Publications by authors named "Kenneth Rogers"

141 Publications

Applications and Error Ratios of Calibration Techniques in EOS, Orthoroentgenogram, and Teleoroentgenogram for Length Measurement: A Comparative Study.

J Pediatr Orthop 2021 Sep 21. Epub 2021 Sep 21.

Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE.

Background: Accurate length measurements of extremity bones are essential in treating limb deformities and length discrepancies in children.

Objective: This study aimed to determine errors in common techniques used to measure lower limb lengths in children.

Methods: Precision and instrument errors in length measurements were studied utilizing electro-optical system (EOS), orthoroentgenogram, and teleoroentgenogram The goal was to measure a 70-cm metallic rod phantom (average length of the lower extremity of a 10-year-old boy in the 50th percentile) in 3 phases. In Phase 1, the length measurements were performed in an EOS unit with internal calibrations, a magball/magstrip in various scan positions, and measurement with TraumaCAD software. In Phase 2, the measurements were repeated utilizing a single radiation "shot" teleoroentgenogram. In Phase 3, an orthoroentgenogram was utilized with a radiopaque ruler reference. The reliability and validity of measurements were calibrated by 4 physicians (a radiologist, senior orthopaedic attending, and 2 orthopaedic fellows).

Results: EOS measurements utilizing internal references had excellent accuracy (for a 700-mm real length, magnification error (ME)] of 0.09%. Teleoroentgenogram with a magball reference and measurements performed with automatic calibration by TraumaCAD program results in ME of 1.83% with insignificant intraobserver/interobserver difference. Teleoroentgenogram with a magball or magstrip reference measured manually showed that the magball has higher intraobserver/interobserver variance than magstrip, with a 6.60 and 0.33-mm SD, respectively. The length by manual measurement utilizing the magstrip has ME of 2.21%. Orthoroentgenogram is accurate with ME of 0.26%, but does not allow anatomical analysis and is also radiation-costly.

Conclusion: EOS and orthoroentgenogram are very accurate for length measurements. Teleoroentgenogram is less accurate in measuring length; however, addition of an external reference (magball, magstrip) placed lateral to the target improves accuracy. Automatic calibration with computer-based analysis of the external reference improves the accuracy more than manual calibration. If manual calibration is utilized, the length measurement is less accurate with the magball than the magstrip.

Level Of Evidence: Level II-comparative in vitro study.
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http://dx.doi.org/10.1097/BPO.0000000000001931DOI Listing
September 2021

The change in sagittal plane gait patterns from childhood to maturity in bilateral cerebral palsy.

Gait Posture 2021 Aug 28;90:154-160. Epub 2021 Aug 28.

Nemours/Alfred I. duPont Hospital for Children, 1600 Rockland Rd., Wilmington, DE 19803, United States. Electronic address:

Background: The longitudinal stability of sagittal gait patterns in diplegic cerebral palsy (CP), stratified using the Rodda classification, is currently unknown.

Research Question: What is the trajectory of sagittal plane gait deformities as defined by the Rodda classification in a large cohort treated with orthopedic surgery guided by gait analysis?

Methods: A retrospective study utilized gait analysis to evaluate sagittal gait parameters before age 8 and after age 15 years. Individual limbs were categorized at each time point according to the Rodda classification based on mean sagittal plane knee and ankle angle during stance. Welch's t-tests compared gait variables from early childhood with maturity and examined changes associated with plantarflexor lengthening surgery.

Results: 100 youth with CP were evaluated twice: at a mean age of 5.49 ± 1.18 and 19.09 ± 4.32 years, respectively. Gross Motor Function Classification System distribution at maturity was I (10.5 %), II (55.2 %), III (28.6 %), and IV (5.7 %). At the initial visit, most limbs were in either true equinus (30 %) or jump-knee gait (26.5 %). At maturity, crouch gait (52.5 %) was the most common classification, of which 47.6 % were mild (1-3 standard deviations from age-matched norm; 21°-30°) and 52.4 % moderate or severe. For the entire cohort, at initial and final visits, respectively, mean knee flexion in stance was 26.8°±14.8° and 25.9°±11.4° (p = 0.320), ankle dorsiflexion in stance increased from -0.3°±11.5° to 9.0°±6.0° (p < 0.001), and passive knee flexion contracture was -2.3°±7.0° and -3.9°±8.0° (p = 0.043). In children who started in true equinus, apparent equinus, and crouch, there was no difference in stance phase knee flexion at maturity between those who underwent plantarflexor lengthenings versus those who did not (p > 0.18).

Significance: The trend in this cohort was toward crouch with increased stance phase ankle dorsiflexion from early childhood to maturity. Plantarflexor lengthenings were not a significant factor in the progression of stance phase knee flexion.
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http://dx.doi.org/10.1016/j.gaitpost.2021.08.022DOI Listing
August 2021

Cooperation Between Systemic IgG1 and Mucosal Dimeric IgA2 Monoclonal Anti-HIV Env Antibodies: Passive Immunization Protects Indian Rhesus Macaques Against Mucosal SHIV Challenges.

Front Immunol 2021 3;12:705592. Epub 2021 Aug 3.

Texas Biomedical Research Institute, San Antonio, TX, United States.

Understanding the interplay between systemic and mucosal anti-HIV antibodies can provide important insights to develop new prevention strategies. We used passive immunization systemic and/or mucosal routes to establish cause-and-effect between well-characterized monoclonal antibodies and protection against intrarectal (i.r.) SHIV challenge. In a pilot study, for which we re-used animals previously exposed to SHIV but completely protected from viremia by different classes of anti-HIV neutralizing monoclonal antibodies (mAbs), we made a surprise finding: low-dose intravenous (i.v.) HGN194-IgG1, a human neutralizing mAb against the conserved V3-loop crown, was ineffective when given alone but protected 100% of animals when combined with i.r. applied HGN194-dIgA2 that by itself had only protected 17% of the animals. Here we sought to confirm the unexpected synergy between systemically administered IgG1 and mucosally applied dIgA HGN194 forms using six groups of naïve macaques (n=6/group). Animals received i.v. HGN194-IgG1 alone or combined with i.r.-administered dIgA forms; controls remained untreated. HGN194-IgG1 i.v. doses were given 24 hours before - and all i.r. dIgA doses 30 min before - i.r. exposure to a single high-dose of SHIV-1157ipEL-p. All controls became viremic. Among passively immunized animals, the combination of IgG1+dIgA2 again protected 100% of the animals. In contrast, single-agent i.v. IgG1 protected only one of six animals (17%) - consistent with our pilot data. IgG1 combined with dIgA1 or dIgA1+dIgA2 protected 83% (5/6) of the animals. The dIgA1+dIgA2 combination without the systemically administered dose of IgG1 protected 67% (4/6) of the macaques. We conclude that combining suboptimal antibody defenses at systemic and mucosal levels can yield synergy and completely prevent virus acquisition.
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http://dx.doi.org/10.3389/fimmu.2021.705592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8370093PMC
August 2021

Hip Displacement in MECP2 Disorders: Prevalence and Risk Factors.

J Pediatr Orthop 2021 Oct;41(9):e800-e803

Department of Orthopedic Surgery, Division of Cerebral Palsy, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE.

Background: Methyl-CpG binding protein 2 (MECP2) disorders, including Rett syndrome and MECP2 duplication syndrome, are typified by profound intellectual disability, spasticity, and decline in gross motor function. Unlike scoliosis, linked to disease severity, little has been reported regarding the hip. The aim of this study was to report the prevalence and risk factors of hip displacement (HD) in MECP2 disorders.

