Publications by authors named "Patrick T McGann"

50 Publications

Hydroyxurea improves cerebral oxygen saturation in children with sickle cell anemia.

Am J Hematol 2021 Feb 3. Epub 2021 Feb 3.

Division of Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

Neurologic complications are common in patients with sickle cell anemia (SCA), but conventional tools such as MRI and transcranial Doppler ultrasonography (TCD) do not fully assess cerebrovascular pathology. Cerebral tissue oximetry measures mixed oxygen saturation in the frontal lobes (S O ) and provides early prognostic information about tissue at risk of ischemic injury. Untreated patients with SCA have significantly lower S O than healthy controls that declines with age. Hydroxyurea is effective in preventing many SCA-related complications, but the degree to which it preserves normal neurophysiology is unclear. We analyzed participants enrolled in the Therapeutic Response Evaluation and Adherence Trial (TREAT, NCT02286154), which enrolled participants initiating hydroxyurea using individualized dosing (new cohort) and those previously taking hydroxyurea (old cohort) and was designed to monitor the long-term benefits of hydroxyurea. Cerebral oximetry was performed at baseline and annually. For the new cohort (median starting age = 12 months, n = 55), mean baseline S O was normal before starting hydroxyurea (mean 65%, 95% CI 58-72%) and significantly increased after 2 years (mean 72%, 95% CI 65-79%, p < .001). The S O for patients receiving long-term hydroxyurea (median age = 9.6 years) was normal at study entry (mean 66%, 95% CI 58-74%) and remained stable across 2 years. Both cohorts had significantly higher S O than published data from predominantly untreated SCA patients. Cerebral oximetry is a non-invasive method to assess cerebrovascular pathology that complements conventional imaging. Our results indicate that hydroxyurea suggests protection against neurophysiologic changes seen in untreated SCA.
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http://dx.doi.org/10.1002/ajh.26120DOI Listing
February 2021

Academic Challenges and School Service Utilization in Children with Sickle Cell Disease.

J Pediatr 2021 Mar 1;230:182-190. Epub 2020 Dec 1.

Cincinnati Children's Hospital Medical Center, Cincinnati, OH; University of Cincinnati College of Medicine, Cincinnati, OH.

Objectives: To describe the academic concerns and risk strata of children with sickle cell disease (SCD) as identified through a parent-directed screening tool and to compare the rates of these concerns with actual school service utilization in the clinic population.

Study Design: We completed a retrospective review of patients with SCD referred to the school intervention program during the 2017-2018 and 2018-2019 school years because of a school-related concern raised by parents or noted by the clinical team. All parents completed the Brief School Needs Inventory (BSNI), a validated parent-response tool used to stratify academic risk. Rates of special education services, grade retention, and results from neuropsychologic testing were captured. Clinical history, the use of disease-modifying therapy, and results from laboratory and neuroimaging studies were also obtained. Descriptive statistics were performed to examine demographic information, clinical history, and BSNI results.

Results: In total, 137 unique patients (age range, 14 months to 19 years) completed the BSNI during the study period, for 181 events. According to BSNI risk-stratification, 45% of patients were deemed low, 36% moderate, and 19% high academic risk. Over one-half of parents were concerned about their ability to advocate for their child's needs. Despite legal qualification for a Section 504 accommodation plan, only 20% had established plans. Academic concerns were common with 31% of children reporting an individualized education program and 20% with grade retention/remediation.

Conclusions: Concerns for academic challenges remain high among parents of children with SCD; however, school service utilization remains disproportionately low attributable to numerous reasons.
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http://dx.doi.org/10.1016/j.jpeds.2020.11.062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914200PMC
March 2021

Hydroxyurea Optimization through Precision Study (HOPS): study protocol for a randomized, multicenter trial in children with sickle cell anemia.

Trials 2020 Nov 27;21(1):983. Epub 2020 Nov 27.

University of Cincinnati College of Medicine, Cincinnati, OH, USA.

Background: Sickle cell disease (SCD) is a severe and devastating hematological disorder that affects over 100,000 persons in the USA and millions worldwide. Hydroxyurea is the primary disease-modifying therapy for the SCD, with proven benefits to reduce both short-term and long-term complications. Despite the well-described inter-patient variability in pharmacokinetics (PK), pharmacodynamics, and optimal dose, hydroxyurea is traditionally initiated at a weight-based dose with a subsequent conservative dose escalation strategy to avoid myelosuppression. Because the dose escalation process is time consuming and requires frequent laboratory checks, many providers default to a fixed dose, resulting in inadequate hydroxyurea exposure and suboptimal benefits for many patients. Results from a single-center trial of individualized, PK-guided dosing of hydroxyurea for children with SCD suggest that individualized dosing achieves the optimal dose more rapidly and provides superior clinical and laboratory benefits than traditional dosing strategies. However, it is not clear whether these results were due to individualized dosing, the young age that hydroxyurea treatment was initiated in the study, or both. The Hydroxyurea Optimization through Precision Study (HOPS) aims to validate the feasibility and benefits of this PK-guided dosing approach in a multi-center trial.

Methods: HOPS is a randomized, multicenter trial comparing standard vs. PK-guided dosing for children with SCD as they initiate hydroxyurea therapy. Participants (ages 6 months through 21 years), recruited from 11 pediatric sickle cell centers across the USA, are randomized to receive hydroxyurea either using a starting dose of 20 mg/kg/day (Standard Arm) or a PK-guided dose (Alternative Arm). PK data will be collected using a novel sparse microsampling approach requiring only 10 μL of blood collected at 3 time-points over 3 h. A protocol-guided strategy more aggressive protocols is then used to guide dose escalations and reductions in both arms following initiation of hydroxyurea. The primary endpoint is the mean %HbF after 6 months of hydroxyurea.

