Publications by authors named "Nicholas Fletcher"

119 Publications

The role of the surgical care practitioner during the COVID-19 pandemic: An audit of experiences.

J Perioper Pract 2021 03 8;31(3):108-113. Epub 2021 Feb 8.

Department of Urology, James Cook Hospital, Middlesbrough, UK.

Introduction: The Surgical Care Practitioner is a medical associate profession role, working to an advanced level, undertaken by registered nurses, operating department practitioners or physiotherapists, on completion of a Royal College of Surgeons accredited course. The COVID-19 pandemic has led to all heath care professionals needing to adapt to help support the health care system as it tackles its effect.

Aim: Audit of roles undertaken by Surgical Care Practitioners during the COVID-19 pandemic in the context of Royal College of Surgeons (2014) Curriculum to review the utilisation of this medical associate profession role.

Method: The online questionnaire service, SurveyMonkey®, was used to collect data on the activities being undertaken by the Surgical Care Practitioner during the COVID-19 pandemic.

Results: Eighty Surgical Care Practitioners from across seven different surgical specialties within the United Kingdom completed the online survey. Nearly half stated that they remained mostly working in their substantive role, just less than a third helped in critical care units, with the remaining redeployed in equal shares to emergency departments or assisting on wards with nurses and as part of medical teams. A brief description of their activities was also recorded.

Conclusion: This audit has demonstrated the versatility of the Surgical Care Practitioner and ability to adapt during the pandemic.
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http://dx.doi.org/10.1177/1750458920977377DOI Listing
March 2021

Characterization of the Biodistribution of a Silica Vesicle Nanovaccine Carrying a Protective Antigen With Live Animal Imaging.

Front Bioeng Biotechnol 2020 18;8:606652. Epub 2021 Jan 18.

Queensland Alliance for Agriculture and Food Innovation, The University of Queensland, Brisbane, QLD, Australia.

Development of veterinary subunit vaccines comes with a spectrum of challenges, such as the choice of adjuvant, antigen delivery vehicle, and optimization of dosing strategy. Over the years, our laboratory has largely focused on investigating silica vesicles (SVs) for developing effective veterinary vaccines for multiple targets. (cattle tick) are known to have a high impact on cattle health and the livestock industry in the tropical and subtropical regions. Development of vaccine using Bm86 antigen against has emerged as an attractive alternative to control ticks. In this study, we have investigated the biodistribution of SV in a live animal model, as well as further explored the SV ability for vaccine development. Rhodamine-labeled SV-140-C (Rho-SV-140-C) vesicles were used to adsorb the Cy5-labeled Bm86 antigen (Cy5-Bm86) to enable detection and characterization of the biodistribution of SV as well as antigen in a small animal model for up to 28 days using optical fluorescence imaging. We tracked the biodistribution of SVs and Bm86 antigen at different timepoints (days 3, 8, 13, and 28) in BALB/c mice. The biodistribution analysis by live imaging as well as by measuring the fluorescent intensity of harvested organs over the duration of the experiment (28 days) showed greater accumulation of SVs at the site of injection. The Bm86 antigen biodistribution was traced in lymph nodes, kidney, and liver, contributing to our understanding how this delivery platform successfully elicits antibody responses in the groups administered antigen in combination with SV. Selected tissues (skin, lymph nodes, spleen, kidney, liver, and lungs) were examined for any cellular abnormalities by histological analysis. No adverse effect or any other abnormalities were observed in the tissues.
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http://dx.doi.org/10.3389/fbioe.2020.606652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848120PMC
January 2021

Short term outcomes of an enhanced recovery after surgery (ERAS) pathway versus a traditional discharge pathway after posterior spinal fusion for adolescent idiopathic scoliosis.

Spine Deform 2021 Jan 18. Epub 2021 Jan 18.

British Columbia Children's Hospital, Vancouver, BC, USA.

Purpose: Enhanced Recovery after Surgery (ERAS) pathways have been shown to decrease length of stay (LOS) after posterior spinal fusion (PSF) for adolescent idiopathic scoliosis (AIS). The aim of this study was to compare immediate post-operative outcomes following an ERAS pathway with a traditional pathway for AIS.

Methods: A prospective dual-center study of patients treated using an ERAS pathway (203 patients) or a traditional discharge (TD) pathway (73 patients) was performed with focus on pain at discharge, quality of life at one month, and return to school/work.

Results: LOS was 55% less in the ERAS group (4.8 days TD vs. 2.2 days ERAS, p < 0.001). Length of surgery (4.8 h TD vs. 2.8 h, p < 0.001) and EBL (500 cc vs. 240 cc, p < 0.001) were greater in the TD group, likely related to larger curve magnitudes ((62.0° TD vs. 54.0° ERAS, p < 0.001), a higher percentage of patients undergoing osteotomies (94% vs. 46%, p < 0.001) and more levels fused (11.4 ± 1.6 vs. 10.1 ± 2.6, p < 0.001) in the TD group. Regression analysis showed no difference in Visual Analog Score (VAS) score at discharge or quality of recovery using the QOR9 instrument between groups at follow up. There was no difference in return to school (p = 0.43) and parents' return to work (p = 0.61) between the groups.