Methods: This was a retrospective, comparative study. Children with a genetically confirmed MECP2 disorder were included. The primary outcome measure was the prevalence of HD (migration percentage>30%). Secondary outcomes included age at HD onset, ambulatory status, presence of clinically relevant scoliosis, genetic severity, presence of seizures, and associated comorbidities. Analysis of proportions of categorical variables was performed using χ2 testing (P=0.05).

Results: Fifty-six patients (54 Rett syndrome and 2 MECP2 duplication syndrome), diagnosed at 6.6 (SD: 4.7) years, met the inclusion criteria. The prevalence of HD was 36% [onset, 7.7 (SD: 3.8) y]. Risk factors for HD were nonwalker status (P=0.04), scoliosis (P=0.001), and refractory epilepsy (P=0.04).

Conclusions: The prevalence of HD in MECP2 disorders is comparable to cerebral palsy, associated with proxy measures of disease severity. These results can be used to develop hip surveillance programs for MECP2 disorders, allowing for timely management.

Level Of Evidence: Level III.
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http://dx.doi.org/10.1097/BPO.0000000000001898DOI Listing
October 2021

Viremia controls Env-specific antibody-secreting cell responses in SIV-infected macaques pre- and post-ART.

AIDS 2021 Jun 18. Epub 2021 Jun 18.

Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA, 30329 - USA Division of Pathology, Yerkes National Primate Research Center, Emory University, Atlanta, GA, 30329 - USA Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322 - USA Current address: Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP - 05508-000 - Brazil Current address: National Primate Research Center (NPRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang, Korea Current address: New Iberia Research Center, University of Louisiana at Lafayette, New Iberia - LA, 70560 - USA Current address: Department of Pharmaceutical and Experimental Neuroscience, University of Nebraska Medical Center, Omaha - NE - 58800 - USA.

Objective: To investigate the kinetics of Env (gp140)-specific antibody-secreting cells (ASCs) during acute and early chronic simian immunodeficiency virus (SIV) infection, and prior to and post-antiretroviral therapy (ART) in rhesus macaques (RMs).

Design And Methods: At week 0, RMs were inoculated intravenously with SIVmac239 and the viral loads were allowed to develop. Daily ART was initiated at week 5 post infection until week 18, though the animals were monitored until week 28 for the following parameters: enumeration of SIV gp140-specific ASCs by ELISPOT; quantification of viremia and SIV gp140-specific IgG titers through qRT-PCR and ELISA, respectively; estimation of monocytes, follicular helper T cells (Tfh), and memory B cell frequencies using polychromatic flow cytometry.

Results: Direct correlations were consistently found between blood SIV gp140-specific ASC responses and viremia or SIV Env-specific IgG titers. In contrast, SIV gp140-specific ASC responses showed inverse correlations with the percentage of total memory B cells in the blood. In lymph nodes (LNs), the magnitude of the SIV gp140-specific ASC responses also followed the viral load kinetics. In contrast, the number of SIV gp140-specific ASCs presented did not correlate with frequencies of circulating activated monocyte (CD14+CD16+) or Tfh cells.

Conclusion: Blood and/or LN viral loads may regulate the onset and magnitude of SIV gp140-specific ASCs during SIV infection and following ART in RMs.
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http://dx.doi.org/10.1097/QAD.0000000000002998DOI Listing
June 2021

Single-event multilevel surgery in cerebral palsy: Value added by a co-surgeon.

Medicine (Baltimore) 2021 Jun;100(24):e26294

National Academy of Medicine Fellowship, American Osteopathic Association, Chicago, IL, USA.

Abstract: The aim of this study was to compare outcomes for single-event multilevel surgery (SEMLS) in cerebral palsy (CP) performed by 1 or 2 attending surgeons.A retrospective review of patients with CP undergoing SEMLS was performed. Patients undergoing SEMLS performed by a single senior surgeon were compared with patients undergoing SEMLS by the same senior surgeon and a consistent second attending surgeon. Due to heterogeneity of the type and quantity of SEMLS procedures included in this study, a scoring system was utilized to stratify patients to low and high surgical burden. The SEMLS events scoring less than 18 points were categorized as low burden surgery and SEMLS scoring 18 or more points were categorized as high burden surgery. Operative time, estimated blood loss, hospital length of stay, and operating room (OR) utilization costs were compared.In low burden SEMLS, 10 patients had SEMLS performed by a single surgeon and 8 patients had SEMLS performed by 2 surgeons. In high burden SEMLS, 10 patients had SEMLS performed by a single surgeon and 12 patients had SEMLS performed by 2 surgeons. For high burden SEMLS, operative time was decreased by a mean of 69 minutes in cases performed by 2 co-surgeons (P = 0.03). Decreased operative time was associated with an estimated savings of $2484 per SEMLS case. In low burden SEMLS, a trend toward decreased operative time was associated for cases performed by 2 co-surgeons (182 vs 221 minutes, P = 0.11). Decreased operative time was associated with an estimated savings of $1404 per low burden SEMLS case. No difference was found for estimated blood loss or hospital length of stay between groups in high and low burden SEMLS.Employing 2 attending surgeons in SEMLS decreased operative time and OR utilization cost, particularly in patients with a high surgical burden. These findings support the practice of utilizing 2 attending surgeons for SEMLS in patients with CP.Level of Evidence: Level III.
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http://dx.doi.org/10.1097/MD.0000000000026294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213317PMC
June 2021

Risk Factors for Failure of Pavlik Harness Treatment in Infants With Dislocated Hips That Are Evaluated by Dynamic Sonography.

J Pediatr Orthop 2021 Jul;41(6):e386-e391

Department of Orthopaedic Surgery, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE.

Background: Frankly dislocated hips occur in ∼1% to 3% of infants with developmental dysplasia of the hip and are often difficult to treat. In the most severely dislocated hips, the femoral head is positioned outside the posterior/lateral rim of the acetabulum and is irreducible, that is, the femoral head will not reduce by positioning the leg. The purpose of this study was to determine risk factors, using univariate and multivariate analyses, for Pavlik harness failure in infants who initially presented with irreducible/dislocated hips (confirmed by dynamic sonography).

Methods: Following institutional review board approval, 124 infants (170 hips) with frankly dislocated hips treated using a Pavlik harness between 2000 and 2018 were evaluated. Patients' demographic characteristics, clinical findings, dynamic sonographic findings (dislocated-fixed vs. dislocated-mobile), age at onset of Pavlik harness treatment, duration of harness usage, and follow-up treatments were recorded. Univariate analyses were used to determine risk factors for treatment failure.

Results: In frankly dislocated hips (confirmed by dynamic sonography to be positioned outside the posterior/lateral rim of the acetabulum), Pavlik harness treatment was successful in 104 of 170 hips (61%) while it failed in 66 hips. Mean follow-up was 4.86±4.20 years. Univariate analysis determined the risk factors to be onset of treatment after the seventh week of age (P=0.049) and initial mobility (dislocated-fixed group) (P<0.001) by dynamic sonography. In addition, multivariate analysis (P=0.007) showed infants of multigravida mothers (non-firstborn) to be another risk factor for failure. Six percent of hips with no risk factors failed Pavlik harness treatment, those with 1 risk factor had 42% failure, 2 risk factors had 69% failure, and all 3 risk factors had 100% failure.