Discussion: HOPS will answer important questions about the clinical feasibility, benefits, and safety of PK-guided dosing of hydroxyurea for children with SCD with potential to change the treatment paradigm from a standard weight-based approach to one that safely and effectively optimize the laboratory and clinical response.

Trial Registration: ClinicalTrials.gov NCT03789591 . Registered on 28 December 2018.
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http://dx.doi.org/10.1186/s13063-020-04912-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691962PMC
November 2020

AnemoCheck-LRS: an optimized, color-based point-of-care test to identify severe anemia in limited-resource settings.

BMC Med 2020 11 16;18(1):337. Epub 2020 Nov 16.

Division of Hematology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, MLC 11027, Cincinnati, OH, 45229, USA.

Background: Severe anemia is common and frequently fatal for hospitalized patients in limited-resource settings. Lack of access to low-cost, accurate, and rapid diagnosis of anemia impedes the delivery of life-saving care and appropriate use of the limited blood supply. The WHO Haemoglobin Colour Scale (HCS) is a simple low-cost test but frequently inaccurate. AnemoCheck-LRS (limited-resource settings) is a rapid, inexpensive, color-based point-of-care (POC) test optimized to diagnose severe anemia.

Methods: Deidentified whole blood samples were diluted with plasma to create variable hemoglobin (Hb) concentrations, with most in the severe (≤ 7 g/dL) or profound (≤ 5 g/dL) anemia range. Each sample was tested with AnemoCheck-LRS and WHO HCS independently by three readers and compared to Hb measured by an electronic POC test (HemoCue 201) and commercial hematology analyzer.

Results: For 570 evaluations within the limits of detection of AnemoCheck-LRS (Hb ≤ 8 g/dL), the average difference between AnemoCheck-LRS and measured Hb was 0.5 ± 0.4 g/dL. In contrast, the WHO HCS overestimated Hb with an absolute difference of 4.9 ± 1.3 g/dL for samples within its detection range (Hb 4-14 g/dL, n = 405). AnemoCheck-LRS was much more sensitive (92%) for the diagnosis of profound anemia than WHO HCS (22%).

Conclusions: AnemoCheck-LRS is a rapid, inexpensive, and accurate POC test for anemia. AnemoCheck-LRS is more accurate than WHO HCS for detection of low Hb levels, severe anemia that may require blood transfusion. AnemoCheck-LRS should be tested prospectively in limited-resource settings where severe anemia is common, to determine its utility as a screening tool to identify patients who may require transfusion.
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http://dx.doi.org/10.1186/s12916-020-01793-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667733PMC
November 2020

Severe infusion-related reaction to crizanlizumab in an adolescent with sickle cell disease.

Am J Hematol 2020 12 30;95(12):E338-E339. Epub 2020 Sep 30.

Division of Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

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http://dx.doi.org/10.1002/ajh.26002DOI Listing
December 2020

When Actions Speak Louder Than Words - Racism and Sickle Cell Disease.

N Engl J Med 2020 Nov 1;383(20):1902-1903. Epub 2020 Sep 1.

From the Department of Pediatrics, Boston Medical Center, and the Department of Medicine, Boston Children's Hospital - both in Boston (A.P.-H.); and the Division of Hematology, Cincinnati Children's Hospital Medical Center, and the Department of Pediatrics, University of Cincinnati College of Medicine - both in Cincinnati (P.T.M.).

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http://dx.doi.org/10.1056/NEJMp2022125DOI Listing
November 2020

Changing the Clinical Paradigm of Hydroxyurea Treatment for Sickle Cell Anemia Through Precision Medicine.

Clin Pharmacol Ther 2021 Jan 8;109(1):73-81. Epub 2020 Oct 8.

Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

Sickle cell anemia (SCA) is a common and devastating inherited blood disorder, affecting millions of people across the world. Without treatment, SCA results in tremendous morbidity and early mortality. Hydroxyurea is the primary and most well-established pharmacologic therapy with proven benefits to ameliorate the clinical course of SCA, primarily due to its ability to increase the expression of fetal hemoglobin (HbF), which prevents sickling of red blood cells. The optimal induction of HbF depends upon selection and maintenance of the proper dose that maximizes benefits and minimizes toxicity. Due to the significant interpatient variability in hydroxyurea pharmacokinetics, pharmacodynamics, and dosing, most patients treated with hydroxyurea receive suboptimal doses and have only modest treatment responses. Recognizing this variability, using a precision medicine approach, we developed and prospectively evaluated an individualized dosing model for children with SCA, designed to optimize the hydroxyurea dose and clinical response. We utilize novel laboratory methods and a sparse sampling strategy requiring only 10 μL of blood collected 15 minutes, 60 minutes, and 180 minutes after a test dose. We use Bayesian adaptive control to estimate hydroxyurea exposure and to select an individual, optimal starting dose. This dosing model has resulted in HbF responses >30-40%, levels beyond what is achieved with traditional weight-based dosing and trial and error dose escalation. This hydroxyurea dosing strategy, if widely implemented, has the potential to change the treatment paradigm of hydroxyurea therapy and improve outcomes for the millions of patients with SCA across the world.
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http://dx.doi.org/10.1002/cpt.2028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902468PMC
January 2021

Multidrug-Resistant Organisms from Ophthalmic Cultures: Antibiotic Resistance and Visual Acuity.