Conclusion: Patients managed with an ERAS pathway had similar pain scores at discharge than those managed with a TD pathway. Both groups showed evidence of rapid return to normalcy by the first follow up visit.
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http://dx.doi.org/10.1007/s43390-020-00282-3DOI Listing
January 2021

Engineering Fluorescent Gold Nanoclusters Using Xanthate-Functionalized Hydrophilic Polymers: Toward Enhanced Monodispersity and Stability.

Nano Lett 2021 01 22;21(1):476-484. Epub 2020 Dec 22.

Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville Campus, 381 Royal Parade, Parkville Victoria 3052, Australia.

We introduce xanthate-functionalized poly(cyclic imino ethers)s (PCIEs), specifically poly(2-ethyl-2-oxazoline) and poly(2-ethyl-2-oxazine) given their stealth characteristics, as an attractive alternative to conventional thiol-based ligands for the synthesis of highly monodisperse and fluorescent gold nanoclusters (AuNCs). The xanthate in the PCIEs interacts with Au ions, acting as a well-controlled template for the direct formation of PCIE-AuNCs. This method yields red-emitting AuNCs with a narrow emission peak (λ = 645 nm), good quantum yield (4.3-4.8%), long fluorescence decay time (∼722-844 ns), and unprecedented product yield (>98%). The PCIE-AuNCs exhibit long-term colloidal stability, biocompatibility, and antifouling properties, enabling a prolonged blood circulation, lower nonspecific accumulation in major organs, and better renal clearance when compared with AuNCs without polymer coating. The advances made here in the synthesis of metal nanoclusters using xanthate-functionalized PCIEs could propel the production of highly monodisperse, biocompatible, and renally clearable nanoprobes in large-scale for different theranostic applications.
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http://dx.doi.org/10.1021/acs.nanolett.0c03930DOI Listing
January 2021

Understanding the role of colon-specific microparticles based on retrograded starch/pectin in the delivery of chitosan nanoparticles along the gastrointestinal tract.

Eur J Pharm Biopharm 2021 Jan 10;158:371-378. Epub 2020 Dec 10.

São Paulo State University (UNESP), School of Pharmaceutical Sciences, Araraquara, SP 14801-902, Brazil. Electronic address:

The encapsulation of nanoparticles within microparticles designed for specific delivery to the colon is a relevant strategy to avoid premature degradation or release of nanoparticles during their passage through the stomach and upper gastrointestinal tract (GIT), allowing the targeted delivery of chemotherapeutics to the colon after oral administration. Here, we designed an oral multiparticulate system to achieve targeted release in the colon. In this sense, chitosan nanoparticles (CS NPs) encapsulated with 5-fluorouracil (5-FU) and incorporated into retrograded starch and pectin (RS/P) microparticles were developed and their in vivo distribution along the mouse GIT after oral administration was monitored using multispectral optical imaging. In vitro release studies revealed that the encapsulation of CS NPs into RS/P microparticles promoted greater control of 5-FU release rates, with a significant reduction (53%) in acid media that might replicate that found in the stomach following oral administration. The evaluation of the in vivo biodistribution of the CS NPs in mice showed a faster clearance in the distribution pattern along the mouse GIT, i.e., a shorter transit time of CS NPs compared to CS NPs-loaded RS/P microparticles. Additionally, CS NPs alone showed non-specific absorption into the blood-stream with associated kidney accumulation, while for the CS NPs-loaded RS/P microparticles no significant accumulation was observed in blood or major clearance organs. This suggests the specific degradability of RS/P by the colon microbiota appears to have been decisive in the higher protection of the CS NPs along the GIT until release in the colon, preventing unwanted absorption into the bloodstream and major organs following oral administration. Our findings represent a proof of concept for the use of RS/P microparticles as potential carriers for delivering drug-loaded nanoparticles to the colon and this work will contribute to the development of oral-systems for colorectal cancer therapy.
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http://dx.doi.org/10.1016/j.ejpb.2020.12.004DOI Listing
January 2021

The Impact of Polymer Size and Cleavability on the Intravenous Pharmacokinetics of PEG-Based Hyperbranched Polymers in Rats.

Nanomaterials (Basel) 2020 Dec 8;10(12). Epub 2020 Dec 8.

School of Biomedical Sciences, The University of Queensland, St Lucia 4072, Queensland, Australia.

A better understanding of the impact of molecular size and linkers is important for PEG-based hyperbranched polymers (HBPs) intended as tailored drug delivery vehicles. This study aimed to evaluate the effects of crosslinker chemistry (cleavable disulphide versus non-cleavable ethylene glycol methacrylate (EGDMA) linkers) and molecular weight within the expected size range for efficient renal elimination (22 vs. 48 kDa) on the intravenous pharmacokinetic and biodistribution properties of Zr-labelled HBPs in rats. All HBPs showed similar plasma pharmacokinetics over 72 h, despite differences in linker chemistry and size. A larger proportion of HBP with the cleavable linker was eliminated via the urine and faeces compared to a similar-sized HBP with the non-cleavable linker, while size had no impact on the proportion of the dose excreted. The higher molecular weight HBPs accumulated in organs of the mononuclear phagocyte system (liver and spleen) more avidly than the smaller HBP. These results suggest that HBPs within the 22 to 48 kDa size range show no differences in plasma pharmacokinetics, but distinct patterns of organ biodistribution and elimination are evident.
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http://dx.doi.org/10.3390/nano10122452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762536PMC
December 2020

Risk factors for gastrointestinal complications after spinal fusion in children with cerebral palsy.

