lower Bayley Scales of Infant and Toddler Development, 3rd Edition, scores.

Conclusions: Risk factors for ICH varied by timing of bleed. Bilateral and increasing grade of ICH were associated with death or NDI in infants born extremely preterm.
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http://dx.doi.org/10.1016/j.jpeds.2021.06.071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8551011PMC
November 2021

Acute and Chronic Placental Abnormalities in a Multicenter Cohort of Newborn Infants with Hypoxic-Ischemic Encephalopathy.

J Pediatr 2021 Oct 16;237:190-196. Epub 2021 Jun 16.

Department of Neurology, University of California San Francisco, San Francisco, CA.

Objective: To examine the frequency of placental abnormalities in a multicenter cohort of newborn infants with hypoxic-ischemic encephalopathy (HIE) and to determine the association between acuity of placental abnormalities and clinical characteristics of HIE.

Study Design: Infants born at ≥36 weeks of gestation (n = 500) with moderate or severe HIE were enrolled in the High-dose Erythropoietin for Asphyxia and Encephalopathy Trial. A placental pathologist blinded to clinical information reviewed clinical pathology reports to determine the presence of acute and chronic placental abnormalities using a standard classification system.

Results: Complete placental pathologic examination was available for 321 of 500 (64%) trial participants. Placental abnormalities were identified in 273 of 321 (85%) and were more common in infants ≥40 weeks of gestation (93% vs 81%, P = .01). A combination of acute and chronic placental abnormalities (43%) was more common than either acute (20%) or chronic (21%) abnormalities alone. Acute abnormalities included meconium staining of the placenta (41%) and histologic chorioamnionitis (39%). Chronic abnormalities included maternal vascular malperfusion (25%), villitis of unknown etiology (8%), and fetal vascular malperfusion (6%). Infants with chronic placental abnormalities exhibited a greater mean base deficit at birth (-15.9 vs -14.3, P = .049) than those without such abnormalities. Patients with HIE and acute placental lesions had older mean gestational ages (39.1 vs 38.0, P < .001) and greater rates of clinically diagnosed chorioamnionitis (25% vs 2%, P < .001) than those without acute abnormalities.

Conclusions: Combined acute and chronic placental abnormalities were common in this cohort of infants with HIE, underscoring the complex causal pathways of HIE.

Trial Registration: ClinicalTrials.gov: NCT02811263.
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http://dx.doi.org/10.1016/j.jpeds.2021.06.023DOI Listing
October 2021

Cytokine and chemokine responses to injury and treatment in a nonhuman primate model of hypoxic-ischemic encephalopathy treated with hypothermia and erythropoietin.

J Cereb Blood Flow Metab 2021 08 7;41(8):2054-2066. Epub 2021 Feb 7.

Department of Pediatrics, University of Washington, Seattle, WA, USA.

Predicting long-term outcome in infants with hypoxic-ischemic encephalopathy (HIE) remains an ongoing clinical challenge. We investigated plasma biomarkers and their association with 6-month outcomes in a nonhuman primate model of HIE with or without therapeutic hypothermia (TH) and erythropoietin (Epo). Twenty-nine were randomized to control cesarean section (n = 7) or 20 min of umbilical cord occlusion (UCO, n = 22) with either no treatment (n = 11) or TH/Epo (n = 11). Initial injury severity was scored using 30-min arterial pH, base deficit, and 10-min Apgar score. Twenty-four plasma cytokines, chemokines, and growth factors were measured 3, 6, 24, 72, and 96 h after UCO. Interleukin 17 (IL-17) and macrophage-derived chemokine (MDC) differentiated the normal/mild from moderate/severe injury groups. Treatment with TH/Epo was associated with increased monocyte chemotactic protein-4 (MCP-4) at 3 h-6h, and significantly lower MCP-4 and MDC at 24 h-72h, respectively. IL-12p40 was lower at 24 h-72h in animals with death/cerebral palsy (CP) compared to survivors without CP. Baseline injury severity was the single best predictor of death/CP, and predictions did not improve with the addition of biomarker data. Circulating chemokines associated with the peripheral monocyte cell lineage are associated with severity of injury and response to therapy, but do not improve ability to predict outcomes.
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http://dx.doi.org/10.1177/0271678X21991439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8327104PMC
August 2021

Transfusions and neurodevelopmental outcomes in extremely low gestation neonates enrolled in the PENUT Trial: a randomized clinical trial.

Pediatr Res 2021 07 11;90(1):109-116. Epub 2021 Jan 11.

Department of Pediatrics, University of Washington, Seattle, WA, USA.

Background: Outcomes of extremely low gestational age neonates (ELGANs) may be adversely impacted by packed red blood cell (pRBC) transfusions. We investigated the impact of transfusions on neurodevelopmental outcome in the Preterm Erythropoietin (Epo) Neuroprotection (PENUT) Trial population.

Methods: This is a post hoc analysis of 936 infants 24-0/6 to 27-6/7 weeks' gestation enrolled in the PENUT Trial. Epo 1000 U/kg or placebo was given every 48 h × 6 doses, followed by 400 U/kg or sham injections 3 times a week through 32 weeks postmenstrual age. Six hundred and twenty-eight (315 placebo, 313 Epo) survived and were assessed at 2 years of age. We evaluated associations between BSID-III scores and the number and volume of pRBC transfusions.

Results: Each transfusion was associated with a decrease in mean cognitive score of 0.96 (95% CI of [-1.34, -0.57]), a decrease in mean motor score of 1.51 (-1.91, -1.12), and a decrease in mean language score of 1.10 (-1.54, -0.66). Significant negative associations between BSID-III score and transfusion volume and donor exposure were observed in the placebo group but not in the Epo group.

Conclusions: Transfusions in ELGANs were associated with worse outcomes. We speculate that strategies to minimize the need for transfusions may improve outcomes.