Mil Med 2020 08;185(7-8):e1002-e1007

Department of Ophthalmology, Brooke Army Medical Center, 3551 Roger Brooke Drive, San Antonio, TX 78234.

Introduction: There is a growing trend of multidrug-resistant organisms (MDRO). The goal of this study was to characterize MDRO at a single center from ophthalmic cultures to better understand how treatments were tailored and to assess effect on visual acuity.

Materials And Methods: The MDRO data were collected by the Multidrug-Resistant Organism Repository and Surveillance Network from the Brooke Army Medical Center clinical laboratory. Both patient- and isolate-specific data were collected and qualitatively analyzed. Primary outcome measures were organism and type of resistance, anatomic location of isolate, initial and final antibiotic choice, and visual acuity.

Results: Thirty-one bacterial culture samples were analyzed from 29 patients. Twenty-two (72%) were Gram-positive and all were methicillin-resistant Staphylococcus aureus (MRSA). Nine (29%) were Gram-negative and of these five were Pseudomonas spp. Fourteen (45%) isolates were cultured from the cornea, nine (29%) from the lid, four (13%) from the conjunctiva, and four (13%) from other locations. The majority (66.6%) required adjustment of initial antibiotics following ocular culture results. Sixteen adult patients had recorded initial and final visual acuities. Fifteen of those 16 patients had stable or improved visual acuities following treatment of the infection, but five patients had a final visual acuity less than 20/200.

Conclusion: This study demonstrated a high frequency of corneal MDRO infections and specifically MRSA and Pseudomonas spp. isolates. Antibiotic treatments frequently required adjustment. Further prospective study of visual outcomes from ophthalmic MDRO cultures is needed.
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http://dx.doi.org/10.1093/milmed/usaa111DOI Listing
August 2020

The Increasing Global Burden of Childhood Disability: A Call for Action.

Pediatrics 2020 07 17;146(1). Epub 2020 Jun 17.

Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; and.

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http://dx.doi.org/10.1542/peds.2020-1119DOI Listing
July 2020

End points for sickle cell disease clinical trials: renal and cardiopulmonary, cure, and low-resource settings.

Blood Adv 2019 12;3(23):4002-4020

Division of Pediatric Hematology Oncology and Stem Cell Transplant, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO.

To address the global burden of sickle cell disease and the need for novel therapies, the American Society of Hematology partnered with the US Food and Drug Administration to engage the work of 7 panels of clinicians, investigators, and patients to develop consensus recommendations for clinical trial end points. The panels conducted their work through literature reviews, assessment of available evidence, and expert judgment focusing on end points related to patient-reported outcome, pain (non-patient-reported outcomes), the brain, end-organ considerations, biomarkers, measurement of cure, and low-resource settings. This article presents the findings and recommendations of the end-organ considerations, measurement of cure, and low-resource settings panels as well as relevant findings and recommendations from the biomarkers panel.
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http://dx.doi.org/10.1182/bloodadvances.2019000883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6963248PMC
December 2019

Robust clinical and laboratory response to hydroxyurea using pharmacokinetically guided dosing for young children with sickle cell anemia.

Am J Hematol 2019 08 12;94(8):871-879. Epub 2019 Jun 12.

Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.

Hydroxyurea is FDA-approved and now increasingly used for children with sickle cell anemia (SCA), but dosing strategies, pharmacokinetic (PK) profiles, and treatment responses for individual patients are highly variable. Typical weight-based dosing with step-wise escalation to maximum tolerated dose (MTD) leads to predictable laboratory and clinical benefits, but often takes 6 to 12 months to achieve. The Therapeutic Response Evaluation and Adherence Trial (TREAT, NCT02286154) was a single-center study designed to prospectively validate a novel personalized PK-guided hydroxyurea dosing strategy with a primary endpoint of time to MTD. Enrolled participants received a single oral 20 mg/kg dose of hydroxyurea, followed by a sparse PK sampling approach with three samples collected over three hours. Analysis of individual PK data into a population PK model generated a starting dose that targets the MTD. The TREAT cohort (n = 50) was young, starting hydroxyurea at a median age of 11 months (IQR 9-26 months), and PK-guided starting doses were high (27.7 ± 4.9 mg/kg/d). Time to MTD was 4.8 months (IQR 3.3-9.3), significantly shorter than comparison studies (p < 0.0001), thus meeting the primary endpoint. More remarkably, the laboratory response for participants starting with a PK-guided dose was quite robust, achieving higher hemoglobin (10.1 ± 1.3 g/dL) and HbF (33.3 ± 9.1%) levels than traditional dosing. Though higher than traditional dosing, PK-guided doses were safe without excess hematologic toxicities. Our data suggest early initiation of hydroxyurea, using a personalized dosing strategy for children with SCA, provides laboratory and clinical response beyond what has been seen historically, with traditional weight-based dosing.
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http://dx.doi.org/10.1002/ajh.25510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639795PMC
August 2019

Use of whole-genome sequencing to guide a Clostridioides difficile diagnostic stewardship program.

Infect Control Hosp Epidemiol 2019 07 15;40(7):804-806. Epub 2019 May 15.

Departments of Infection Prevention and Infectious Diseases,MedStar Washington Hospital Center,Washington,DC.

Whole-genome sequencing (WGS) has yielded new insights into the transmission patterns of healthcare facility-onset Clostridioides difficile infection (HO-CDI). WGS results prompted a focused diagnostic stewardship program, which was associated with a significant and sustained decrease in HO-CDI at large, urban hospital.
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http://dx.doi.org/10.1017/ice.2019.124DOI Listing
July 2019

Hydroxyurea for children with sickle cell anemia: Prescribe it early and often.