Spine Deform 2021 Mar 17;9(2):567-578. Epub 2020 Nov 17.

Department of Orthopaedic Surgery, University Hospital Cleveland Medical Center, Rainbow Babies and Children's Hospital, 201 Adelbert Road, Cleveland, OH, 44106, USA.

Design: Prospective cerebral palsy (CP) registry review.

Objectives: (1) Evaluate the incidence/risk factors of gastrointestinal (GI) complications in CP patients after spinal fusion (SF); and (2) investigate the validity of the modified Clavien-Dindo-Sink classification.

Background: Perioperative GI complications result in increased length of stay (LOS) and patient morbidity/mortality. However, none have analyzed the outcomes of GI complications using an objective classification system.

Methods: A prospective/multicenter CP database identified 425 children (mean, 14.4 ± 2.9 years; range, 7.9-21 years) who underwent SF. GI complications were categorized using the modified Clavien-Dindo-Sink classification. Grades I-II were minor complications and grades III-V major. Patients with and without GI complications were compared.

Results: 87 GI complications developed in 69 patients (16.2%): 39 minor (57%) and 30 major (43%). Most common were pancreatitis (n = 45) and ileus (n = 22). Patients with preoperative G-tubes had 2.2 × odds of developing a GI complication compared to oral-only feeders (OR 2.2; 95% CI 0.98-4.78; p = 0.006). Similarly, combined G-tube/oral feeders had 6.7 × odds compared to oral-only (OR 6.7; 95% CI 3.10-14.66; p < 0.001). The likelihood of developing a GI complication was 3.4 × with normalized estimated blood loss (nEBL) ≥ 3 ml/kg/level fused (OR 3.41; 95% CI 1.95-5.95; p < 0.001). Patients with GI complications had more fundoplications (29% vs. 17%; p = 0.03) and longer G-tube fasting periods (3 days vs. 2 days; p < 0.001), oral fasting periods (5 days vs. 2 days; p < 0.001), ICU admissions (6 days vs. 3 days; p = 0.002), and LOS (15 days vs. 8 days; p < 0.001). LOS correlated with the Clavien-Dino-Sink classification.

Conclusion: Gastrointestinal complications such as pancreatitis and ileus are not uncommon after SF in children with CP. This is the first study to investigate the validity of the modified Clavien-Dindo-Sink classification in GI complications after SF. Our results suggest a correlation between complication severity grade and LOS. The complexity of perioperative enteral nutritional supplementation requires prospective studies dedicated to enteral feeding protocols.

Level Of Evidence: Therapeutic-level III.
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http://dx.doi.org/10.1007/s43390-020-00233-yDOI Listing
March 2021

Effects of race on blood loss in spinal fusions for adolescent idiopathic scoliosis.

J Neurosurg Pediatr 2020 Nov 6:1-5. Epub 2020 Nov 6.

3Department of Orthopaedic Surgery, Children's Healthcare of Atlanta, Georgia.

Objective: Posterior spinal fusion (PSF) for adolescent idiopathic scoliosis (AIS) can be associated with significant blood loss. It has been suggested that blood loss is greater in different racial groups. The purpose of this study was to evaluate differences in blood loss between African American and Caucasian patients undergoing PSF for AIS.

Methods: A retrospective review was performed of patients aged 10-18 years with AIS who were treated with PSF from 2014 to 2017 at a single children's healthcare system. Patient demographic, radiographic, and operative data were obtained from medical records. Intraoperative blood loss was calculated using the formula described by Waters et al. Patients who declined reporting their race or had prior spinal surgery, neuromuscular or syndromic diagnoses, a history of cardiac or thoracic surgery, or a bleeding disorder were excluded. Blood loss variables were log-transformed for normality and modeled using multivariable linear regression.

Results: A total of 433 PSFs for AIS qualified for the analysis. The average age was 14.1 years, and 73.7% of the patients were female. With respect to race, 44.6% identified themselves as African American. There was no significant difference in blood loss (p = 0.31) or blood loss per level fused (p = 0.36) in African American patients. African American patients, however, did have significantly lower preoperative hemoglobin and hematocrit levels and greater operating room time than Caucasian patients (p < 0.001). There was no difference between race and transfusion rate.

Conclusions: There appears to be no relationship between race and blood loss during PSF for AIS. Standardized protocols for minimizing perioperative blood loss can be applied to both Caucasian and African American patients.
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http://dx.doi.org/10.3171/2020.7.PEDS2049DOI Listing
November 2020

Managing Resident Workforce and Education During the COVID-19 Pandemic: Evolving Strategies and Lessons Learned.

JB JS Open Access 2020 Apr-Jun;5(2):e0045. Epub 2020 Apr 15.

Emory University School of Medicine, Atlanta, Georgia.

Background: The novel coronavirus and associated Coronavirus Disease 2019 (COVID-19) is rapidly spreading throughout the world, with robust growth in the United States. Its drastic impact on the global population and international health care is swift, evolving, and unpredictable. The effects on orthopaedic surgery departments are predominantly indirect, with widespread cessation of all nonessential orthopaedic care. Although this is vital to the system-sustaining measures of isolation and resource reallocation, there is profound detriment to orthopaedic training programs.

Methods: In the face of new pressures on the finite timeline on an orthopaedic residency, the Emory University School of Medicine Department of Orthopaedics has devised a 5-pronged strategy based on the following: (1) patient and provider safety, (2) uninterrupted necessary care, (3) system sustainability, (4) adaptability, and (5) preservation of vital leadership structures.