Impact: Transfusion number, volume, and donor exposure in the neonatal period are associated with worse neurodevelopmental (ND) outcome at 2 years of age, as assessed by the Bayley Infant Scales of Development, Third Edition (BSID-III). The impact of neonatal packed red blood cell transfusions on the neurodevelopmental outcome of preterm infants is unknown. We speculate that strategies to minimize the need for transfusions may improve neurodevelopmental outcomes.
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http://dx.doi.org/10.1038/s41390-020-01273-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797706PMC
July 2021

High-Dose Erythropoietin in Extremely Low Gestational Age Neonates Does Not Alter Risk of Retinopathy of Prematurity.

Neonatology 2020 28;117(5):650-657. Epub 2020 Oct 28.

Division of Neonatology, Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington, USA.

Introduction: The Preterm Erythropoietin (Epo) Neuroprotection (PENUT) Trial sought to determine the safety and efficacy of early high-dose Epo as a potential neuroprotective treatment. We hypothesized that Epo would not increase the incidence or severity of retinopathy of prematurity (ROP).

Methods: A total of 941 infants born between 24-0/7 and 27-6/7 weeks' gestation were randomized to 1,000 U/kg Epo or placebo intravenously for 6 doses, followed by subcutaneous or sham injections of 400 U/kg Epo 3 times a week through 32 weeks post-menstrual age. In this secondary analysis of PENUT trial data, survivors were evaluated for ROP. A modified intention-to-treat approach was used to compare treatment groups. In addition, risk factors for ROP were evaluated using regression methods that account for multiples and allow for adjustment for treatment and gestational age at birth.

Results: Of 845 subjects who underwent ROP examination, 503 were diagnosed with ROP with similar incidence and severity between treatment groups. Gestational age at birth, birth weight, prenatal magnesium sulfate, maternal antibiotic exposure, and presence of heart murmur at 2 weeks predicted the development of any ROP, while being on high-frequency oscillator or high-frequency jet ventilation (HFOV/HFJV) at 2 weeks predicted severe ROP.

Conclusion: Early high-dose Epo followed by maintenance dosing through 32 weeks does not increase the risk of any or severe ROP in extremely low gestational age neonates. Gestational age, birth weight, maternal treatment with magnesium sulfate, antibiotic use during pregnancy, and presence of a heart murmur at 2 weeks were associated with increased risk of any ROP. Treatment with HFOV/HFJV was associated with an increased risk of severe ROP.
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http://dx.doi.org/10.1159/000511262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855231PMC
August 2021

A Randomized Trial Comparing Antibiotics with Appendectomy for Appendicitis.

N Engl J Med 2020 11 5;383(20):1907-1919. Epub 2020 Oct 5.

The affiliations of the members of the writing committee are as follows: the University of Washington (D.R.F., G.H.D., S.M., A.K.S., E.F., D.C.L., B.A.C., P.J.H., L.G.K.), the Washington State Hospital Association (B.B.), Harborview Medical Center (H.E., J.C.), the Swedish Medical Center (K.A.M.), and the Virginia Mason Medical Center (J.T.Y., A.W.), Seattle, Madigan Army Medical Center, Tacoma (V.S., K.M.), and Providence Regional Medical Center Everett, Everett (C.S.F., S.M.S.) - all in Washington; Beth Israel Deaconess Medical Center (N.I.S., S.R.O.) and Boston University Medical Center (S.E.S., F.T.D.) - both in Boston; Columbia University Medical Center (K.F.), Tisch Hospital, NYU Langone Medical Center (P.A.-C., W.C.), Bellevue Hospital Center, NYU School of Medicine (P.A.-C., W.C.), and Weill Cornell Medical Center (R.J.W., S.C.) - all in New York; Henry Ford Health, Detroit (J.J., J.H.P.), and the University of Michigan, Ann Arbor (H.B.A., P.K.P.); University of Iowa Hospitals and Clinics, Iowa City (B.A.F., D.A.S.); the University of Texas Lyndon B. Johnson Medical Center (M.K.L.) and the University of Texas Health Science Center at Houston (L.S.K.) - both in Houston; the University of Mississippi Medical Center, Jackson (M.E.K.); Maine Medical Center, Portland (B.C., D.W.C.); Ohio State University Medical Center, Columbus (A.R., S.S.); Rush University Medical Center, Chicago (T.P.P.); UCHealth University of Colorado Hospital, Denver (L.F., M.S.); Harbor UCLA Medical Center (D.A.D., A.H.K.), Olive View UCLA Medical Center (G.J.M., D.S., A.K.), and Ronald Reagan UCLA Medical Center (D.A.T.) - all in Los Angeles; and Vanderbilt University Medical Center, Nashville (C.M.T., W.H.S.).

Background: Antibiotic therapy has been proposed as an alternative to surgery for the treatment of appendicitis.

Methods: We conducted a pragmatic, nonblinded, noninferiority, randomized trial comparing antibiotic therapy (10-day course) with appendectomy in patients with appendicitis at 25 U.S. centers. The primary outcome was 30-day health status, as assessed with the European Quality of Life-5 Dimensions (EQ-5D) questionnaire (scores range from 0 to 1, with higher scores indicating better health status; noninferiority margin, 0.05 points). Secondary outcomes included appendectomy in the antibiotics group and complications through 90 days; analyses were prespecified in subgroups defined according to the presence or absence of an appendicolith.

Results: In total, 1552 adults (414 with an appendicolith) underwent randomization; 776 were assigned to receive antibiotics (47% of whom were not hospitalized for the index treatment) and 776 to undergo appendectomy (96% of whom underwent a laparoscopic procedure). Antibiotics were noninferior to appendectomy on the basis of 30-day EQ-5D scores (mean difference, 0.01 points; 95% confidence interval [CI], -0.001 to 0.03). In the antibiotics group, 29% had undergone appendectomy by 90 days, including 41% of those with an appendicolith and 25% of those without an appendicolith. Complications were more common in the antibiotics group than in the appendectomy group (8.1 vs. 3.5 per 100 participants; rate ratio, 2.28; 95% CI, 1.30 to 3.98); the higher rate in the antibiotics group could be attributed to those with an appendicolith (20.2 vs. 3.6 per 100 participants; rate ratio, 5.69; 95% CI, 2.11 to 15.38) and not to those without an appendicolith (3.7 vs. 3.5 per 100 participants; rate ratio, 1.05; 95% CI, 0.45 to 2.43). The rate of serious adverse events was 4.0 per 100 participants in the antibiotics group and 3.0 per 100 participants in the appendectomy group (rate ratio, 1.29; 95% CI, 0.67 to 2.50).