Pediatr Blood Cancer 2019 08 30;66(8):e27778. Epub 2019 Apr 30.

Division of Hematology, University of Cincinnati College of Medicine, Cincinnati, Ohio.

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http://dx.doi.org/10.1002/pbc.27778DOI Listing
August 2019

Non-transfusion-dependent β-Thalassemia Because of a Single β-Thalassemia Mutation and Coinherited α-Globin Gene Triplication: Need for Increased Awareness to Prevent Incorrect and Delayed Diagnosis.

J Pediatr Hematol Oncol 2020 08;42(6):e494-e496

Division of Hematology.

The thalassemias are genetically complex and usually autosomal recessive. We describe 5 unrelated individuals with non-transfusion-dependent β-thalassemia (NTDT), some with apparently dominant transmission, because of a single β-thalassemia mutation coinherited with a triplicated α-globin locus. Each had an initial, incorrect diagnosis of β-thalassemia trait. The correct diagnosis of NTDT was made at a mean of 7 years of age. Despite reports of this compound genotype causing NTDT, it remains unfamiliar to many clinicians. To increase awareness, we highlight its varied and sometimes subtle clinical and laboratory features and the need for comprehensive genetic testing for timely and correct diagnosis.
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http://dx.doi.org/10.1097/MPH.0000000000001470DOI Listing
August 2020

Rapid detection of colistin resistance protein MCR-1 by LC-MS/MS.

Clin Proteomics 2019 26;16. Epub 2019 Feb 26.

3Department of Laboratory Medicine, Clinical Center, Microbiology Service, National Institutes of Health, 10 Center Drive, Bethesda, MD USA.

Background: Colistin (polymyxin E) and polymixin B are important bactericidal antibiotics used in the treatment of serious infections caused by multi-drug resistant Gram-negative organisms. Transferrable plasmid-mediated colistin resistance, conferred by the product of the - gene, has emerged as a global healthcare threat. Consequently, the rapid detection of the MCR-1 protein in clinical bacterial isolates has become increasingly important. We used a genoproteomic approach to identify unique peptides of the MCR-1 protein that could be detected rapidly by liquid chromatography tandem mass spectrometry (LC-MS/MS).

Methods: MCR-1 tryptic peptides that were efficiently ionized and readily detectable were characterized in a set of --containing isolates with triple quadrupole LC-MS. Three optimal peptides were selected for the development of a rapid multiple reaction monitoring LC-MS/MS assay for the MCR-1 protein. To investigate the feasibility of rapid detection of the MCR-1 protein in bacterial isolates using this assay, a blinded 99-sample test set was built that included three additional --containing clinical isolates tested in triplicate (9 samples) and 90 negative control isolates.

Results: All of the --containing isolates in the test set were accurately identified with no false positive detections by three independent, blinded operators, yielding an overall performance of 100% sensitivity and specificity for multiple operators. Among the three peptides tested in this study, the best performing was DTFPQLAK. The isolate-to-result time for the assay as implemented is less than 90 min.

Conclusions: This work demonstrates the feasibility of rapid detection of the MCR-1 protein in bacterial isolates by LC-MS/MS.
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http://dx.doi.org/10.1186/s12014-019-9228-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6390366PMC
February 2019

Identification of the OXA-48 Carbapenemase Family by Use of Tryptic Peptides and Liquid Chromatography-Tandem Mass Spectrometry.

J Clin Microbiol 2019 05 26;57(5). Epub 2019 Apr 26.

Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA

Phenotypic detection of the OXA-48-type class D β-lactamases in is challenging. We describe a rapid (less than 90 min) assay for the identification of OXA-48 family carbapenemases in subcultured bacterial isolates based on a genoproteomic approach. Following trypsin digestion to ascertain theoretical core peptides common to the OXA-48 family, liquid chromatography-tandem mass spectrometry (LC-MS/MS) data-dependent acquisition was used to identify candidate peptide markers. Two peptides were selected based on performance characteristics: ANQAFLPASTFK, a core peptide common to all 12 OXA-48 family β-lactamase members, and YSVVPVYQEFAR, a highly specific peptide common to 11 of 12 OXA-48 family proteins providing the basis for an LC-MS/MS multiple reaction monitoring assay. An accuracy assessment was performed that included 98 isolates, 26 of which were OXA-48 positive. Two additional specificity assessments were performed including a mixture of isolates positive for OXA-48, KPC, NDM, VIM, and IMP carbapenemases. A combination of expert rules and expert judgment was applied by blinded operators to identify positive isolates. All isolates containing an OXA-48 family carbapenemase across all three test sets were correctly identified with no false positives, demonstrating 100% sensitivity (95% confidence interval [CI], 91.2% to 100%) and 100% specificity (95% CI, 96.2% to 100%) for the assay. These findings provide a framework for an LC-MS/MS-based method for the direct detection of OXA-48 family carbapenemases from cultured isolates that may have utility in predicting carbapenem resistance and tracking hospital outbreaks of OXA-48-carrying organisms.
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http://dx.doi.org/10.1128/JCM.01240-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6498012PMC
May 2019

Bacteraemia due to in a patient with chronic kidney disease, refractory hypertension and sarcoidosis.

JMM Case Rep 2018 Nov 31;5(11):e005169. Epub 2018 Oct 31.

Walter Reed National Military Medical Center, Bethesda, MD, USA.