Results: Our 5 tenants support a 2-team system, whereby the residents are divided into cycling "active-duty" and "working remotely" factions. In observation of the potential incubation period of viral symptoms, phase transitions occur every 2 weeks with strict adherence to team assignments. Intrateam redundancy can accommodate potential illness to ensure a stable unit of able residents. Active duty residents participate in in-person surgical encounters and virtual ambulatory encounters, whereas remotely working residents participate in daily video-conferenced faculty-lead, case-based didactics and pursue academic investigation, grant writing, and quality improvement projects. To sustain this, faculty and administrative 2-team systems are also in place to protect the leadership and decision-making components of the department.

Conclusions: The novel coronavirus has decimated the United States healthcare system, with an unpredictable duration, magnitude, and variability. As collateral damage, orthopaedic residencies are faced with new challenges to provide care and educate residents in the face of safety, resource redistribution, and erosion of classic learning opportunities. Our adaptive approach aims to be a generalizable tactic to optimize our current landscape.
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http://dx.doi.org/10.2106/JBJS.OA.20.00045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408274PMC
April 2020

Postoperative Dexamethasone Following Posterior Spinal Fusion for Adolescent Idiopathic Scoliosis.

J Bone Joint Surg Am 2020 Oct;102(20):1807-1813

Children's Healthcare of Atlanta, Atlanta, Georgia.

Background: Surgeons have hesitated to use steroids in patients undergoing posterior spinal fusion because of the risk of wound complications. The literature has supported the use of postoperative steroids in other areas of orthopaedics on the basis of more rapid recovery and improved postoperative pain control. We hypothesized that a short course of postoperative dexamethasone following posterior spinal fusion for the treatment of adolescent idiopathic scoliosis (AIS) would decrease opioid usage without increasing wound-healing problems.

Methods: Consecutive patients undergoing posterior spinal fusion for the treatment of AIS from 2015 to 2018 at a single hospital were included. A review of demographic characteristics, curve characteristics, surgical data, and postoperative clinic notes was performed. Opioid usage was determined by converting all postoperative opioids given into morphine milligram equivalents (MME).

Results: Sixty-five patients underwent posterior spinal fusion for the treatment of AIS without postoperative steroids (the NS group), and 48 patients were managed with 3 doses of postoperative steroids (the WS group) (median, 8.0 mg/dose). There was no difference between the groups in terms of curve magnitude, number of vertebrae fused, or estimated blood loss. There was a 39.6% decrease in total MME used and a 29.5% decrease in weight-based MME used in the group receiving postoperative steroids (82.0 mg [1.29 mg/kg] in the NS group versus 49.5 mg [0.91 mg/kg] in the WS group]; p < 0.001). This difference persisted after accounting for gabapentin, ketorolac, and diazepam usage; surgical time; curve size; levels fused; and number of osteotomies (median decrease, 0.756 mg/kg [95% CI, 0.307 to 1.205 mg/kg]; p = 0.001). Three patients in the NS group (4.6%) and 4 patients in the WS group (8.3%) developed wound dehiscence requiring wound care (p = 0.53). One patient in the NS group required surgical debridement for the treatment of an infection. Patients in the WS group were more likely to walk at the time of the initial physical therapy evaluation (60.4% versus 35.4%; p = 0.013).

Conclusions: A short course of postoperative steroids after posterior spinal fusion was associated with a 40% decrease in the use of opioids, with no increase in wound complications. Surgeons may consider the use of perioperative steroids in an effort to decrease the use of postoperative opioids following posterior spinal fusion for the treatment of AIS.

Level Of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.
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http://dx.doi.org/10.2106/JBJS.20.00259DOI Listing
October 2020

Controlling the Biological Fate of Micellar Nanoparticles: Balancing Stealth and Targeting.

ACS Nano 2020 10 16;14(10):13739-13753. Epub 2020 Sep 16.

Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, QLD 4072, Australia.

Integrating nanomaterials with biological entities has led to the development of diagnostic tools and biotechnology-derived therapeutic products. However, to optimize the design of these hybrid bionanomaterials, it is essential to understand how controlling the biological interactions will influence desired outcomes. Ultimately, this knowledge will allow more rapid translation from the bench to the clinic. In this paper, we developed a micellar system that was assembled using modular antibody-polymer amphiphilic materials. The amphiphilic nature was established using either poly(ethylene glycol) (PEG) or a single-chain variable fragment (scFv) from an antibody as the hydrophile and a thermoresponsive polymer (poly(oligoethylene glycol) methyl ether methacrylate) as the hydrophobe. By varying the ratios of these components, a series of nanoparticles with different antibody content was self-assembled, where the surface presentation of targeting ligand was carefully controlled. and analysis of these systems identified a mismatch between the optimal targeting ligand density to achieve maximum cell association compared to tumor accumulation . For this system, we determined an optimum antibody density for both longer circulation and enhanced targeting to tumors that balanced stealthiness of the particle (to evade immune recognition as determined in both mouse models and in whole human blood) with enhanced accumulation achieved through receptor binding on tumor cells in solid tumors. This approach provides fundamental insights into how different antibody densities affect the interaction of designed nanoparticles with both target cells and immune cells, thereby offering a method to probe the intricate interplay between increased targeting efficiency and the subsequent immune response to nanoparticles.
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http://dx.doi.org/10.1021/acsnano.0c06033DOI Listing
October 2020

Effect of Chain-End Chemistries on the Efficiency of Coupling Antibodies to Polymers Using Unnatural Amino Acids.