Conclusions: In our patients with frankly dislocated irreducible hips, 39% of hip failed Pavlik harness treatment. Independent multivariate, logistic regression analysis, and multivariate analysis determining the risk factors for failure of Pavlik harness treatment were onset of treatment after the seventh week of age, infants of multigravida mothers, and initial hip mobility (fixed-dislocated hips) by dynamic sonography.

Level Of Evidence: Level III.
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http://dx.doi.org/10.1097/BPO.0000000000001799DOI Listing
July 2021

PET/CT targeted tissue sampling reveals virus specific dIgA can alter the distribution and localization of HIV after rectal exposure.

PLoS Pathog 2021 Jun 1;17(6):e1009632. Epub 2021 Jun 1.

Department of Cell and Developmental Biology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.

Human immunodeficiency virus (HIV) vaccines have not been successful in clinical trials. Dimeric IgA (dIgA) in the form of secretory IgA is the most abundant antibody class in mucosal tissues, making dIgA a prime candidate for potential HIV vaccines. We coupled Positron Emission Tomography (PET) imaging and fluorescent microscopy of 64Cu-labeled, photoactivatable-GFP HIV (PA-GFP-BaL) and fluorescently labeled dIgA to determine how dIgA antibodies influence virus interaction with mucosal barriers and viral penetration in colorectal tissue. Our results show that HIV virions rapidly disseminate throughout the colon two hours after exposure. The presence of dIgA resulted in an increase in virions and penetration depth in the transverse colon. Moreover, virions were found in the mesenteric lymph nodes two hours after viral exposure, and the presence of dIgA led to an increase in virions in mesenteric lymph nodes. Taken together, these technologies enable in vivo and in situ visualization of antibody-virus interactions and detailed investigations of early events in HIV infection.
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http://dx.doi.org/10.1371/journal.ppat.1009632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195437PMC
June 2021

Orthopaedic Manifestations of Transverse Myelitis in Children.

J Pediatr Orthop 2021 May 13. Epub 2021 May 13.

Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE Seton Hall Orthopaedics, St. Joseph's University Medical Center, Paterson, NJ Icahn School of Medicine at Mount Sinai, New York, NY Department of Orthopaedic Surgery, Nemours Children's Specialty Care, Jacksonville, FL.

Background: Transverse myelitis (TM) is a rare inflammatory disorder of the spinal cord. It can have a heterogeneous presentation with sensory, motor, and autonomic dysfunction. Neurological sequelae of TM include autonomic dysfunction, motor weakness, and/or spasticity. Studies describing orthopaedic deformities and treatments associated with TM are nonexistent. This purpose of this study was to describe the orthopaedic manifestations of TM in children.

Methods: A multicenter retrospective review was conducted of patients, 0 to 21 years of age, with TM presenting over a 15-year period at 4 academic children's hospitals. Those with confirmed diagnosis of TM and referred to an orthopaedic surgeon were included. Demographics, orthopaedic manifestations, operative/nonoperative treatments, and complications were recorded. Descriptive statistics were used for data reporting.

Results: Of 119 patients identified with TM, 37 saw an orthopaedic surgeon. By etiology, 23 were idiopathic (62%), 10 infectious (27%), 3 (8%) inflammatory/autoimmune, and 1 (3%) vascular. The mean age at diagnosis was 6.7 (SD: 5.5) years and at orthopaedic presentation was 8.4 (SD: 5.2) years. Orthopaedic manifestations included scoliosis in 13 (35%), gait abnormalities in 7 (19%), foot deformities in 7 (19%), upper extremity issues in 7 (19%), symptomatic spasticity in 6 (16%), lower extremity muscle contractures in 6 (16%), fractures in 6 (16%), hip displacement in 3 (8%), pain in 2 (5%), and limb length discrepancy in 2 (5%) patients. Seven children (19%) were seen for establishment of care. In all, 14 (38%) underwent operative intervention, mainly for soft-tissue and scoliosis management. Four patients had baclofen pump placement for spasticity management. Postoperative complications occurred in 36% of cases, most commonly because of infection. Neither topographic pattern nor location of lesion had a significant relationship with need for hip or spine surgery.

Conclusions: This report describes the orthopaedic manifestations associated with TM in children, nearly 40% of whom required operative intervention(s). Understanding the breadth of musculoskeletal burden incurred in TM can help develop surveillance programs to identify and treat these deformities in a timely manner.

Level Of Evidence: Level IV.
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http://dx.doi.org/10.1097/BPO.0000000000001845DOI Listing
May 2021

Adjuvanting a subunit COVID-19 vaccine to induce protective immunity.

Nature 2021 06 19;594(7862):253-258. Epub 2021 Apr 19.

Tulane National Primate Research Center, Covington, LA, USA.

The development of a portfolio of COVID-19 vaccines to vaccinate the global population remains an urgent public health imperative. Here we demonstrate the capacity of a subunit vaccine, comprising the SARS-CoV-2 spike protein receptor-binding domain displayed on an I53-50 protein nanoparticle scaffold (hereafter designated RBD-NP), to stimulate robust and durable neutralizing-antibody responses and protection against SARS-CoV-2 in rhesus macaques. We evaluated five adjuvants including Essai O/W 1849101, a squalene-in-water emulsion; AS03, an α-tocopherol-containing oil-in-water emulsion; AS37, a Toll-like receptor 7 (TLR7) agonist adsorbed to alum; CpG1018-alum, a TLR9 agonist formulated in alum; and alum. RBD-NP immunization with AS03, CpG1018-alum, AS37 or alum induced substantial neutralizing-antibody and CD4 T cell responses, and conferred protection against SARS-CoV-2 infection in the pharynges, nares and bronchoalveolar lavage. The neutralizing-antibody response to live virus was maintained up to 180 days after vaccination with RBD-NP in AS03 (RBD-NP-AS03), and correlated with protection from infection. RBD-NP immunization cross-neutralized the B.1.1.7 SARS-CoV-2 variant efficiently but showed a reduced response against the B.1.351 variant. RBD-NP-AS03 produced a 4.5-fold reduction in neutralization of B.1.351 whereas the group immunized with RBD-NP-AS37 produced a 16-fold reduction in neutralization of B.1.351, suggesting differences in the breadth of the neutralizing-antibody response induced by these adjuvants. Furthermore, RBD-NP-AS03 was as immunogenic as a prefusion-stabilized spike immunogen (HexaPro) with AS03 adjuvant. These data highlight the efficacy of the adjuvanted RBD-NP vaccine in promoting protective immunity against SARS-CoV-2 and have led to phase I/II clinical trials of this vaccine (NCT04742738 and NCT04750343).
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http://dx.doi.org/10.1038/s41586-021-03530-2DOI Listing
June 2021

Elicitation of broadly protective sarbecovirus immunity by receptor-binding domain nanoparticle vaccines.

bioRxiv 2021 Mar 16. Epub 2021 Mar 16.