Introduction: spp. are yellow-pigmented Gram-positive coryneform rods found in various environmental sources, such as soil and water samples. They rarely cause human infection, mostly infecting immunocompromised patients and catheter insertion sites, making them challenging to identify in clinical settings.

Case Presentation: We report a case of a 61-year-old female on long-term prednisone therapy for sarcoidosis with minimal exposure to environmental sources, who presented with an overtly infected Hickman catheter site and presyncope. The patient had a central venous catheter (CVC) that had been in place for the previous 6 years for treatment of refractory hypertension and congestive heart failure. Blood cultures obtained from the CVC on initial presentation were positive for a mixed infection, which was subcultured and grew , , and based on the Becton Dickinson Phoenix Automated Microbiology System. The , designated as isolate 4120, was further analysed, since infections associated with this organism are uncommon, and it was the only organism to grow from the patient's catheter tip. Matrix-assisted laser desorption ionization-time of flight MS identified isolate 4120 as . To resolve the conflicting results, additional analyses of isolate 4120 were carried out and compared to several reference strains. Isolate 4120 was found to have intermediate susceptibility to ciprofloxacin and non-susceptibility to vancomycin. Morphology, susceptibility, biochemical characteristics and whole-genome sequencing confirmed the clinical isolate as .

Conclusion: In this case, we identified an organism that is rarely seen in clinical settings and characterized it with a comprehensive laboratory analysis. The patient in our case responded to replacement of the CVC, and treatment with levofloxacin by mouth and intravenous vancomycin.
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http://dx.doi.org/10.1099/jmmcr.0.005169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6321868PMC
November 2018

Hydroxyurea for Children with Sickle Cell Anemia in Sub-Saharan Africa.

N Engl J Med 2019 01 1;380(2):121-131. Epub 2018 Dec 1.

From Centre Hospitalier Monkole, Kinshasa, Democratic Republic of Congo (L.T.); the Department of Medicine, University Health Network and Mt. Sinai Hospital, and the University of Toronto, Toronto (G.T.); the Kenya Medical Research Institute (KEMRI)-Wellcome Trust Research Program, Kilifi, Kenya (T.N.W.); the Department of Medicine, Imperial College London, London (T.N.W.); Hospital Pediátrico David Bernardino, Luanda, Angola (B.S.); Mbale Clinical Research Institute and Mbale Regional Referral and Teaching Hospital-Busitema University, Mbale, Uganda (P.O.-O.); the Division of Hematology, Department of Pediatrics, Cincinnati Children's Hospital (A.L., S.E.S., T.S.L., P.T.M., R.E.W.), University of Cincinnati College of Medicine (A.L., P.T.M., R.E.W.), and the Global Health Center, Cincinnati Children's Hospital Medical Center (S.E.S., P.T.M., R.E.W.), Cincinnati; and Cohen Children's Medical Center, New Hyde Park, and the Zucker School of Medicine at Hofstra/Northwell, Hempstead - both in New York (B.A.).

Background: Hydroxyurea is an effective treatment for sickle cell anemia, but few studies have been conducted in sub-Saharan Africa, where the burden is greatest. Coexisting conditions such as malnutrition and malaria may affect the feasibility, safety, and benefits of hydroxyurea in low-resource settings.

Methods: We enrolled children 1 to 10 years of age with sickle cell anemia in four sub-Saharan countries. Children received hydroxyurea at a dose of 15 to 20 mg per kilogram of body weight per day for 6 months, followed by dose escalation. The end points assessed feasibility (enrollment, retention, and adherence), safety (dose levels, toxic effects, and malaria), and benefits (laboratory variables, sickle cell-related events, transfusions, and survival).

Results: A total of 635 children were fully enrolled; 606 children completed screening and began receiving hydroxyurea at a mean (±SD) dose of 17.5±1.8 mg per kilogram per day. The retention rate was 94.2% at 3 years of treatment. Hydroxyurea therapy led to significant increases in both the hemoglobin and fetal hemoglobin levels. Dose-limiting toxic events regarding laboratory variables occurred in 5.1% of the participants, which was below the protocol-specified threshold for safety. During the treatment phase, 20.6 dose-limiting toxic effects per 100 patient-years occurred, as compared with 20.7 events per 100 patient-years before treatment. As compared with the pretreatment period, the rates of clinical adverse events decreased with hydroxyurea use, including rates of vaso-occlusive pain (98.3 vs. 44.6 events per 100 patient-years; incidence rate ratio, 0.45; 95% confidence interval [CI], 0.37 to 0.56), nonmalaria infection (142.5 vs. 90.0 events per 100 patient-years; incidence rate ratio, 0.62; 95% CI, 0.53 to 0.72), malaria (46.9 vs. 22.9 events per 100 patient-years; incidence rate ratio, 0.49; 95% CI, 0.37 to 0.66), transfusion (43.3 vs. 14.2 events per 100 patient-years; incidence rate ratio, 0.33; 95% CI, 0.23 to 0.47), and death (3.6 vs. 1.1 deaths per 100 patient-years; incidence rate ratio, 0.30; 95% CI, 0.10 to 0.88).

Conclusions: Hydroxyurea treatment was feasible and safe in children with sickle cell anemia living in sub-Saharan Africa. Hydroxyurea use reduced the incidence of vaso-occlusive events, infections, malaria, transfusions, and death, which supports the need for wider access to treatment. (Funded by the National Heart, Lung, and Blood Institute and others; REACH ClinicalTrials.gov number, NCT01966731 .).
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http://dx.doi.org/10.1056/NEJMoa1813598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454575PMC
January 2019

An intervention to control an ICU outbreak of carbapenem-resistant Acinetobacter baumannii: long-term impact for the ICU and hospital.