Macromol Rapid Commun 2020 Nov 16;41(21):e2000294. Epub 2020 Sep 16.

Australian Institute for Bioengineering and Nanotechnology, Centre for Advanced Imaging, ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, ARC Training Centre for Innovation in Biomedical Imaging Technology, The University of Queensland, Brisbane, 4072, Australia.

Novel conjugates that incorporate strategies for increasing the therapeutic payload, such as targeted polymeric delivery vehicles, have great potential in overcoming limitations of conventional antibody therapies that often exhibit immunogenicity and limited drug loading. Click chemistry has significantly expanded the toolbox of effective strategies for developing hybrid polymer-biomolecule conjugates, however, effective systems require orthogonality between the polymer and biomolecule chemistries to achieve efficient coupling. Here, three cycloaddition-based strategies for antibody conjugation to polymeric carriers are explored and show that a purely radical-based method for polymer synthesis and subsequent biomolecule attachment has a trade-off between coupling efficiency of the antibody and the ability to synthesize polymers with controlled chemical properties. It is shown that careful consideration of both coupling chemistries as well as the potential effect of how this modulates the chemical properties of the polymer nanocarrier should be considered during the development of such systems. The strategies described offer insight into improving conjugate development for therapeutic and theranostic applications. In this system, polymerization using conventional and established reversible addition fragmentation chain transfer (RAFT) agents, followed by multiple post-modification steps, always leads to systems with more defined chemical architectures compared to strategies that utilize alkyne-functional RAFT agents.
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http://dx.doi.org/10.1002/marc.202000294DOI Listing
November 2020

An overview of sacral neuromodulation: a treatment for patients with symptoms of lower urinary tract dysfunction.

Br J Nurs 2020 Aug;29(15):848-856

Urology Surgical Care Practitioner, Department of Urology, Salford Royal NHS Foundation Trust.

This article provides an introduction to patient selection for, and the processes involved in, sacral neuromodulation (SNM) device implantation as a treatment for urinary symptoms. SNM has been an option to treat lower urinary tract dysfunction for more than 20 years and is a treatment for both overactive bladder syndrome (OAB) and female non-obstructed chronic urinary retention (FCUR). It is recognised by the National Institute for Health and Care Excellence as a therapeutic option for OAB and FCUR. SNM has its place in the pathway for the treatment of both conditions and, in the correctly assessed patient, can be the last option before considering major surgical intervention.
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http://dx.doi.org/10.12968/bjon.2020.29.15.848DOI Listing
August 2020

Next-Generation Polymeric Nanomedicines for Oncology: Perspectives and Future Directions.

Macromol Rapid Commun 2020 Sep 7;41(18):e2000319. Epub 2020 Aug 7.

Centre for Advanced Imaging (CAI) and Australian Institute for Bioengineering and Nanotechnology (AIBN), ARC Centre of Excellence in Convergent Bio-Nano Science and Technology and ARC Training Centre for Innovation in Biomedical Imaging Technology, The University of Queensland, St. Lucia, QLD, 4072, Australia.

Precision polymers as advanced nanomedicines represent an appealing approach for the treatment of otherwise untreatable malignancies. By taking advantage of unique nanomaterial properties and implementing judicious design strategies, polymeric nanomedicines are able to be produced that overcome many barriers to effective treatment. Current key research focus areas anticipated to produce the greatest impact in polymer applications in nanomedicine for oncology include new strategies to achieve "active" targeting, polymeric pro-drug activation, and combinatorial polymer drug delivery approaches in combination with enhanced understanding of complex bio-nano interactions. These approaches, both in isolation or combination, form the next generation of precision nanomedicines with significant anticipated future health outcomes. Of necessity, these approaches will combine an intimate understanding of biological interactions with advanced materials design. This perspectives piece aims to highlight emerging opportunities that promise to be game changers in the nanomedicine oncology field. Discussed herein are current and next generation polymeric nanomedicines with a focus towards structures that are, or could, undergo clinical translation as well as highlight key advances in the field.
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http://dx.doi.org/10.1002/marc.202000319DOI Listing
September 2020

Hyperbranched Poly(2-oxazoline)s and Poly(ethylene glycol): A Structure-Activity Comparison of Biodistribution.

Biomacromolecules 2020 08 20;21(8):3318-3331. Epub 2020 Jul 20.

Centre for Advanced Imaging, The University of Queensland, Brisbane, Queensland 4072, Australia.