Understanding the ability of SARS-CoV-2 vaccine-elicited antibodies to neutralize and protect against emerging variants of concern and other sarbecoviruses is key for guiding vaccine development decisions and public health policies. We show that a clinical stage multivalent SARS-CoV-2 receptor-binding domain nanoparticle vaccine (SARS-CoV-2 RBD-NP) protects mice from SARS-CoV-2-induced disease after a single shot, indicating that the vaccine could allow dose-sparing. SARS-CoV-2 RBD-NP elicits high antibody titers in two non-human primate (NHP) models against multiple distinct RBD antigenic sites known to be recognized by neutralizing antibodies. We benchmarked NHP serum neutralizing activity elicited by RBD-NP against a lead prefusion-stabilized SARS-CoV-2 spike immunogen using a panel of single-residue spike mutants detected in clinical isolates as well as the B.1.1.7 and B.1.351 variants of concern. Polyclonal antibodies elicited by both vaccines are resilient to most RBD mutations tested, but the E484K substitution has similar negative consequences for neutralization, and exhibit modest but comparable neutralization breadth against distantly related sarbecoviruses. We demonstrate that mosaic and cocktail sarbecovirus RBD-NPs elicit broad sarbecovirus neutralizing activity, including against the SARS-CoV-2 B.1.351 variant, and protect mice against severe SARS-CoV challenge even in the absence of the SARS-CoV RBD in the vaccine. This study provides proof of principle that sarbecovirus RBD-NPs induce heterotypic protection and enables advancement of broadly protective sarbecovirus vaccines to the clinic.
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http://dx.doi.org/10.1101/2021.03.15.435528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986998PMC
March 2021

Adjuvanting a subunit SARS-CoV-2 nanoparticle vaccine to induce protective immunity in non-human primates.

bioRxiv 2021 Feb 11. Epub 2021 Feb 11.

The development of a portfolio of SARS-CoV-2 vaccines to vaccinate the global population remains an urgent public health imperative. Here, we demonstrate the capacity of a subunit vaccine under clinical development, comprising the SARS-CoV-2 Spike protein receptor-binding domain displayed on a two-component protein nanoparticle (RBD-NP), to stimulate robust and durable neutralizing antibody (nAb) responses and protection against SARS-CoV-2 in non-human primates. We evaluated five different adjuvants combined with RBD-NP including Essai O/W 1849101, a squalene-in-water emulsion; AS03, an alpha-tocopherol-containing squalene-based oil-in-water emulsion used in pandemic influenza vaccines; AS37, a TLR-7 agonist adsorbed to Alum; CpG 1018-Alum (CpG-Alum), a TLR-9 agonist formulated in Alum; or Alum, the most widely used adjuvant. All five adjuvants induced substantial nAb and CD4 T cell responses after two consecutive immunizations. Durable nAb responses were evaluated for RBD-NP/AS03 immunization and the live-virus nAb response was durably maintained up to 154 days post-vaccination. AS03, CpG-Alum, AS37 and Alum groups conferred significant protection against SARS-CoV-2 infection in the pharynges, nares and in the bronchoalveolar lavage. The nAb titers were highly correlated with protection against infection. Furthermore, RBD-NP when used in conjunction with AS03 was as potent as the prefusion stabilized Spike immunogen, HexaPro. Taken together, these data highlight the efficacy of the RBD-NP formulated with clinically relevant adjuvants in promoting robust immunity against SARS-CoV-2 in non-human primates.
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http://dx.doi.org/10.1101/2021.02.10.430696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885918PMC
February 2021

The Impact of Spinal Fusion on Hip Displacement in Cerebral Palsy.

Indian J Orthop 2021 Feb 9;55(1):176-182. Epub 2020 Oct 9.

Department of Orthopedics, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE USA.

Background And Study Aims: The aims of this study were to determine the risk of progressive hip subluxation in children with CP after spinal fusion for scoliosis and how frequent the hips follow-up should be scheduled.

Patients And Methods: Pelvis radiography [migration index (MI) and pelvic obliquity (PO)] of Gross Motor Function Classification System (GMFCS) levels IV and V children with CP who received spinal fusion and pelvic fixation were reviewed retrospectively. This population was categorized into three groups based on the MI at spinal fusion: G1 = 0-29%; G2 = 30-59%; and G3 = 60-100%.

Results: Fifty children (age 7.5-15.0 years) and categorized into 3 groups (G1 = 19, G2 = 23, G3 = 8; 100 hips in total). Preoperative and last follow-up MI were 22 ± 7% and 30 ± 20% (G1), 41 ± 9% and 43 ± 22% (G2), 92 ± 15% and 97 ± 10% (G3). The MIs at spinal fusion between groups were statistically different ( < 0.001). In G1, the mean MI progression was 5% and 25% at 12 months and 62 months, respectively. In G2, the mean MI progression was 9% and 25% at 12 months and 32 months, respectively. The progression more than 10% occurred within 2 years in G1 and within 1 year in G2. There was no difference between groups based on preoperative degree of PO ( = 0.653) and correction rate in PO ( = 0.421).

Conclusions: In GMFCS IV and V children with the highest risk for progression occurred with increasing preoperative MI, especially over 50%. Hips should be monitored continuously after spinal fusion until hip stability is documented.
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http://dx.doi.org/10.1007/s43465-020-00271-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851297PMC
February 2021

Intraoperative Neurological Monitoring in Lower Limb Surgery for Patients With Mucopolysaccharidoses.

J Pediatr Orthop 2021 Mar;41(3):182-189

Gillette Children's Specialty Healthcare, Saint Paul.

Background: There are reports of spinal cord injury (SCI) occurring after lower extremity (LE) surgery in children with mucopolysaccharidoses (MPS). Intraoperative neurological monitoring (IONM) has been adopted in some centers to assess real-time spinal cord function during these procedures. The aim of this investigation was to review 3 specialty centers' experiences with MPS patients undergoing LE surgery. We report how IONM affected care and the details of spinal cord injuries in these patients.

Methods: All pediatric MPS patients who underwent LE surgery between 2001 and 2018 were reviewed at 3 children's orthopaedic specialty centers. Demographic and surgical details were reviewed. Estimated blood loss (EBL), surgical time, positioning, use of IONM, and changes in management as a result of IONM were recorded. Details of any spinal cord injuries were examined in detail.

Results: During the study period, 92 patients with MPS underwent 252 LE surgeries. IONM was used in 83 of 252 (32.9%) surgeries, and intraoperative care was altered in 17 of 83 (20.5%) cases, including serial repositioning (n=7), aggressive blood pressure management (n=6), and abortion of procedures (n=8). IONM was utilized in cases with larger EBL (279 vs. 130 mL) and longer operative time (274 vs. 175 min) compared with procedures without IONM. Three patients without IONM sustained complete thoracic SCI postoperatively, all from cord infarction in the upper thoracic region. These 3 cases were characterized by long surgical time (328±41 min) and substantial EBL (533±416 mL or 30.5% of total blood volume; range, 11% to 50%). No LE surgeries accompanied by IONM experienced SCI.

Conclusions: Patients with MPS undergoing LE orthopaedic surgery may be at risk for SCI, particularly if the procedures are long or are expected to have large EBL. One hypothesis for the etiology of SCI in this setting is hypoperfusion of the upper thoracic spinal cord due to prolonged intraoperative or postoperative hypotension. IONM during these procedures may mitigate the risk of SCI by identifying real-time changes in spinal cord function during surgery, inciting a change in the surgical plan.

Level Of Evidence: Level III-retrospective comparative series.
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http://dx.doi.org/10.1097/BPO.0000000000001720DOI Listing
March 2021

Cervical kyphosis: A predominant feature of patients with osteogenesis imperfecta type 5.

Bone Rep 2020 Dec 21;13:100735. Epub 2020 Nov 21.

Division of Orthogenetics, Department of Pediatrics, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA.