Crit Care 2018 11 21;22(1):319. Epub 2018 Nov 21.

General Intensive Care Unit, Shaare Zedek Medical Center, Hebrew University, Jerusalem, Israel.

Background: Following a fatal intensive care unit (ICU) outbreak of carbapenem-resistant Acinetobacter baumanii (CRAB) in 2015, an aggressive infection control intervention was instituted. We outline the intervention and long-term changes in the incidence and prevalence of CRAB.

Methods: The infection control intervention included unit closure (3 days), environmental cleaning, hand hygiene interventions, and environmental culturing. CRAB acquisition and prevalence and colistin use were compared for the 1 year before and 2 years after the intervention.

Results: Following the intervention, ICU CRAB acquisition decreased significantly from 54.6 (preintervention) to 1.9 (year 1) to 5.6 cases (year 2)/1000 admissions (p < 0.01 for comparisons with preintervention period.). Unexpectedly, ICU CRAB admission prevalence also decreased from 56.5 to 5.8 to 13 cases/1000 admissions (p < 0.001) despite the infection control intervention's being directed at the ICU alone. In parallel, hospital CRAB prevalence decreased from 4.4 to 2.4 to 2.5 cases/1000 admissions (p < 0.001), possibly as a result of decreased discharge of CRAB carriers from the ICU to the wards (58.5 to 1.9 to 7.4 cases/1000 admissions; p < 0.001). ICU colistin consumption decreased from 200 to 132 to 75 defined daily dose (DDD)/1000 patient-days (p < 0.05). Hospital colistin consumption decreased from 21.2 to 19.4 to 14.1 DDD/1000 patient-days (p < 0.05).

Conclusions: The ICU infection control intervention was highly effective, long-lasting, and associated with a decrease in last-line antibiotic use. The intervention was associated with the unexpected finding that hospital CRAB prevalence also decreased.
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http://dx.doi.org/10.1186/s13054-018-2247-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6249923PMC
November 2018

Prevalence of inherited blood disorders and associations with malaria and anemia in Malawian children.

Blood Adv 2018 11;2(21):3035-3044

Department of Pediatrics and.

In sub-Saharan Africa, inherited causes of anemia are common, but data are limited regarding the geographical prevalence and coinheritance of these conditions and their overall contributions to childhood anemia. To address these questions in Malawi, we performed a secondary analysis of the 2015-2016 Malawi Micronutrient Survey, a nationally and regionally representative survey that estimated the prevalence of micronutrient deficiencies and evaluated both inherited and noninherited determinants of anemia. Children age 6 to 59 months were sampled from 105 clusters within the 2015-2016 Malawi Demographic Health Survey. Hemoglobin, ferritin, retinol binding protein, malaria, and inflammatory biomarkers were measured from venous blood. Molecular studies were performed using dried blood spots to determine the presence of sickle cell disease or trait, α-thalassemia trait, and glucose-6-phosphate dehydrogenase (G6PD) deficiency. Of 1279 eligible children, 1071 were included in the final analysis. Anemia, iron deficiency, and malaria were common, affecting 30.9%, 21.5%, and 27.8% of the participating children, respectively. α-Thalassemia trait was common (>40% of children demonstrating deletion of 1 [33.1%] or 2 [10.0%] α-globin genes) and associated with higher prevalence of anemia ( < .001). Approximately 20% of males had G6PD deficiency, which was associated with a 1.0 g/dL protection in hemoglobin decline during malaria infection ( = .02). These data document that inherited blood disorders are common and likely play an important role in the prevalence of anemia and malaria in Malawian children.
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http://dx.doi.org/10.1182/bloodadvances.2018023069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6234379PMC
November 2018

Hereditary elliptocytosis-associated alpha-spectrin mutation p.L155dup as a modifier of sickle cell disease severity.

Pediatr Blood Cancer 2019 02 4;66(2):e27531. Epub 2018 Nov 4.

Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

The broad phenotypic variability among individuals with sickle cell disease (SCD) suggests the presence of modifying factors. We identified two unrelated SCD patients with unusually severe clinical and laboratory phenotype that were found to carry the hereditary elliptocytosis-associated alpha-spectrin mutation c.460_462dupTTG (p.L155dup), a mutation enriched due to positive selective pressure of malaria, similar to the SCD globin mutations. A high index of suspicion for additional hematologic abnormalities may be indicated for challenging patients with SCD. These cases highlight the validity of specialized testing such as ektacytometry and next-generation sequencing for patients and family members to assess genotype/phenotype correlations.
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http://dx.doi.org/10.1002/pbc.27531DOI Listing
February 2019

The Collaborative Role of North American Departments of Pediatrics in Global Child Health.

Pediatrics 2018 07 12;142(1). Epub 2018 Jun 12.

Division of Global Pediatrics, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota; and.