Conclusions: For the treatment of appendicitis, antibiotics were noninferior to appendectomy on the basis of results of a standard health-status measure. In the antibiotics group, nearly 3 in 10 participants had undergone appendectomy by 90 days. Participants with an appendicolith were at a higher risk for appendectomy and for complications than those without an appendicolith. (Funded by the Patient-Centered Outcomes Research Institute; CODA ClinicalTrials.gov number, NCT02800785.).
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http://dx.doi.org/10.1056/NEJMoa2014320DOI Listing
November 2020

The Effect of Including Benchmark Prevalence Data of Common Imaging Findings in Spine Image Reports on Health Care Utilization Among Adults Undergoing Spine Imaging: A Stepped-Wedge Randomized Clinical Trial.

JAMA Netw Open 2020 09 1;3(9):e2015713. Epub 2020 Sep 1.

Department of Biostatistics, University of Washington, Seattle.

Importance: Lumbar spine imaging frequently reveals findings that may seem alarming but are likely unrelated to pain. Prior work has suggested that inserting data on the prevalence of imaging findings among asymptomatic individuals into spine imaging reports may reduce unnecessary subsequent interventions.

Objective: To evaluate the impact of including benchmark prevalence data in routine spinal imaging reports on subsequent spine-related health care utilization and opioid prescriptions.

Design, Setting, And Participants: This stepped-wedge, pragmatic randomized clinical trial included 250 401 adult participants receiving care from 98 primary care clinics at 4 large health systems in the United States. Participants had imaging of their backs between October 2013 and September 2016 without having had spine imaging in the prior year. Data analysis was conducted from November 2018 to October 2019.

Interventions: Either standard lumbar spine imaging reports (control group) or reports containing age-appropriate prevalence data for common imaging findings in individuals without back pain (intervention group).

Main Outcomes And Measures: Health care utilization was measured in spine-related relative value units (RVUs) within 365 days of index imaging. The number of subsequent opioid prescriptions written by a primary care clinician was a secondary outcome, and prespecified subgroup analyses examined results by imaging modality.

Results: We enrolled 250 401 participants (of whom 238 886 [95.4%] met eligibility for this analysis, with 137 373 [57.5%] women and 105 497 [44.2%] aged >60 years) from 3278 primary care clinicians. A total of 117 455 patients (49.2%) were randomized to the control group, and 121 431 patients (50.8%) were randomized to the intervention group. There was no significant difference in cumulative spine-related RVUs comparing intervention and control conditions through 365 days. The adjusted median (interquartile range) RVU for the control group was 3.56 (2.71-5.12) compared with 3.53 (2.68-5.08) for the intervention group (difference, -0.7%; 95% CI, -2.9% to 1.5%; P = .54). Rates of subsequent RVUs did not differ between groups by specific clinical findings in the report but did differ by type of index imaging (eg, computed tomography: difference, -29.3%; 95% CI, -42.1% to -13.5%; magnetic resonance imaging: difference, -3.4%; 95% CI, -8.3% to 1.8%). We observed a small but significant decrease in the likelihood of opioid prescribing from a study clinician within 1 year of the intervention (odds ratio, 0.95; 95% CI, 0.91 to 1.00; P = .04).

Conclusions And Relevance: In this study, inserting benchmark prevalence information in lumbar spine imaging reports did not decrease subsequent spine-related RVUs but did reduce subsequent opioid prescriptions. The intervention text is simple, inexpensive, and easily implemented.

Trial Registration: ClinicalTrials.gov Identifier: NCT02015455.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.15713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489827PMC
September 2020

Effect of High-Dose Erythropoietin on Blood Transfusions in Extremely Low Gestational Age Neonates: Post Hoc Analysis of a Randomized Clinical Trial.

JAMA Pediatr 2020 10;174(10):933-943

Department of Biostatistics, University of Washington, Seattle.

Importance: Extremely preterm infants are among the populations receiving the highest levels of transfusions. Erythropoietin has not been recommended for premature infants because most studies have not demonstrated a decrease in donor exposure.

Objectives: To determine whether high-dose erythropoietin given within 24 hours of birth through postmenstrual age of 32 completed weeks will decrease the need for blood transfusions.

Design, Setting, And Participants: The Preterm Erythropoietin Neuroprotection Trial (PENUT) is a randomized, double-masked clinical trial with participants enrolled at 19 sites consisting of 30 neonatal intensive care units across the United States. Participants were born at a gestational age of 24 weeks (0-6 days) to 27 weeks (6-7 days). Exclusion criteria included conditions known to affect neurodevelopmental outcomes. Of 3266 patients screened, 2325 were excluded, and 941 were enrolled and randomized to erythropoietin (n = 477) or placebo (n = 464). Data were collected from December 12, 2013, to February 25, 2019, and analyzed from March 1 to June 15, 2019.

Interventions: In this post hoc analysis, erythropoietin, 1000 U/kg, or placebo was given every 48 hours for 6 doses, followed by 400 U/kg or sham injections 3 times a week through postmenstrual age of 32 weeks.

Main Outcomes And Measures: Need for transfusion, transfusion numbers and volume, number of donor exposures, and lowest daily hematocrit level are presented herein.