Objectives: Osteogenesis imperfecta (OI) is a heterogeneous group of genetic disorders of connective tissue that cause skeletal fragility and extra-skeletal manifestations. Classically, four different types of OI were distinguished. Type 5 OI was added due to its distinct clinical and radiographic features. In 2012, two independent groups identified a recurrent heterozygous c.-14C>T mutation in as the responsible genetic change for this type of OI. To our knowledge, cervical kyphosis has not been identified in the literature as a finding in type 5 OI patients. This is a retrospective review of a cohort of patients with type 5 OI and a description of associated cervical spine deformity.

Methods: After institutional review board approval, a retrospective review identified 13 patients with type 5 OI. Clinical, radiologic, and genetic data from 2002 to 2020 were reviewed.

Results: We identified 13 patients with clinical diagnosis of type 5 OI. Twelve had molecular confirmation and the classic , c.14C>T gene mutation was identified. The remaining individual did not undergo genetic testing. Dentinogenesis imperfecta was observed in one patient, while blue sclerae or hearing loss were not present. All patients had at least one fracture and four underwent intramedullary rodding. Radiologic features included subphyseal metaphyseal radiodense line in 12/13 patients (92%), interosseous membrane calcification in seven of 13 patients (54%) (more commonly noted in the upper extremities), and hypertrophic callus in six of 13 patients (46%). Thoracolumbar spinal deformities were seen in six of 13 patients (46%) with two of these individuals requiring surgery. Cervical kyphosis was noted in nine of 13 individuals (69%) ranging in age from 3 months to 22 years. Anterior wedging of the cervical vertebral bodies was noted in the absence of any fractures. Six of nine individuals demonstrated listhesis of C2-C3 or C3-C4 segment. Magnetic resonance imaging studies were performed and reviewed in patients with cervical kyphosis and subluxation; three patients showed narrowing of spinal canal without cervical cord compression and one asymptomatic patient showed impingement of the spinal cord.

Conclusions: Cervical kyphosis appears to be a common feature of type 5 OI. It can be a presenting and apparently life-long association and does not appear to be caused by vertebral body fractures. Evaluation for cervical kyphosis should be performed in patients with a suspected or confirmed diagnosis of type 5 OI. Furthermore, if cervical kyphosis is noted in an individual with OI, type 5 OI should be considered.Level of evidence: IV.
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http://dx.doi.org/10.1016/j.bonr.2020.100735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718132PMC
December 2020

Safety and Immunological Evaluation of Interleukin-21 Plus Anti-α4β7 mAb Combination Therapy in Rhesus Macaques.

Front Immunol 2020 17;11:1275. Epub 2020 Jul 17.

Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, United States.

Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections compromise gut immunological barriers, inducing high levels of inflammation and a severe depletion of intestinal CD4 T cells. Expression of α4β7 integrin promotes homing of activated T cells to intestinal sites where they become preferentially infected; blockade of α4β7 with an anti-α4β7 monoclonal antibody (mAb) prior to infection has been reported to reduce gut SIV viremia in rhesus macaques (RMs). Interleukin-21 (IL-21) administration in antiretroviral therapy-treated, SIV-infected RMs reduces gut inflammation and improves gut integrity. We therefore hypothesized that the combination of IL-21 and anti-α4β7 mAb therapies could synergize to reduce inflammation and HIV persistence. We co-administered two intravenous doses of rhesus anti-α4β7 mAb (50 mg/kg) combined with seven weekly subcutaneous infusions of IL-21-IgFc (100 μg/kg) in four healthy, SIV-uninfected RMs to evaluate the safety and immunological profiles of this intervention in blood and gut. Co-administration of IL-21 and anti-α4β7 mAb showed no toxicity at the given dosages as assessed by multiple hematological and chemical parameters and did not alter the bioavailability of the therapeutics or result in the generation of antibodies against the anti-α4β7 mAb or IL-21-IgFc. Upon treatment, the frequency of CD4 memory T cells expressing β7 increased in blood and decreased in gut, consistent with an inhibition of activated CD4 T-cell homing to the gut. Furthermore, the frequency of T cells expressing proliferation and immune activation markers decreased in blood and, more profoundly, in gut. The combined IL-21 plus anti-α4β7 mAb therapy is well-tolerated in SIV-uninfected RMs and reduces the gut homing of α4β7 CD4 T cells as well as the levels of gut immune activation.
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http://dx.doi.org/10.3389/fimmu.2020.01275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7379916PMC
April 2021

Evaluation of Risk Factors for Cerebrospinal Leakage in Pediatric Patients With Cerebral Palsy Treated With Intrathecal Baclofen.

J Pediatr Orthop 2020 Jul;40(6):e522-e526

Department of Orthopaedic Surgery, Alfred I. duPont Hospital for Children, Wilmington, DE.

Background: Insertion of an intrathecal baclofen (ITB) pump can provide significant benefits in patients with cerebral palsy (CP). However, there are little data describing the risk of complications. Specifically, there is a lack of data describing the incidence of cerebrospinal fluid (CSF) leakage and risk factors following ITB placement. The purpose of our study was to describe risk factors for developing CSF leak in pediatric patients with CP treated with ITB and to report the treatment and outcome of CSF leaks.

Methods: Following institutional review board approval, 720 ITB procedures in 341 children with CP were identified retrospectively over a 15-year study period. Patients' demographic characteristics, medical comorbidities, muscle tone patterns, feeding tube status, seizure history, inpatient events, ITB-related CSF leak and headache complaints and their management, and other complications were evaluated.

Results: Eighty-five (24.9%) patients experienced 90 CSF leak episodes over a follow-up time of 6.3±3.9 years. There were 72 episodes of headache as a result of CSF leakage in 61 (71.7%) of these 85 patients. There was a positive correlation between the risk of CSF leak and preoperative comorbidities such as epilepsy/seizure history, feeding tube, mixed type CP, and dystonic type CP. The risk of CSF leak after primary ITB administration was 5.8% (20/341), and the risk after secondary ITB procedures due to complications was 24.2% (32/132). There was no significant relationship between CSF leak and primary ITB (P=0.21), but the risk of CSF leak was positively correlated to the secondary ITB due to complications (P<0.05).

Conclusions: CSF leak was fairly common (25% incidence), and it correlated with epilepsy/seizure history, feeding tube, mixed type CP, and dystonic type CP. Recurrent ITB procedures were a risk factor for CSF leak. Half of these patients had self-limited symptoms that improved with conservative medical treatment, and the epidural blood patch was successful in resistant cases. Successful treatment of CSF leakage complications allows patients to continue ITB.

Level Of Evidence: Level III.
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http://dx.doi.org/10.1097/BPO.0000000000001472DOI Listing
July 2020

Sprengel Deformity in Biological Sisters.

J Am Acad Orthop Surg Glob Res Rev 2020 04 2;4(4). Epub 2020 Apr 2.

Department of Orthopaedic Surgery, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE.

Sprengel deformity is the main congenital shoulder deformity seen in children. First described by Otto Sprengel in 1891, it consists of a high-riding, dysplastic, and malrotated scapula leading to functional and cosmetic impairments. It has never been reported in siblings.

Case Presentation: Two sisters, 8 and 9 years old, presented for an evaluation of atraumatic limitation in the shoulder range of motion and neck webbing with an unknown family history. Physical examination revealed a small high-riding scapula, webbed neck, and painless limitation in shoulder abduction (<70°) and flexion (<80°). The 9-year-old sibling had a bilateral shoulder involvement, and the younger had unilateral. Imaging revealed bony and fibrous omovertebral connections between the dysplastic scapulas and cervical spine along with Klippel-Feil deformities. Both sisters underwent scapula repositioning via a modified Woodward procedure. The omovertebral connection was resected followed by scapula derotation and inferior migration. Both had a dramatic improvement in cosmesis and near-complete restoration of shoulder function at follow-up.