Appeals for health equity call for departments of pediatrics to improve the health of all children including those from underserved communities in North America and around the world. Consequently, North American (NA) departments of pediatrics have a role in global child health (GCH) which focuses on providing health care to underserved children worldwide. In this review, we describe how NA departments of pediatrics can collaboratively engage in GCH education, clinical practice, research, and advocacy and summarize best practices, challenges, and next steps for engaging in GCH in each of these areas. For GCH in low- and middle-income countries (LMICs), best practices start with the establishment of ethical, equitable, and collaborative partnerships with LMIC communities, organizations, and institutions engaged in GCH who are responsible for the vast majority of work done in GCH. Other best practices include adequate preparation of trainees and clinicians for GCH experiences; alignment with local clinical and research priorities; contributions to local professional development and ongoing monitoring and evaluation. Challenges for departments include generating funding for GCH activities; recruitment and retention of GCH-focused faculty members; and challenges meeting best practices, particularly adequate preparation of trainees and clinicians and ensuring mutual benefit and reciprocity in NA-LMIC collaborations. We provide examples of how departments have overcome these challenges and suggest next steps for development of the role of NA departments of pediatrics in GCH. Collaborative implementation of best practices in GCH by LMIC-NA partnerships can contribute to reductions of child mortality and morbidity globally.
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http://dx.doi.org/10.1542/peds.2017-2966DOI Listing
July 2018

Model-based dosing with concentration feedback as an integral part of personalized hydroxycarbamide management.

Br J Clin Pharmacol 2018 07 17;84(7):1410-1412. Epub 2018 Apr 17.

Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

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http://dx.doi.org/10.1111/bcp.13585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6005594PMC
July 2018

Utilization trends and safety of intravenous iron replacement in pediatric specialty care: A large retrospective cohort study.

Pediatr Blood Cancer 2018 06 25;65(6):e26995. Epub 2018 Jan 25.

Division of Hematology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

Background: Iron deficiency is a common and clinically diverse hematologic disorder in childhood for which oral iron is often an infeasible or ineffective treatment option. Intravenous (IV) iron can be an efficient and highly successful means of iron replacement but its use has not been well-characterized on a large scale in pediatrics.

Procedure: All IV iron doses administered to patients for iron replacement therapy at a tertiary pediatric hospital from January 2010 through October 2016 were evaluated. Analyses included patient demographics, underlying medical conditions, and detailed information for each dose. Individual chart review was performed to identify infusion-related reactions. Nephrology patients as well as those patients 21 years or older at the time of the first infusion were excluded.

Results: A total of 1,088 doses of IV iron administered to 194 patients met inclusion criteria. A wide variety of specialties prescribed IV iron, with gastroenterology, hematology, and hospital medicine being the highest users in this cohort. A majority of patients (68%) required multiple infusions and dosing was highly variable, ranging from 1.3-1,030 mg per infusion. Premedication use was infrequent (10.3% of doses) and no severe infusion-associated reactions occurred.

Conclusions: IV iron is commonly prescribed by certain pediatric specialties but there is little standardization in the indications, formulations, or dosing. These data suggest that IV iron should be considered a safe alternative for iron deficiency treatment in pediatrics when oral iron is either unsuccessful or contraindicated.
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http://dx.doi.org/10.1002/pbc.26995DOI Listing
June 2018

Realizing effectiveness across continents with hydroxyurea: Enrollment and baseline characteristics of the multicenter REACH study in Sub-Saharan Africa.

Am J Hematol 2018 08 27;93(4):537-545. Epub 2018 Jan 27.

Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

Despite its well-described safety and efficacy in the treatment of sickle cell anemia (SCA) in high-income settings, hydroxyurea remains largely unavailable in sub-Saharan Africa, where more than 75% of annual SCA births occur and many comorbidities exist. Realizing Effectiveness Across Continents with Hydroxyurea (REACH, ClinicalTrials.gov NCT01966731) is a prospective, Phase I/II open-label trial of hydroxyurea designed to evaluate the feasibility, safety, and benefits of hydroxyurea treatment for children with SCA in four sub-Saharan African countries. Following comprehensive training of local research teams, REACH was approved by local Ethics Committees and achieved full enrollment ahead of projections with 635 participants enrolled over a 30-month period, despite half of families living >12 km from their clinical site. At enrollment, study participants (age 5.4 ± 2.4 years) had substantial morbidity, including a history of vaso-occlusive pain (98%), transfusion (68%), malaria (85%), and stroke (6%). Significant differences in laboratory characteristics were noted across sites, with lower hemoglobin concentrations (P < .01) in Angola (7.2 ± 1.0 g/dL) and the DRC (7.0 ± 0.9 g/dL) compared to Kenya (7.4 ± 1.1 g/dL) and Uganda (7.5 ± 1.1 g/dL). Analysis of known genetic modifiers of SCA demonstrated a high frequency of α-thalassemia (58.4% with at least a single α-globin gene deletion) and G6PD deficiency (19.7% of males and 2.4% of females) across sites. The CAR β-globin haplotype was present in 99% of participants. The full enrollment to REACH confirms the feasibility of conducting high-quality SCA research in Africa; this study will provide vital information to guide safe and effective dosing of hydroxyurea for children with SCA living in Africa.
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http://dx.doi.org/10.1002/ajh.25034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5870803PMC
August 2018

Simultaneous point-of-care detection of anemia and sickle cell disease in Tanzania: the RAPID study.

Ann Hematol 2018 Feb 16;97(2):239-246. Epub 2017 Nov 16.

Division of Hematology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, MLC 11027, Cincinnati, OH, 45229, USA.