In light of research reporting abnormal pharmacokinetic behavior for therapeutics and formulations containing poly(ethylene glycol) (PEG), a renewed emphasis has been placed on exploring alternative surrogate materials and tailoring specific materials to distinct nanomedicine applications. Poly(2-oxazolines) (POx) have shown great promise in this regard; however, a comparison of POx and PEG interactions with components of the immune system is needed to inform on their distinct suitability. Herein, the interaction of isolated immune cells following injection of hyperbranched polymers comprised of PEG or hydrophilic POx macromonomers was determined via flow cytometry. All materials showed similar association with all of the splenic immune cells analyzed. Interestingly, splenic CD68 and CD11b macrophages showed similar levels of polymer association, despite CD11b being a smaller population, suggesting CD68 is linked to increased recognition and phagocytosis of these nanomaterials. This is of interest given that CD68 is a scavenger receptor and directly facilitates the clearance of cellular debris and promotion of phagocytosis, as opposed to CD11b, which is associated with the mediating inflammation via the production of cytokines as well as complement-mediated uptake of foreign particles. In the liver, PEG and poly(2-methyl oxazoline) hyperbranched polymers showed no discernible differences in their cellular association, while hyperbranched poly(2-ethyl oxazoline) showed increased association with dendrocytes and CD68 macrophages, suggesting that this material exhibited a greater propensity to interact with components of the immune system. This work highlights the importance of how subtle changes in chemical structure can influence the immune response.
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http://dx.doi.org/10.1021/acs.biomac.0c00765DOI Listing
August 2020

Doing Our Part to Conserve Resources: Determining Whether All Personal Protective Equipment Is Mandatory for Closed Reduction and Percutaneous Pinning of Supracondylar Humeral Fractures.

J Bone Joint Surg Am 2020 Jul;102(13):e66

Emory University School of Medicine, Atlanta, Georgia.

Background: Closed reduction and percutaneous pinning (CRPP) of supracondylar humeral fractures is one of the most common procedures performed in pediatric orthopaedics. The use of full, standard preparation and draping with standard personal protective equipment (PPE) may not be necessary during this procedure. This is of particular interest in the current climate as we face unprecedented PPE shortages due to the current COVID-19 pandemic.

Methods: This is a retrospective chart review of 1,270 patients treated with CRPP of a supracondylar humeral fracture at 2 metropolitan pediatric centers by 10 fellowship-trained pediatric orthopaedic surgeons. One surgeon in the group did not wear a mask when performing CRPP of supracondylar humeral fractures, and multiple surgeons in the group utilized a semisterile preparation technique (no sterile gown or drapes). Infectious outcomes were compared between 2 groups: full sterile preparation and semisterile preparation. We additionally analyzed a subgroup of patients who had semisterile preparation without surgeon mask use. Hospital cost data were used to estimate annual cost savings with the adoption of the semisterile technique.

Results: In this study, 1,270 patients who underwent CRPP of a supracondylar humeral fracture and met inclusion criteria were identified. There were 3 deep infections (0.24%). These infections all occurred in the group using full sterile preparation and surgical masks. No clinically relevant pin-track infections were noted. There were no known surgeon occupational exposures to bodily fluid. It is estimated that national adoption of this technique in the United States could save between 18,612 and 22,162 gowns and masks with costs savings of $3.7 million to $4.4 million annually.

Conclusions: We currently face critical shortages of PPE due to the COVID-19 pandemic. Data from this large series suggest that a semisterile technique during CRPP of supracondylar humeral fractures is a safe practice. We anticipate that this could preserve approximately 20,000 gowns and masks in the United States over the next year. Physicians are encouraged to reevaluate their daily practice to identify safe opportunities for resource preservation.

Level Of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.
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http://dx.doi.org/10.2106/JBJS.20.00567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7224617PMC
July 2020

Understanding the Uptake of Nanomedicines at Different Stages of Brain Cancer Using a Modular Nanocarrier Platform and Precision Bispecific Antibodies.

ACS Cent Sci 2020 May 28;6(5):727-738. Epub 2020 Apr 28.

Centre for Advanced Imaging, The University of Queensland, St Lucia, Queensland 4072, Australia.

Increasing accumulation and retention of nanomedicines within tumor tissue is a significant challenge, particularly in the case of brain tumors where access to the tumor through the vasculature is restricted by the blood-brain barrier (BBB). This makes the application of nanomedicines in neuro-oncology often considered unfeasible, with efficacy limited to regions of significant disease progression and compromised BBB. However, little is understood about how the evolving tumor-brain physiology during disease progression affects the permeability and retention of designer nanomedicines. We report here the development of a modular nanomedicine platform that, when used in conjunction with a unique model of how tumorigenesis affects BBB integrity, allows investigation of how nanomaterial properties affect uptake and retention in brain tissue. By combining different longitudinal imaging techniques (including positron emission tomography and magnetic resonance imaging), we have evaluated the retention of nanomedicines with predefined physicochemical properties (size and surface functionality) and established a relationship between structure and tissue accumulation as a function of a new parameter that measures BBB leakiness; this offers significant advancements in our ability to relate tumor accumulation of nanomedicines to more physiologically relevant parameters. Our data show that accumulation of nanomedicines in brain tumor tissue is better correlated with the of the BBB than actual tumor . This was evaluated by establishing brain tumors using a spontaneous and endogenously derived glioblastoma model providing a unique opportunity to assess these parameters individually and compare the results across multiple mice. We also quantitatively demonstrate that smaller nanomedicines (20 nm) can indeed cross the BBB and accumulate in tumors at earlier stages of the disease than larger analogues, therefore opening the possibility of developing patient-specific nanoparticle treatment interventions in earlier stages of the disease. Importantly, these results provide a more predictive approach for designing efficacious personalized nanomedicines based on a particular patient's condition.
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http://dx.doi.org/10.1021/acscentsci.9b01299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7256936PMC
May 2020

Fusions ending above the sagittal stable vertebrae in adolescent idiopathic scoliosis: does it matter?