Results: A total of 936 patients (488 male [52.1%]) were included in the analysis, with a mean (SD) gestational age of 25.6 (1.2) weeks and mean (SD) birth weight of 799 (189) g. Erythropoietin treatment (vs placebo) decreased the number of transfusions (unadjusted mean [SD], 3.5 [4.0] vs 5.2 [4.4]), with a relative rate (RR) of 0.66 (95% CI, 0.59-0.75); the cumulative transfused volume (mean [SD], 47.6 [60.4] vs 76.3 [68.2] mL), with a mean difference of -25.7 (95% CI, 18.1-33.3) mL; and donor exposure (mean [SD], 1.6 [1.7] vs 2.4 [2.0]), with an RR of 0.67 (95% CI, 0.58-0.77). Despite fewer transfusions, erythropoietin-treated infants tended to have higher hematocrit levels than placebo-treated infants, most noticeable at gestational week 33 in infants with a gestational age of 27 weeks (mean [SD] hematocrit level in erythropoietin-treated vs placebo-treated cohorts, 36.9% [5.5%] vs 30.4% [4.6%] (P < .001). Of 936 infants, 160 (17.1%) remained transfusion free at the end of 12 postnatal weeks, including 43 in the placebo group and 117 in the erythropoietin group (P < .001).

Conclusions And Relevance: These findings suggest that high-dose erythropoietin as used in the PENUT protocol was effective in reducing transfusion needs in this population of extremely preterm infants.

Trial Registration: ClinicalTrials.gov Identifier: NCT01378273.
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http://dx.doi.org/10.1001/jamapediatrics.2020.2271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432302PMC
October 2020

Erythropoietin in Preterm Infants. Reply.

N Engl J Med 2020 05;382(19):1862-1863

University of Washington, Seattle, WA

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http://dx.doi.org/10.1056/NEJMc2002493DOI Listing
May 2020

A Randomized Trial of Erythropoietin for Neuroprotection in Preterm Infants.

N Engl J Med 2020 01;382(3):233-243

From the University of Washington, Seattle (S.E.J., B.A.C., D.E.M., P.T.V., P.J.H.); Florida Hospital Orlando, Orlando (R.W.), the University of Florida, Gainesville (M.W.), South Miami Hospital, South Miami (J.E.P.), and Johns Hopkins All Children's Hospital, St. Petersburg (V.M.) - all in Florida; the University of Arkansas for Medical Sciences, Little Rock (S.E.C.); the University of Louisville, Louisville, KY (T.R.); Methodist Children's Hospital, San Antonio, TX (K.A.A.); Children's Hospital and Clinics of Minnesota (E.B.-S.) and University of Minnesota Masonic Children's Hospital (R.R., N.F.), Minneapolis, and Children's Minnesota, St. Paul (A.L.) - all in Minnesota; the University of Utah, Salt Lake City (M.B.); Maria Fareri Children's Hospital at Westchester Medical Center, Valhalla, NY (E.F.L.); Wake Forest School of Medicine, Winston-Salem (L.C.D.), and the University of North Carolina, Chapel Hill (T.M.O.) - both in North Carolina; Beth Israel Deaconess Medical Center (I.D.F.) and Boston University (K.K.) - both in Boston; Prentice Women's Hospital (J.Y.K.) and Children's Hospital of the University of Illinois (N.S.) - both in Chicago; Johns Hopkins University, Baltimore (M.M.G.), and the National Institute of Neurological Disorders and Stroke, Bethesda (A.L.H.) - both in Maryland; and the University of New Mexico, Albuquerque (R.K.O., J.L.).

Background: High-dose erythropoietin has been shown to have a neuroprotective effect in preclinical models of neonatal brain injury, and phase 2 trials have suggested possible efficacy; however, the benefits and safety of this therapy in extremely preterm infants have not been established.

Methods: In this multicenter, randomized, double-blind trial of high-dose erythropoietin, we assigned 941 infants who were born at 24 weeks 0 days to 27 weeks 6 days of gestation to receive erythropoietin or placebo within 24 hours after birth. Erythropoietin was administered intravenously at a dose of 1000 U per kilogram of body weight every 48 hours for a total of six doses, followed by a maintenance dose of 400 U per kilogram three times per week by subcutaneous injection through 32 completed weeks of postmenstrual age. Placebo was administered as intravenous saline followed by sham injections. The primary outcome was death or severe neurodevelopmental impairment at 22 to 26 months of postmenstrual age. Severe neurodevelopmental impairment was defined as severe cerebral palsy or a composite motor or composite cognitive score of less than 70 (which corresponds to 2 SD below the mean, with higher scores indicating better performance) on the Bayley Scales of Infant and Toddler Development, third edition.

Results: A total of 741 infants were included in the per-protocol efficacy analysis: 376 received erythropoietin and 365 received placebo. There was no significant difference between the erythropoietin group and the placebo group in the incidence of death or severe neurodevelopmental impairment at 2 years of age (97 children [26%] vs. 94 children [26%]; relative risk, 1.03; 95% confidence interval, 0.81 to 1.32; P = 0.80). There were no significant differences between the groups in the rates of retinopathy of prematurity, intracranial hemorrhage, sepsis, necrotizing enterocolitis, bronchopulmonary dysplasia, or death or in the frequency of serious adverse events.

Conclusions: High-dose erythropoietin treatment administered to extremely preterm infants from 24 hours after birth through 32 weeks of postmenstrual age did not result in a lower risk of severe neurodevelopmental impairment or death at 2 years of age. (Funded by the National Institute of Neurological Disorders and Stroke; PENUT ClinicalTrials.gov number, NCT01378273.).
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http://dx.doi.org/10.1056/NEJMoa1907423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060076PMC
January 2020

High-Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL): A Randomized Controlled Trial - Background, Aims, and Study Protocol.

Neonatology 2018 7;113(4):331-338. Epub 2018 Mar 7.

Department of Neurology, Division of Child Neurology, University of California, San Francisco, California, USA.

Background: Hypoxic-ischemic encephalopathy (HIE) remains an important cause of neonatal death and frequently leads to significant long-term disability in survivors. Therapeutic hypothermia, while beneficial, still leaves many treated infants with lifelong disabilities. Adjunctive therapies are needed, and erythropoietin (Epo) has the potential to provide additional neuroprotection.

Objectives: The aim of this study was to review the current incidence, mechanism of injury, and sequelae of HIE, and to describe a new phase III randomized, placebo-controlled trial of Epo neuroprotection in term and near-term infants with moderate to severe HIE treated with therapeutic hypothermia.