Conclusions: Although uncommon, Sprengel deformity results in notable derangement of shoulder function. If untreated, children experience difficulty with most overhead activities and often have cosmetic reports. Although no previous genetic link has been identified, its presence in biological sisters suggests that more research is needed.
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http://dx.doi.org/10.5435/JAAOSGlobal-D-19-00120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188265PMC
April 2020

The effectiveness of epidural blood patch in patients with cerebral palsy treated with intrathecal baclofen implantation.

Paediatr Anaesth 2020 02 14;30(2):153-160. Epub 2020 Jan 14.

Department of Orthopaedic Surgery, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA.

Background: Cerebrospinal fluid leak and postdural puncture spinal headache following intrathecal baclofen therapy are known complications. Although primary treatments are conservative, epidural blood patch is an alternative in patients with persistent and severe symptoms.

Aim: The purpose of this article is to review the effectiveness of epidural blood patch for the treatment of spinal headache and cerebrospinal fluid leak associated with intrathecal baclofen treatment in children with cerebral palsy.

Methods: Our database was reviewed for epidural blood patch in 341 pediatric patients with cerebral palsy who underwent primary intrathecal baclofen treatment from 2004 to 2018 at one institution. The number of patches, time frame of treatment, and effectiveness of the epidural blood patch were collected. All patients treated with epidural blood patch were evaluated for primary and secondary intrathecal baclofen-related procedures, and subsequent treatment of intrathecal baclofen associated with cerebrospinal fluid leak and spinal headache.

Results: Twenty-nine epidural blood patch procedures were performed on 26 patients who had received intrathecal baclofen procedures. Of these 26 patients, four had a secondary epidural blood patch. The incidence of spinal headache/cerebrospinal fluid leak was 31% (107/341), and 81/107 (76%) patients with spinal headache/cerebrospinal fluid leak responded to conservative treatments. Success rate for initial epidural blood patch was 79.3% (23/29). The second epidural blood patch was performed in four patients after failure of initial epidural blood patch. Second epidural blood patch success rate was 75% (3/4).

Conclusion: Spinal headache and cerebrospinal fluid leak are known complications after intrathecal baclofen treatment in children with cerebral palsy. When conservative treatments are unsuccessful, epidural blood patch can be used with confidence for these patients. In patients with ongoing symptoms, it is possible to obtain success by repeating the epidural blood patch to continue intrathecal baclofen treatment and avoid aggressive surgery.
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http://dx.doi.org/10.1111/pan.13791DOI Listing
February 2020

Evaluation of Fracture and Osteotomy Union in the Setting of Osteogenesis Imperfecta: Reliability of the Modified Radiographic Union Score for Tibial Fractures (RUST).

J Pediatr Orthop 2020 Jan;40(1):48-52

Department of Orthopaedics.

Background: Evaluation of the union of osteotomies and fractures in patients with osteogenesis imperfecta (OI) is a critical component of patient care. Studies of the OI patient population have so far used varied criteria to evaluate bony union. The radiographic union score for tibial fractures (RUST), which was subsequently revised to the modified RUST, is an objective standardized method of evaluating fracture healing. We sought to evaluate the reliability of the modified RUST in the setting of the tibias of patients with OI.

Methods: Tibial radiographs of 30 patients with OI fractures, or osteotomies were scored by 3 observers on 2 separate occasions. Each of the 4 cortices was given a score (1=no callus, 2=callus present, 3=bridging callus, and 4=remodeled, fracture not visible) and the modified RUST is the sum of these scores (range, 4 to 16). The interobserver and intraobserver reliabilities were evaluated using intraclass coefficients (ICC) with 95% confidence intervals.

Results: The ICC representing the interobserver reliability for the first iteration of scores was 0.926 (0.864 to 0.962) and for the second series was 0.915 (0.845 to 0.957). The ICCs representing the intraobserver reliability for each of the 3 reviewers for the measurements in series 1 and 2 were 0.860 (0.707 to 0.934), 0.994 (0.986 to 0.997), and 0.974 (0.946 to 0.988).

Conclusions: The modified RUST has excellent interobserver and intraobserver reliability in the setting of OI despite challenges related to the poor quality of the bone and its dysplastic nature. The application and routine use of the modified RUST in the OI population will help standardize our evaluation of osteotomy and fracture healing.

Level Of Evidence: Level III-retrospective study of nonconsecutive patients.
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http://dx.doi.org/10.1097/BPO.0000000000001068DOI Listing
January 2020

Cervical Spine Deformities in Children With Rhizomelic Chondrodysplasia Punctata.

J Pediatr Orthop 2019 Oct;39(9):e680-e686

Department of Orthopedics, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE.

Background: Cervical spine deformity in rhizomelic chondrodysplasia punctata (RCDP) has been described with different findings reported in the literature. However, available literature provides limited data from a few cases with magnetic resonance imaging (MRI) of the cervical spine. Our report describes the MRI findings in a group of children with RCDP, aiming to reach a better understanding of this pathology.

Methods: An Institutional Review Board-approved RCDP Registry was created at our institution with the goal of identifying pertinent medical issues over the lifespan of individuals with RCDP. Records of children within the registry were evaluated, and magnetic resonance images obtained between 2004 and 2015, were available for review. The levels of spinal canal stenosis were recorded and the severity of the stenosis was decided based on adults' parameters. Cord compression and myelomalacia were confirmed on the axial images. Sagittal lumbar spine magnetic resonance images were also evaluated when available, and the presence of tethered cord and fatty filum was recorded.

Results: Twenty-six children (15 boys and 11 girls) were identified in the RCDP Registry. Eleven children (6 boys and 5 girls) had sagittal MRI of the cervical spine available for review. Age at the time of MRI study was variable (1 wk to 32 mo). All patients except 1 had stenosis of the cervical spinal canal. Myelomalacia of the cord was noted only in this patient.

Conclusions: This study suggests that, in children with RCDP, cervical spinal stenosis and cord compression are a real risk, and children with this diagnosis should have monitoring for these issues. Tethered cord is also a possible finding that needs to be evaluated. Full sagittal spine MRI is necessary to detect the possible deformities at the cervical and lumbar levels.
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http://dx.doi.org/10.1097/BPO.0000000000001014DOI Listing
October 2019

Engineering of a Lectibody Targeting High-Mannose-Type Glycans of the HIV Envelope.

Mol Ther 2019 11 9;27(11):2038-2052. Epub 2019 Aug 9.