Spine Deform 2020 10 13;8(5):983-989. Epub 2020 May 13.

Department of Orthopedics, Emory University, 59 Executive Park Dr. S, Atlanta, GA, 30329, USA.

Study Design: Retrospective cohort study.

Objective: To validate whether fusions that end proximal to the sagittal stable vertebrae are at risk for developing distal junctional kyphosis in adolescent idiopathic scoliosis.

Background: Posterior spinal fusion is routinely used for the treatment of patients with adolescent idiopathic scoliosis. Fusions that end in either the lower thoracic or upper lumbar spine have the advantage of preserving motion segments. However, fusions ending proximal to the sagittal stable vertebrae has been shown to be at higher risk for developing distal junctional kyphosis.

Methods: A multi-center database of prospectively enrolled subjects was queried for patients with adolescent idiopathic scoliosis that had Lenke type 1, 2 and 3 curves treated with posterior pedicle screw instrumentation. PA (posterior-anterior) and lateral full-length scoliosis films were obtained on each patient. PA radiographs were viewed to determine the coronal deformity and lateral radiographs to determine the sagittal deformity. Distal junctional kyphosis was defined as a greater than 10° increase in segmental kyphosis between the LIV and the LIV + 1 vertebra.

Results: 346 patients were included with 85% being female and mean age of cohort 14.2 [Formula: see text] 2.08 years. At 5 years postoperatively, there was significant difference occurrence of distal junctional kyphosis dependent on whether the LIV relative to SSV with only 2.2% of fusions below the SSV developing DJK compared to 6.5% for fusions ending at the SSV and 15% for fusions with LIV above the SSV (p < 0.001). There was no statistical difference in revision rates based on the relationship of LIV to SSV.

Conclusion: There is an increased risk for development of DJK in patients with AIS treated with posterior fusion where the LIV was chosen proximal to the SSV.

Level Evidence: Level III.
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http://dx.doi.org/10.1007/s43390-020-00118-0DOI Listing
October 2020

Targeted beta therapy of prostate cancer with Lu-labelled Miltuximab® antibody against glypican-1 (GPC-1).

EJNMMI Res 2020 May 7;10(1):46. Epub 2020 May 7.

Australian Prostate Cancer Research Centre - Queensland, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, 37 Kent Street, Woolloongabba, Queensland, 4102, Australia.

Purpose: Chimeric antibody Miltuximab®, a human IgG1 engineered from the parent antibody MIL-38, is in clinical development for solid tumour therapy. Miltuximab® targets glypican-1 (GPC-1), a cell surface protein involved in tumour growth, which is overexpressed in solid tumours, including prostate cancer (PCa). This study investigated the potential of Zr-labelled Miltuximab® as an imaging agent, and Lu-labelled Miltuximab® as a targeted beta therapy, in a mouse xenograft model of human prostate cancer.

Methods: Male BALB/c nude mice were inoculated subcutaneously with GPC-1-positive DU-145 PCa cells. In imaging and biodistribution studies, mice bearing palpable tumours received (a) 2.62 MBq [Zr]Zr-DFO-Miltuximab® followed by PET-CT imaging, or (b) 6 MBq [Lu]Lu-DOTA-Miltuximab® by Cerenkov imaging, and ex vivo assessment of biodistribution. In an initial tumour efficacy study, mice bearing DU-145 tumours were administered intravenously with 6 MBq [Lu]Lu-DOTA-Miltuximab® or control DOTA-Miltuximab® then euthanised after 27 days. In a subsequent survival efficacy study, tumour-bearing mice were given 3 or 10 MBq of [Lu]Lu-DOTA-Miltuximab®, or control, and followed up to 120 days.

Results: Antibody accumulation in DU-145 xenografts was detected by PET-CT imaging using [Zr]Zr-DFO-Miltuximab® and confirmed by Cerenkov luminescence imaging post injection of [Lu]Lu-DOTA-Miltuximab®. Antibody accumulation was higher (% IA/g) in tumours than other organs across multiple time points. A single injection with 6 MBq of [Lu]Lu-DOTA-Miltuximab® significantly inhibited tumour growth as compared with DOTA-Miltuximab® (control). In the survival study, mice treated with 10 MBq [Lu]Lu-DOTA-Miltuximab® had significantly prolonged survival (mean 85 days) versus control (45 days), an effect associated with increased cancer cell apoptosis. Tissue histopathology assessment showed no abnormalities associated with [Lu]Lu-DOTA-Miltuximab®, in line with other observations of tolerability, including body weight stability.

Conclusion: These findings demonstrate the potential utility of Miltuximab® as a PET imaging agent ([Zr]Zr-DFO-Miltuximab®) and a beta therapy ([Lu]Lu-DOTA-Miltuximab®) in patients with PCa or other GPC-1 expressing tumours.
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http://dx.doi.org/10.1186/s13550-020-00637-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7206480PMC
May 2020

Direct Comparison of Poly(ethylene glycol) and Phosphorylcholine Drug-Loaded Nanoparticles In Vitro and In Vivo.

Biomacromolecules 2020 06 12;21(6):2320-2333. Epub 2020 May 12.

Centre for Advanced Macromolecular Design (CAMD), School of Chemistry, University of New South Wales, Sydney, NSW 2052, Australia.