Methods: This article presents an overview of HIE, neuroprotective functions of Epo, and the design of a double-blind, placebo-controlled, multicenter trial of high-dose Epo administration, enrolling 500 neonates ≥36 weeks of gestation with moderate or severe HIE diagnosed by clinical criteria.

Results And Conclusions: Epo has robust neuroprotective effects in preclinical studies, and phase I/II trials suggest that multiple high doses of Epo may provide neuroprotection against brain injury in term infants. The High Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) Trial will evaluate whether high-dose Epo reduces the combined outcome of death or neurodevelopmental disability when given in conjunction with hypothermia to newborns with moderate/severe HIE.
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http://dx.doi.org/10.1159/000486820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5980685PMC
September 2019

Systemic effects of epidural steroid injections for spinal stenosis.

Pain 2018 May;159(5):876-883

Comparative Effectiveness, Cost and Outcomes Research Center, University of Washington, Seattle, WA, USA.

This analysis of the lumbar epidural steroid injections for spinal stenosis multicenter randomized controlled trial data identifies the degree of and risk factors for cortisol suppression after epidural steroid injections in older adults with spinal stenosis. Four hundred patients aged 50 years and older with back or leg pain and central lumbar spinal stenosis completed baseline demographic and psychosocial measures. Morning serum cortisol levels were measured at baseline and 3 weeks after initial injection. Patients were randomized to receive epidural injections of either local anesthetic with corticosteroid (n = 200) or local anesthetic only (n = 200). The specific corticosteroid was chosen at the treating physician's discretion (methylprednisolone, betamethasone, triamcinolone, or dexamethasone). Thirty-two patients (20.3%) treated with corticosteroid experienced cortisol reduction at 3 weeks of >50% compared with 10 patients (6.7%) treated with lidocaine only (adjusted treatment effect = 3.5, 95% confidence interval: 1.6-7.9, P = 0.002). The effect on 3-week cortisol changes did not differ by demographic or patient-level characteristics. Those treated with methylprednisolone or triamcinolone had an average 3-week cortisol reduction of 41.0% (P = 0.005) and 41.6% (P < 0.001) from baseline, respectively, whereas patients treated with betamethasone or dexamethasone were not significantly different than comparable patients in the lidocaine arm. The higher rates of cortisol suppression at 3 weeks in those receiving epidural corticosteroid injections, particularly with longer-acting insoluble corticosteroid formulations, are consistent with sustained systemic absorption of corticosteroid.
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http://dx.doi.org/10.1097/j.pain.0000000000001158DOI Listing
May 2018

Long-term outcomes of a large, prospective observational cohort of older adults with back pain.

Spine J 2018 09 31;18(9):1540-1551. Epub 2018 Jan 31.

Comparative Effectiveness, Cost and Outcomes Research Center, University of Washington, 4333 Brooklyn Ave, Seattle, WA, 98105, USA; Department of Biostatistics, University of Washington, 1959 NE Pacific St, Seattle, WA, 98195, USA.

Background Context: Although back pain is common among older adults, there is relatively little research on the course of back pain in this age group.

Purpose: Our primary goals were to report 2-year outcomes of older adults initiating primary care for back pain and to examine the relative importance of patient factors versus medical interventions in predicting 2-year disability and pain.

Study Design/setting: This study used a predictive model using data from a prospective, observational cohort from a primary care setting.

Patient Sample: The study included patients aged ≥65 years at the time of new primary care visits for back pain.

Outcome Measures: Self-reported 2-year disability (Roland-Morris Disability Questionnaire [RDQ]) and back pain (0-10 numerical rating scale [NRS]).

Methods: We developed our models using a machine learning least absolute shrinkage and selection operator approach. We evaluated the predictive value of baseline characteristics and the incremental value of interventions that occurred between 0 and 90 days, and the change in patient disability and pain from 0 to 90 days. Limitations included confounding by indication and unmeasured confounding.

Results: Of 4,665 patients (89%) with follow-up, both RDQ (from mean 9.6 [95% confidence interval {CI} 9.4-9.7] to mean 8.3 [95% CI 8.0-8.5]) and back pain NRS (from mean 5.0 [95% CI 4.9-5.1] to mean 3.5 [95% CI 3.4-3.6]) scores improved slightly. Only 16% (15%-18%) reported no back pain-related disability or back pain at 2 years after initial visits. Regression model parameters explained 40% of the variation (R) in 2-year RDQ scores, and the addition of 0- to 3-month change in RDQ score and pain improved prediction (R=51%). The most consistent predictors of 2-year RDQ scores and back pain NRS scores were 0- to 90-day change in each respective outcome and patient confidence in improvement. Patients experienced 50% and 43% improvement in back pain and disability, respectively, 2 years after their initial visit. However, fewer than 20% of patients had complete resolution of their back pain and disability at that time.

Conclusions: Baseline patient factors were more important than early interventions in explaining disability and pain after 2 years.
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http://dx.doi.org/10.1016/j.spinee.2018.01.018DOI Listing
September 2018

Comparison of Outcomes of antibiotic Drugs and Appendectomy (CODA) trial: a protocol for the pragmatic randomised study of appendicitis treatment.

BMJ Open 2017 Nov 15;7(11):e016117. Epub 2017 Nov 15.

Department of Emergency Medicine, Olive-View UCLA Medical Center, Sylmar, California, USA.

Introduction: Several European studies suggest that some patients with appendicitis can be treated safely with antibiotics. A portion of patients eventually undergo appendectomy within a year, with 10%-15% failing to respond in the initial period and a similar additional proportion with suspected recurrent episodes requiring appendectomy. Nearly all patients with appendicitis in the USA are still treated with surgery. A rigorous comparative effectiveness trial in the USA that is sufficiently large and pragmatic to incorporate usual variations in care and measures the patient experience is needed to determine whether antibiotics are as good as appendectomy.

Objectives: The Comparing Outcomes of Antibiotic Drugs and Appendectomy (CODA) trial for acute appendicitis aims to determine whether the antibiotic treatment strategy is non-inferior to appendectomy.