James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA; Center for Predictive Medicine, University of Louisville School of Medicine, Louisville, KY, USA; Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, USA. Electronic address:

High-mannose-type glycans (HMGs) are aberrantly enriched on HIV envelope glycoproteins. However, there is currently no drug selectively targeting HIV-associated HMGs. Here, we describe a novel HMG-targeting "lectibody," a recombinant Fc-fusion protein comprising human IgG1 Fc and a novel actinohivin lectin variant (Avaren) obtained by structure-guided modifications for improved overall surface charge properties (AvFc). AvFc was engineered and produced using a rapid and scalable plant-based transient overexpression system. The lectibody exhibited potent antiviral activity against HIV-1 groups M and O primary viruses, as well as HIV-2 and simian immunodeficiency virus (SIV) strains, without affecting normal human blood cells. Furthermore, the lectibody induced Fc-mediated cell killing activity against HIV-1-infected cells and selectively recognized SIVmac239-infected macaque mesenteric lymph node cells in vitro. AvFc showed an extended serum half-life in rats and rhesus macaques, while no discernible toxicity was observed upon repeated systemic dosing in mice. These results highlight AvFc's potential as a biotherapeutic targeting HIV-associated HMGs of cell-free virions, as well as productively infected cells, providing a foundation for new anti-HIV strategies. Efficient and cost-effective bioproduction in greenhouse facilities may open unique possibilities for further development of AvFc.
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http://dx.doi.org/10.1016/j.ymthe.2019.07.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839005PMC
November 2019

Developmental dysplasia of the hip and clubfoot treated by Pavlik and Ponseti methods.

J Pediatr Orthop B 2019 Sep;28(5):446-451

Department of Orthopaedic Surgery, Nemours/Alfred I. duPont Hospital for Children, Wilmington, Delaware, USA.

Children having both typical developmental dysplasia of the hip (DDH) and clubfoot are rare, and early treatments of both conditions are recommended. The aim of this study was to evaluate the effects of the Ponseti method of clubfoot treatment on hips with DDH. After institutional review board approval, we identified children treated by the Ponseti and Pavlik methods between 2003 and 2016. During the Ponseti method treatment, the duration of manipulations, number of casts, tenotomies performed, and days in clubfoot orthosis were recorded. During DDH treatment, we registered duration for Pavlik and hip brace usage. Hips had dynamic sonography and radiographic evaluations. The cases were grouped according to the combination of DDH and clubfoot treatments: (a) concurrent, (b) sequential, and (c) hip observation. Seven cases of DDH and clubfoot were identified. The average number of Ponseti casts was 5.8 (range: 4-8 casts). The average number of days following the post-Achilles-tenotomy casting to the end of clubfoot bracing was 870 days (range: 90-1605 days). Eleven (four bilateral cases and three unilateral) clubfeet were corrected initially by the Ponseti method. The average number of days for Pavlik harness treatment was 74 (range: 10-126 days). Additionally, a hip orthosis was utilized in three children for an average of 131 days. At follow-up, all children had a high femoral neck-shaft angle averaging 152° (range: 144°-164°). One child (case 5) developed avascular necrosis of the femoral head, Kalamchi type I. Children with typical and nonsyndromic DDH and clubfoot treated by Pavlik harness and Ponseti methods are associated with abnormal hip development (coxa valga).
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http://dx.doi.org/10.1097/BPB.0000000000000618DOI Listing
September 2019

Valgus Hip Osteotomy in Children With Spondyloepiphyseal Dysplasia Congenita: Midterm Results.

J Pediatr Orthop 2019 Jul;39(6):282-288

Department of Orthopedics, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE.

Background: Coxa vara has been frequently reported in spondyloepiphyseal dysplasia congenita (SEDC), and proximal femoral osteotomy has been described as a useful treatment. The aim of this study was to discuss the clinical, radiographic, and gait outcomes after valgus extension osteotomy of the proximal femur. Changes of lumbar lordosis, associated with coxa vara correction, are reported as well as the outcome differences between different ages.

Methods: Records of children with SEDC, who were followed at our institution between 2004 and 2014, were reviewed; and children had hip surgery were identified. Hip pain and passive range of motion, radiographic neck shaft angle (NSA), and Hilgenreiner trochanteric (H-T) angle, sagittal spinopelvic parameters, and gait data were recorded. Preoperative and last follow-up data were compared. Outcomes were also compared between 3 age groups.

Results: Of the 79 children with SEDC, 26 children (12 boys and 14 girls) had hip osteotomy in 48 hips. Mean age at surgery was 9.6 years and the mean follow-up was 5 years. Preoperative hip pain was noted in 30 hips. At the last follow-up, 3 hips were painful at the extreme range of motion. Passive range of motion, NSA, and H-T improved postoperatively. Although NSA was maintained over the follow-up, H-T deterioration was noted. Spinopelvic measurements changed significantly and gait data remained stable except pelvic tilt that reduced significantly after surgery. The changes of radiographic measurements in each age group were similar to the total group of patients.

Conclusions: In children with SEDC, surgical correction of coxa vara, by proximal femoral valgus osteotomy, is an effective treatment that improves hip pain and range of motion in addition to the radiographic alignment of the proximal femur and the sagittal spinopelvic alignment. Children are expected to maintain their level of function after surgery and to have good results over the midterm regardless of their age at surgery.

Level Of Evidence: Level IV-therapeutic study.
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http://dx.doi.org/10.1097/BPO.0000000000000945DOI Listing
July 2019

Changes in the Position of the Junctional Vertebrae After Posterior Spinal Fusion in Adolescent Idiopathic Scoliosis: Implication in Risk Assessment of Proximal Junctional Kyphosis Development.

J Pediatr Orthop 2020 Feb;40(2):e84-e90

Division of Orthopaedic Surgery, The Children's Hospital of Philadelphia (CHOP), Philadelphia, PA.

Background: The development of proximal junctional kyphosis (PJK) after posterior spinal fusion in adolescent idiopathic scoliosis is a major problem. Changes in the global sagittal parameters as they relate to PJK have been reported after surgery, however, the relationships between the changes in the upper-instrumented vertebra (UIV) during and after surgery as they relate to development of PJK have not been quantified. We hypothesize that the compensatory changes in the unfused segments of the spine over time are correlated with the surgically induced changes in the UIV position.

Methods: Sixty adolescent idiopathic scoliosis patients (with at least 1-year follow-up) who underwent posterior spinal surgery were included retrospectively. Global spinal parameters were calculated using 3-dimensional models of the spine, additional parameters [proximal junctional kyphosis angle (PJKA), cervical lordosis angle] were measured manually before surgery and at 3 postoperative follow-ups. The 3-dimensional position of the vertebral body centroids was calculated for T1, UIV, and lower-instrumented vertebra at all timepoints. The sagittal position of T1, UIV, and lower-instrumented vertebra were correlated to the cervical lordosis, PJKA, lumbar lordosis, and pelvic tilt.

Results: The position of T1 and UIV were significantly more anterior at first erect for patients who developed PJK. The posterior shift of UIV at the most recent follow-up as compared with the preoperative position was significant in both the PJK and non-PJK cohort. A larger anterior shift in UIV at first erect correlated with a larger T1 and UIV posterior shift at the most recent follow-up. At the most recent follow-up, a more posterior position of the UIV correlated with a larger angle of PJKA (P<0.05).

Conclusion: Both a larger anterior shift of UIV between preoperative and first erect and a more posterior position of UIV at the most recent follow-up was correlated with a higher PJKA. A larger anterior shift in the position of the UIV after surgery was associated with a higher posterior shift of UIV at the last follow-up. The surgically induced changes in the UIV are an important parameter associated with the development of PJK.

Level Of Evidence: Level IV.
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http://dx.doi.org/10.1097/BPO.0000000000001400DOI Listing
February 2020

Delayed vaginal SHIV infection in VRC01 and anti-α4β7 treated rhesus macaques.

PLoS Pathog 2019 05 13;15(5):e1007776. Epub 2019 May 13.

Center for Biomedical Research, Population Council, New York, New York, United States of America.