Both anemia and sickle cell disease (SCD) are highly prevalent across sub-Saharan Africa, and limited resources exist to diagnose these conditions quickly and accurately. The development of simple, inexpensive, and accurate point-of-care (POC) assays represents an important advance for global hematology, one that could facilitate timely and life-saving medical interventions. In this prospective study, Robust Assays for Point-of-care Identification of Disease (RAPID), we simultaneously evaluated a POC immunoassay (Sickle SCAN™) to diagnose SCD and a first-generation POC color-based assay to detect anemia. Performed at Bugando Medical Center in Mwanza, Tanzania, RAPID tested 752 participants (age 1 day to 20 years) in four busy clinical locations. With minimally trained medical staff, the SCD POC assay diagnosed SCD with 98.1% sensitivity and 91.1% specificity. The hemoglobin POC assay had 83.2% sensitivity and 74.5% specificity for detection of severe anemia (Hb ≤ 7 g/dL). Interobserver agreement was excellent for both POC assays (r = 0.95-0.96). Results for the hemoglobin POC assay have informed the second-generation assay design to be more suitable for low-resource settings. RAPID provides practical feasibility data regarding two novel POC assays for the diagnosis of anemia and SCD in real-world field evaluations and documents the utility and potential impact of these POC assays for sub-Saharan Africa.
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http://dx.doi.org/10.1007/s00277-017-3182-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5870802PMC
February 2018

Clinical Features of β-Thalassemia and Sickle Cell Disease.

Adv Exp Med Biol 2017 ;1013:1-26

Division of Hematology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, MLC 11027, Cincinnati, OH, 45229, USA.

Sickle cell disease (SCD) and β-thalassemia are among the most common inherited diseases, affecting millions of persons globally. It is estimated that 5-7% of the world's population is a carrier of a significant hemoglobin variant. Without early diagnosis followed by initiation of preventative and therapeutic care, both SCD and β-thalassemia result in significant morbidity and early mortality. Despite great strides in the understanding of the molecular basis and pathophysiology of these conditions, the burden of disease remains high, particularly in limited resource settings. Current therapy relies heavily upon the availability and safety of erythrocyte transfusions to treat acute and chronic complications of these conditions, but frequent transfusions results in significant iron overload, as well as challenges from acquired infections and alloimmunization. Hydroxyurea is a highly effective treatment for SCD but less so for β-thalassemia, and does not represent curative therapy. As technology and use of cellular and gene therapies expand, SCD and thalassemia should be among the highest disease priorities.
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http://dx.doi.org/10.1007/978-1-4939-7299-9_1DOI Listing
April 2018

The pressing need for point-of-care diagnostics for sickle cell disease: A review of current and future technologies.

Blood Cells Mol Dis 2017 09 8;67:104-113. Epub 2017 Aug 8.

UCSF Benioff Children's Hospital Oakland, Oakland, CA, USA.

Sickle cell disease (SCD) is a common and life threatening inherited blood disorder, affecting over 300,000 newborns per year. Over 75% of SCD births occur in sub-Saharan Africa, where the lack of timely and accurate diagnosis results in premature death within the first few years of life for a majority of affected infants. Current methods to diagnosis SCD require expensive laboratory equipment and reagents, and adequately trained laboratory personnel. In addition, test results are often delayed due to transport and batching of samples in a central laboratory. Financial and technical limitations often preclude any form of SCD laboratory testing at the local level in regions where SCD is most prevalent. There has been a recent surge of interest in addressing the global burden of SCD, including improving and optimizing diagnostic capacities. Largely stimulated by a funding opportunity from the NIH, several point-of-care diagnostics have been developed for SCD with a focus on developing devices that are inexpensive, simple, and practical in limited resource settings. In this manuscript, we review the global burden of SCA, including the rationale for the development of POC assays, and carefully review the POC devices currently in development.
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http://dx.doi.org/10.1016/j.bcmd.2017.08.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5868350PMC
September 2017

Sickle cell anemia in sub-Saharan Africa: advancing the clinical paradigm through partnerships and research.

Blood 2017 01 7;129(2):155-161. Epub 2016 Nov 7.

Division of Hematology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati OH.

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http://dx.doi.org/10.1182/blood-2016-09-702324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5234214PMC
January 2017

Stable-Isotope Dilution HPLC-Electrospray Ionization Tandem Mass Spectrometry Method for Quantifying Hydroxyurea in Dried Blood Samples.

Clin Chem 2016 Dec 30;62(12):1593-1601. Epub 2016 Sep 30.

Department of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.

Background: Sickle cell anemia (SCA) is a life-threatening blood disorder characterized by the presence of sickle-shaped erythrocytes. Hydroxyurea is currently the only US Food and Drug Administration-approved treatment and there is a need for a convenient method to monitor compliance and hydroxyurea concentrations, especially in pediatric SCA patients.

Methods: We describe a novel approach to the determination of hydroxyurea concentrations in dried whole blood collected on DMPK-C cards or volumetric absorptive microsampling (VAMS) devices. Hydroxyurea was quantified by electrospray ionization LC-MS/MS using [CN]hydroxyurea as the internal standard. Calibrators were prepared in whole blood applied to DMPK-C cards or VAMS devices.

Results: Calibration curves for blood hydroxyurea measured from DMPK-C cards and VAMS devices were linear over the range 0.5-60 μg/mL. Interassay and intraassay CVs were <15% for blood collected by both methods, and the limit of detection was 5 ng/mL. Whole blood hydroxyurea was stable for up to 60 days on DMPK-C cards and VAMS devices when frozen at -20 °C or -80 °C. Whole blood hydroxyurea concentrations in samples collected on DMPK-C cards or VAMS devices from SCA patients were in close agreement.

Conclusions: This tandem mass spectrometry method permits measurement of hydroxyurea concentrations in small volumes of dried blood applied to either DMPK-C cards or VAMS devices with comparable performance. This method for measuring hydroxyurea from dried blood permits the evaluation of therapeutic drug monitoring, individual pharmacokinetics, and medication adherence using heel/finger-prick samples from pediatric patients with SCA treated with hydroxyurea.
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http://dx.doi.org/10.1373/clinchem.2016.263715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6598440PMC
December 2016