Methods/analysis: CODA is a randomised, pragmatic non-inferiority trial that aims to recruit 1552 English-speaking and Spanish-speaking adults with imaging-confirmed appendicitis. Participants are randomised to appendectomy or 10 days of antibiotics (including an option for complete outpatient therapy). A total of 500 patients who decline randomisation but consent to follow-up will be included in a parallel observational cohort. The primary analytic outcome is quality of life (measured by the EuroQol five dimension index) at 4 weeks. Clinical adverse events, rate of eventual appendectomy, decisional regret, return to work/school, work productivity and healthcare utilisation will be compared. Planned exploratory analyses will identify subpopulations that may have a differential risk of eventual appendectomy in the antibiotic treatment arm.

Ethics And Dissemination: This trial was approved by the University of Washington's Human Subjects Division. Results from this trial will be presented in international conferences and published in peer-reviewed journals.

Trial Registration Number: NCT02800785.
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http://dx.doi.org/10.1136/bmjopen-2017-016117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5695382PMC
November 2017

The Promise and Pitfalls of Using Crowdsourcing in Research Prioritization for Back Pain: Cross-Sectional Surveys.

J Med Internet Res 2017 10 6;19(10):e341. Epub 2017 Oct 6.

Surgical Outcomes Research Center, Department of Surgery, University of Washington, Seattle, WA, United States.

Background: The involvement of patients in research better aligns evidence generation to the gaps that patients themselves face when making decisions about health care. However, obtaining patients' perspectives is challenging. Amazon's Mechanical Turk (MTurk) has gained popularity over the past decade as a crowdsourcing platform to reach large numbers of individuals to perform tasks for a small reward for the respondent, at small cost to the investigator. The appropriateness of such crowdsourcing methods in medical research has yet to be clarified.

Objective: The goals of this study were to (1) understand how those on MTurk who screen positive for back pain prioritize research topics compared with those who screen negative for back pain, and (2) determine the qualitative differences in open-ended comments between groups.

Methods: We conducted cross-sectional surveys on MTurk to assess participants' back pain and allow them to prioritize research topics. We paid respondents US $0.10 to complete the 24-point Roland Morris Disability Questionnaire (RMDQ) to categorize participants as those "with back pain" and those "without back pain," then offered both those with (RMDQ score ≥7) and those without back pain (RMDQ <7) an opportunity to rank their top 5 (of 18) research topics for an additional US $0.75. We compared demographic information and research priorities between the 2 groups and performed qualitative analyses on free-text commentary that participants provided.

Results: We conducted 2 screening waves. We first screened 2189 individuals for back pain over 33 days and invited 480 (21.93%) who screened positive to complete the prioritization, of whom 350 (72.9% of eligible) did. We later screened 664 individuals over 7 days and invited 474 (71.4%) without back pain to complete the prioritization, of whom 397 (83.7% of eligible) did. Those with back pain who prioritized were comparable with those without in terms of age, education, marital status, and employment. The group with back pain had a higher proportion of women (234, 67.2% vs 229, 57.8%, P=.02). The groups' rank lists of research priorities were highly correlated: Spearman correlation coefficient was .88 when considering topics ranked in the top 5. The 2 groups agreed on 4 of the top 5 and 9 of the top 10 research priorities.

Conclusions: Crowdsourcing platforms such as MTurk support efforts to efficiently reach large groups of individuals to obtain input on research activities. In the context of back pain, a prevalent and easily understood condition, the rank list of those with back pain was highly correlated with that of those without back pain. However, subtle differences in the content and quality of free-text comments suggest supplemental efforts may be needed to augment the reach of crowdsourcing in obtaining perspectives from patients, especially from specific populations.
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http://dx.doi.org/10.2196/jmir.8821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5650676PMC
October 2017

Associations of Early Opioid Use With Patient-reported Outcomes and Health Care Utilization Among Older Adults With Low Back Pain.

Clin J Pain 2018 04;34(4):297-305

Department of Radiology, Comparative Effectiveness, Cost, and Outcomes Research Center.

Objectives: The objective of this study was to compare outcomes and health care utilization of older patients who did versus did not fill opioid prescriptions within 90 days of initiating care for low back pain.

Materials And Methods: For patients ≥65 years with new back pain visits, we used propensity scores to match those who filled no opioid prescriptions to those who filled ≥2 opioid prescriptions within 90 days (and the first opioid prescription within 30 d) of the index visit. Over 24 months, we examined patient-reported outcomes, health care utilization, and subsequent opioid prescription fills.

Results: Among 1954 patients eligible for matching, 238 (12%) filled ≥2 opioid prescriptions within 90 days; 200 of these were matched to controls. Patients with versus without early opioid prescriptions had similar patient-reported outcomes but were more likely to have filled ≥1 opioid prescription 18 to 24 months after the index visit (odds ratio [95% confidence interval]=2.4 [1.5-3.9]) and to have had ≥1 visit to the emergency department in the subsequent 24 months (OR, 1.6; 95% confidence interval, 1.0-2.5).

Discussion: Among older patients with new back pain visits, filling ≥2 opioid prescriptions within 90 days of the visit was associated with similar back pain-related outcomes but increased likelihood of filling opioid prescriptions 18 to 24 months later compared with matched patients who did not fill early opioid prescriptions.
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http://dx.doi.org/10.1097/AJP.0000000000000557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837891PMC
April 2018

Using Natural Language Processing of Free-Text Radiology Reports to Identify Type 1 Modic Endplate Changes.

J Digit Imaging 2018 02;31(1):84-90

Comparative Effectiveness, Cost and Outcomes Research Center, University of Washington, Seattle, WA, USA.