VRC01 protects macaques from vaginal SHIV infection after a single high-dose challenge. Infusion of a simianized anti-α4β7 mAb (Rh-α4β7) just prior to, and during repeated vaginal exposures to SIVmac251 partially protected macaques from vaginal SIV infection and rescued CD4+ T cells. To investigate the impact of combining VRC01 and Rh-α4β7 on SHIV infection, 3 groups of macaques were treated with a suboptimal dosing of VRC01 alone or in combination with Rh-α4β7 or with control antibodies prior to the initiation of weekly vaginal exposures to a high dose (1000 TCID50) of SHIVAD8-EO. The combination Rh-α4β7-VRC01 significantly delayed SHIVAD8-EO vaginal infection. Following infection, VRC01-Rh-α4β7-treated macaques maintained higher CD4+ T cell counts and exhibited lower rectal SIV-DNA loads compared to controls. Interestingly, VRC01-Rh-α4β7-treated macaques had fewer IL-17-producing cells in the blood and the gut during the acute phase of infection. Moreover, higher T cell responses to the V2-loop of the SHIVAD8-EO envelope in the VRC01-Rh-α4β7 group inversely correlated with set point viremia. The combination of suboptimal amounts of VRC01 and Rh-α4β7 delayed infection, altered antiviral immune responses and minimized CD4+ T cell loss. Further exploration of the effect of combining bNAbs with Rh-α4β7 on SIV/HIV infection and antiviral immune responses is warranted and may lead to novel preventive and therapeutic strategies.
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http://dx.doi.org/10.1371/journal.ppat.1007776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533011PMC
May 2019

Visualization of early events in mRNA vaccine delivery in non-human primates via PET-CT and near-infrared imaging.

Nat Biomed Eng 2019 05 1;3(5):371-380. Epub 2019 Apr 1.

Wallace H. Coulter Department of Biomedical Engineering, Georgia Tech and Emory University, Atlanta, GA, USA.

Visualization of the spatio-temporal trafficking of vaccines after their delivery would help evaluate the efficacy of candidate formulations and aid their rational design for preclinical and translational studies. Here, we show that a dual radionuclide-near-infrared probe allows for quantitative, longitudinal and non-invasive monitoring, via positron emission tomography-computed tomography and near-infrared imaging of cynomolgus macaques, of the trafficking dynamics to draining lymph nodes of a model messenger RNA vaccine labelled with the probe. After intramuscular administration of the vaccine to the monkeys, we observed the dynamics of the mRNA vaccine at the injection site and in the draining lymph nodes, performed cellular analyses of the involved tissues using flow cytometry and identified through immunofluorescence that professional antigen-presenting cells are the primary cells containing the injected mRNA and encoding the antigen. This approach may reveal spatio-temporal determinants of vaccine efficacy in preclinical and translational studies employing large mammals.
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http://dx.doi.org/10.1038/s41551-019-0378-3DOI Listing
May 2019

Altered brain tissue viscoelasticity in pediatric cerebral palsy measured by magnetic resonance elastography.

Neuroimage Clin 2019 7;22:101750. Epub 2019 Mar 7.

Department of Biomedical Engineering, University of Delaware, Newark, DE, United States; Department of Psychological and Brain Sciences, University of Delaware, Newark, DE, United States. Electronic address:

Cerebral palsy (CP) is a neurodevelopmental disorder that results in functional motor impairment and disability in children. CP is characterized by neural injury though many children do not exhibit brain lesions or damage. Advanced structural MRI measures may be more sensitively related to clinical outcomes in this population. Magnetic resonance elastography (MRE) measures the viscoelastic mechanical properties of brain tissue, which vary extensively between normal and disease states, and we hypothesized that the viscoelasticity of brain tissue is reduced in children with CP. Using a global region-of-interest-based analysis, we found that the stiffness of the cerebral gray matter in children with CP is significantly lower than in typically developing (TD) children, while the damping ratio of gray matter is significantly higher in CP. A voxel-wise analysis confirmed this finding, and additionally found stiffness and damping ratio differences between groups in regions of white matter. These results indicate that there is a difference in brain tissue health in children with CP that is quantifiable through stiffness and damping ratio measured with MRE. Understanding brain tissue mechanics in the pediatric CP population may aid in the diagnosis and evaluation of CP.
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http://dx.doi.org/10.1016/j.nicl.2019.101750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416970PMC
January 2020

Categorization of the Usage of Adjunctive Structural Allograft Bone Graft in Extremity Surgery for Patients with Osteogenesis Imperfecta.

J Long Term Eff Med Implants 2018 ;28(3):205-208

Department of Orthopaedic Surgery, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA.

Structural allograft bone plays a role in orthopedic surgery. Our purpose is to describe the methods of using structural allograft in extremity reconstruction surgery in patients with osteogenesis imperfecta (OI) and create a classification of usage with a single-center review of OI extremity cases from January 2002 to February 2017. Structural allograft was used in 19 bone segments in 15 patients with type III OI. Four categories of usage were defined: (1) interpositional, (2) onlay, (3) inlay, and (4) blocking to prevent rod migration. The mean time to incorporation was 5.4 months (range 1-16). Structural allograft bone incorporates into OI bone and may be a supplement to intramedullary fixation.
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http://dx.doi.org/10.1615/JLongTermEffMedImplants.2018028895DOI Listing
November 2019

Predicting Ambulatory Function Based on Infantile Lower Extremity Posture Types in Amyoplasia Arthrogryposis.

J Pediatr Orthop 2019 Aug;39(7):e531-e535

Orthopaedic Surgery, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE.

Background: Arthrogryposis multiplex congenita (AMC) is a nonprogressive syndrome with multiple rigid joints, fibrotic periarticular tissue, and muscular fibrosis. The most common subgroup is amyoplasia. Ambulation is one of the most significant functions of the lower extremities as it translates to increased functionality and independence in adulthood. There is no predicative scale to determine ambulation at maturity for the infant with amyoplasia. It is believed lower extremity resting position of infants with amyoplasia potentially correlates with ambulation at maturity. The purpose of this study was to classify the infantile position of lower extremities and muscle strength to predict ambulation potential at maturity.

Methods: Children with amyoplasia were retrospectively reviewed and classified into groups based on infantile position of hip-knee alignment and limb muscle function. Sitting, standing, and walking skills from infancy into adulthood were evaluated. The ambulation function was correlated with the infantile position of the lower extremities.

Results: Amyoplasia cases were sorted into 5 types and correlated with ambulatory potential. Type I: mild ambulatory impairment with infantile position of flexed knees and hips but full range of motion. At maturity, all were community ambulators. Type II: moderate ambulatory impairment having infantile position of hip flexion, hip external rotation, and knee flexion contractures. Hip abductors and external rotators had antigravity strength. All stood and walked during the first decade of life with knee ankle foot orthoses. Type III: severe ambulatory impairment having infantile position of hip flexion, abduction, external rotation, and knee flexion contractures but lacked hip muscle recruitment. All used wheelchairs at maturity. Type IV: mild ambulatory impairment with infantile position of extended knees and flexed dislocated hips. At maturity, 90% were community ambulators. Type V: variable ambulatory impairment having asymmetric hip and knee alignment with unilateral hip dysplasia with extended knee and opposite limb flexed. Ambulation skill varied at maturity with 27% full-time wheelchair users.

Conclusions: Amyoplasia can be sorted by infantile position of lower extremities and muscle strength into 5 types to predict ambulatory function.

Level Of Evidence: Level III-Prognostic Study.
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http://dx.doi.org/10.1097/BPO.0000000000001322DOI Listing
August 2019
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