Electronic medical record (EMR) systems provide easy access to radiology reports and offer great potential to support quality improvement efforts and clinical research. Harnessing the full potential of the EMR requires scalable approaches such as natural language processing (NLP) to convert text into variables used for evaluation or analysis. Our goal was to determine the feasibility of using NLP to identify patients with Type 1 Modic endplate changes using clinical reports of magnetic resonance (MR) imaging examinations of the spine. Identifying patients with Type 1 Modic change who may be eligible for clinical trials is important as these findings may be important targets for intervention. Four annotators identified all reports that contained Type 1 Modic change, using N = 458 randomly selected lumbar spine MR reports. We then implemented a rule-based NLP algorithm in Java using regular expressions. The prevalence of Type 1 Modic change in the annotated dataset was 10%. Results were recall (sensitivity) 35/50 = 0.70 (95% confidence interval (C.I.) 0.52-0.82), specificity 404/408 = 0.99 (0.97-1.0), precision (positive predictive value) 35/39 = 0.90 (0.75-0.97), negative predictive value 404/419 = 0.96 (0.94-0.98), and F1-score 0.79 (0.43-1.0). Our evaluation shows the efficacy of rule-based NLP approach for identifying patients with Type 1 Modic change if the emphasis is on identifying only relevant cases with low concern regarding false negatives. As expected, our results show that specificity is higher than recall. This is due to the inherent difficulty of eliciting all possible keywords given the enormous variability of lumbar spine reporting, which decreases recall, while availability of good negation algorithms improves specificity.
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http://dx.doi.org/10.1007/s10278-017-0013-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5788819PMC
February 2018

Reply: Crowdsourcing as a Novel Method to Evaluate Aesthetic Outcomes of Treatment for Unilateral Cleft Lip.

Plast Reconstr Surg 2017 09;140(3):515e

Division of Plastic Surgery, Department of Surgery, University of Washington, Division of Craniofacial and Plastic Surgery, Seattle Children's Hospital, Seattle, Wash.

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http://dx.doi.org/10.1097/PRS.0000000000003635DOI Listing
September 2017

Associations Between Relative Value Units and Patient-Reported Back Pain and Disability.

Gerontol Geriatr Med 2017 Jan-Dec;3:2333721416686019. Epub 2017 Jan 16.

University of Washington, Seattle, WA, USA.

To describe associations between health care utilization measures and patient-reported outcomes (PROs). Primary data were collected from patients ≥65 years with low back pain visits from 2011 to 2013. Six PROs of pain and functionality were collected 12 and 24 months after the index visits and total and spine-specific relative value units (RVUs) from electronic health records were tabulated over 1 year. We calculated correlation coefficients between RVUs and 12- and 24-month PROs and conducted linear regressions with each 12- and 24-month PRO as the outcome variables and RVUs as predictors of interest. We observed very weak correlations between worse PROs at 12 and 24 months and greater 12-month utilization. In regression analyses, we observed slight associations between greater utilization and worse 12- and 24-month PROs. We found that 12-month health care utilization is not strongly associated with PROs at 12 or 24 months.
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http://dx.doi.org/10.1177/2333721416686019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5384601PMC
January 2017

Long-Term Effects of Repeated Injections of Local Anesthetic With or Without Corticosteroid for Lumbar Spinal Stenosis: A Randomized Trial.

Arch Phys Med Rehabil 2017 08 8;98(8):1499-1507.e2. Epub 2017 Apr 8.

Comparative Effectiveness, Cost and Outcomes Research Center, University of Washington, Seattle, WA; Department of Radiology, University of Washington, Seattle, WA; Department of Health Services, University of Washington, Seattle, WA.

Objective: To determine the overall long-term effectiveness of treatment with epidural corticosteroid injections for lumbar central spinal stenosis and the effect of repeat injections, including crossover injections, on outcomes through 12 months.

Design: Multicenter, double-blind, randomized controlled trial comparing epidural injections of corticosteroid plus lidocaine versus lidocaine alone.

Setting: Sixteen clinical sites.

Participants: Participants with imaging-confirmed lumbar central spinal stenosis (N=400).

Interventions: Participants were randomized to receive either epidural injections with corticosteroid plus lidocaine or lidocaine alone with the option of blinded crossover after 6 weeks to receive the alternate treatment. Participants could receive 1 to 2 injections from 0 to 6 weeks and up to 2 injections from 6 to 12 weeks. After 12 weeks, participants received usual care.

Main Outcome Measures: Primary outcomes were the Roland-Morris Disability Questionnaire (RDQ) (range, 0-24, where higher scores indicate greater disability) and leg pain intensity (range, 0 [no pain] to 10 [pain as bad as you can imagine]). Secondary outcomes included opioid use, spine surgery, and crossover rates.

Results: At 12 months, both treatment groups maintained initial observed improvements, with no significant differences between groups on the RDQ (adjusted mean difference, -0.4; 95% confidence interval [CI], -1.6 to 0.9; P=.55), leg pain (adjusted mean difference, 0.1; 95% CI, -0.5 to 0.7; P=.75), opioid use (corticosteroid plus lidocaine: 41.4% vs lidocaine alone: 36.3%; P=.41), or spine surgery (corticosteroid plus lidocaine: 16.8% vs lidocaine alone: 11.8%; P=.22). Fewer participants randomized to corticosteroid plus lidocaine (30%, n=60) versus lidocaine alone (45%, n=90) crossed over after 6 weeks (P=.003). Among participants who crossed over at 6 weeks, the 6- to 12-week RDQ change did not differ between the 2 randomized treatment groups (adjusted mean difference, -1.0; 95% CI, -2.6 to 0.7; P=.24). In both groups, participants crossing over at 6 weeks had worse 12-month trajectories compared with participants who did not choose to crossover.

Conclusions: For lumbar spinal stenosis symptoms, epidural injections of corticosteroid plus lidocaine offered no benefits from 6 weeks to 12 months beyond that of injections of lidocaine alone in terms of self-reported pain and function or reduction in use of opioids and spine surgery. In patients with improved pain and function 6 weeks after initial injection, these outcomes were maintained at 12 months. However, the trajectories of pain and function outcomes after 3 weeks did not differ by injectate type. Repeated injections of either type offered no additional long-term benefit if injections in the first 6 weeks did not improve pain.
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http://dx.doi.org/10.1016/j.apmr.2017.02.029DOI Listing
August 2017

Prioritizing research topics: a comparison of crowdsourcing and patient registry.

Qual Life Res 2018 Jan 5;27(1):41-50. Epub 2017 Apr 5.

Surgical Outcomes Research Center, Department of Surgery, University of Washington, Seattle, WA, USA.

Purpose: A cornerstone of patient-centered outcome research is direct patient involvement throughout the research process. Identifying and prioritizing research topics is a critical but often overlooked point for involvement, as it guides what research questions are asked. We assess the feasibility of involving individuals with low back pain in identifying and prioritizing research topics using two approaches: an existing patient registry and an online crowdsourcing platform. We compare and contrast the diversity of participants recruited, their responses, and resources involved.

Methods: Eligible participants completed a survey ranking their five highest priority topics from an existing list and supplying additional topics not previously identified. We analyzed their responses using descriptive statistics and content analysis.

Results: The patient registry yielded older (mean age 72.4), mostly White (70%), and well-educated (95% high school diploma or higher) participants; crowdsourcing yielded younger (mean age 36.6 years), mostly White (82%), and well-educated (98% high school diploma or higher) participants. The two approaches resulted in similar research priorities by frequency. Both provided open-ended responses that were useful, in that they illuminate additional and nuanced research topics. Overall, both approaches suggest a preference towards topics related to diagnosis and treatment over other topics.

Conclusion: Using a patient registry and crowdsourcing are both feasible recruitment approaches for engagement. Researchers should consider their approach, community, and resources when choosing their recruitment approach, as each approach has its own strengths and weaknesses. These approaches are likely most appropriate to supplement or to complement in-person and ongoing engagement strategies.
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http://dx.doi.org/10.1007/s11136-017-1566-9DOI Listing
January 2018

Crowdsourcing: a valid alternative to expert evaluation of robotic surgery skills.

Am J Obstet Gynecol 2016 Nov 27;215(5):644.e1-644.e7. Epub 2016 Jun 27.

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Lehigh Valley Health Network, Allentown, PA; Department of Obstetrics and Gynecology, Lehigh Valley Health Network, Allentown, PA.

Background: Robotic-assisted gynecologic surgery is common, but requires unique training. A validated assessment tool for evaluating trainees' robotic surgery skills is Robotic-Objective Structured Assessments of Technical Skills.

Objective: We sought to assess whether crowdsourcing can be used as an alternative to expert surgical evaluators in scoring Robotic-Objective Structured Assessments of Technical Skills.

Study Design: The Robotic Training Network produced the Robotic-Objective Structured Assessments of Technical Skills, which evaluate trainees across 5 dry lab robotic surgical drills. Robotic-Objective Structured Assessments of Technical Skills were previously validated in a study of 105 participants, where dry lab surgical drills were recorded, de-identified, and scored by 3 expert surgeons using the Robotic-Objective Structured Assessments of Technical Skills checklist. Our methods-comparison study uses these previously obtained recordings and expert surgeon scores. Mean scores per participant from each drill were separated into quartiles. Crowdworkers were trained and calibrated on Robotic-Objective Structured Assessments of Technical Skills scoring using a representative recording of a skilled and novice surgeon. Following this, 3 recordings from each scoring quartile for each drill were randomly selected. Crowdworkers evaluated the randomly selected recordings using Robotic-Objective Structured Assessments of Technical Skills. Linear mixed effects models were used to derive mean crowdsourced ratings for each drill. Pearson correlation coefficients were calculated to assess the correlation between crowdsourced and expert surgeons' ratings.

Results: In all, 448 crowdworkers reviewed videos from 60 dry lab drills, and completed a total of 2517 Robotic-Objective Structured Assessments of Technical Skills assessments within 16 hours. Crowdsourced Robotic-Objective Structured Assessments of Technical Skills ratings were highly correlated with expert surgeon ratings across each of the 5 dry lab drills (r ranging from 0.75-0.91).

Conclusion: Crowdsourced assessments of recorded dry lab surgical drills using a validated assessment tool are a rapid and suitable alternative to expert surgeon evaluation.
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http://dx.doi.org/10.1016/j.ajog.2016.06.033DOI Listing
November 2016

Subsequent health-care utilization associated with early physical therapy for new episodes of low back pain in older adults.

Spine J 2017 03 17;17(3):380-389. Epub 2016 Oct 17.

Comparative Effectiveness, Cost and Outcomes Research Center, University of Washington, 4333 Brooklyn Ave. NE Box 359455, 14th Floor Seattle, WA 98105.

Background: The association between early physical therapy (PT) and subsequent health-care utilization following a new visit for low back pain is not clear, particularly in the setting of acute low back pain.

Purpose: This study aimed to estimate the association between initiating early PT following a new visit for an episode of low back pain and subsequent back pain-specific health-care utilization in older adults.

Design/setting: This is a prospective cohort study. Data were collected at three integrated health-care systems in the United States through the Back Pain Outcomes using Longitudinal Data (BOLD) registry.

Patient Sample: We recruited 4,723 adults, aged 65 and older, presenting to a primary care setting with a new episode of low back pain.

Outcome Measures: Primary outcome was total back pain-specific relative value units (RVUs), from days 29 to 365. Secondary outcomes included overall RVUs for all health care and use of specific health-care services including imaging (x-ray and magnetic resonance imaging [MRI] or computed tomography [CT]), emergency department visits, physician visits, PT, spinal injections, spinal surgeries, and opioid use.

Methods: We compared patients who had early PT (initiated within 28 days of the index visit) with those not initiating early PT using appropriate, generalized linear models to adjust for potential confounding variables.

Results: Adjusted analysis found no statistically significant difference in total spine RVUs between the two groups (ratio of means 1.19, 95% CI of 0.72-1.96, p=.49). For secondary outcomes, only the difference between total spine imaging RVUs and total PT RVUs was statistically significant. The early PT group had greater PT RVUs; the ratio of means was 2.56 (95% CI of 2.17-3.03, p<.001). The early PT group had greater imaging RVUs; the ratio of means was 1.37 (95% CI of 1.09-1.71, p=.01.) CONCLUSIONS: We found that in a group of older adults presenting for a new episode of low back pain, the use of early PT is not associated with any statistically significant difference in subsequent back pain-specific health-care utilization compared with patients not receiving early PT.
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http://dx.doi.org/10.1016/j.spinee.2016.10.007DOI Listing
March 2017
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