Phosphorylcholine is known to repel the absorption of proteins onto surfaces, which can prevent the formation of a protein corona on the surface of nanoparticles. This can influence the fate of nanoparticles used for drug delivery. This material could therefore serve as an alternative to poly(ethylene glycol) (PEG). Herein, the synthesis of different particles prepared by polymerization-induced self-assembly (PISA) coated with either poly(ethylene glycol) (PEG) or zwitterionic 2-methacryloyloxyethyl phosphorylcholine (MPC) and 4-(-(-penicillaminylacetyl)amino) phenylarsenonous acid (PENAO) was reported. The anticancer drug 4-(-(-penicillaminylacetyl)amino) phenylarsenonous acid (PENAO) was conjugated to the shell-forming block. Interactions of the different coated nanoparticles, which present comparable sizes and size distributions (76-85 nm, PDI = 0.067-0.094), with two-dimensional (2D) and three-dimensional (3D) cultured cells were studied, and their cytotoxicities, cellular uptakes, spheroid penetration, and cell localization profiles were analyzed. While only a minimal difference in behaviour was observed for nanoparticles assessed using in vitro experiment (with PEG-- PENAO-coated micelles showing slightly higher cytotoxicity and better spheroid penetration and cell localization ability), the effect of the different physicochemical properties between nanoparticles had a more dramatic effect on in vivo biodistribution. After 1 h of injection, the majority of the MPC--PENAO-coated nanoparticles were found to accumulate in the liver, making this particle system unfeasible for future biological studies.
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http://dx.doi.org/10.1021/acs.biomac.0c00257DOI Listing
June 2020

Evaluation of pediatric distal femoral physeal fractures and the factors impacting poor outcome requiring further corrective surgery.

J Pediatr Orthop B 2021 Jan;30(1):6-12

Pediatric Division, Department of Orthopaedic Surgery, Emory University School of Medicine, Atlanta, Georgia, USA.

Fractures of the distal femur carry a significant risk of physeal arrest and resulting growth complications which often require additional surgeries to correct the deformity. This study examines the risk of needing corrective procedures as a child approaches skeletal maturity. A retrospective analysis of patients treated at a single institution for distal femoral physeal fractures from 2000 to 2015 was performed. Association between sex, age, Salter-Harris (SH) class, and fracture displacement with the risk of physeal arrest were examined. Association between years of growth remaining to skeletal maturity and the risk of needing additional corrective surgery (defined by leg length difference >2 cm or angular deformity (>5°) was examined using a logistic regression model. One hundred one patients were available for review with an average age of 12.6 ± 3.2 years. Twenty-six patients (25.7%) developed a physeal arrest. Seventy-six percent of these required subsequent surgical intervention to address length and angular deformities Sex, age, and SH class were not significantly associated with physeal arrest (P > 0.05). Percent fracture displacement was significantly associated with physeal arrest (P = 0.02). Years of growth remaining to skeletal maturity were significantly associated with an increased risk of requiring corrective surgery for growth complications (odds ratio: 0.758; 95% confidence interval 0.587-0.979; P = 0.03), however, this association failed to persist when accounting for age. Years of growth remaining to skeletal maturity may predict the need for future interventions and should be accounted for when planning treatment of these challenging injuries.
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http://dx.doi.org/10.1097/BPB.0000000000000733DOI Listing
January 2021

Variability in length of stay following neuromuscular spinal fusion.

Spine Deform 2020 08 14;8(4):725-732. Epub 2020 Feb 14.

Children's Healthcare of Atlanta, 1400 Tullie Rd, Atlanta, GA, 30329, USA.

Background: Patients with neuromuscular scoliosis (NMS) who undergo posterior spinal fusion (PSF) often have long, protracted hospital stays because of numerous comorbidities. Coordinated perioperative pathways can reduce length of hospitalization (LOH) without increasing complications; however, a subset of patients may not be suited to rapid mobilization and early discharge.

Methods: 197 patients with NMS underwent PSF at a single hospital by two surgeons with a post-operative care pathway emphasizing early mobilization, rapid transition to enteral feeds, and discharge prior to first bowel movement. Average LOH was 4.9 days for all patients. Patients were divided into quartiles (< 3 days, 3-5 days, 5-7 days, > 7 days) based on their LOH, and their charts were retrospectively reviewed for preoperative, intraoperative, and postoperative factors associated with their LOH.

Results: Age at surgery, gender, the need for tube feeds, and specific underlying neuromuscular disorder were not significant predictors of LOH; however, severely involved cerebral palsy (CP) patients (GMFCS 4/5) were more likely to have extended stays than GMFCS 1-3 patients (p = 0.02). Radiographic predictors of LOH included major coronal Cobb angle (p = 0.002) and pelvic obliquity (p = 0.02). Intraoperative predictors included longer surgical times, greater numbers of levels fused and need for intraoperative or postoperative blood transfusion (p < 0.05). The need for ICU admission and development of a pulmonary complication were significantly more likely to fall into the extended LOH group (p < 0.05).

Conclusions: Several variables have been identified as significant predictors of LOH after PSF for NMS in the setting of a standardized discharge pathway. Patients with smaller curves and less complex surgeries were more amenable to accelerated discharge. Conversely, patients with severe CP with large curves and pelvic obliquity requiring longer surgeries with more blood loss may not be ideal candidates. These data can be used to inform providers' and families' post-operative expectations.

Level Of Evidence: Therapeutic Level III.
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http://dx.doi.org/10.1007/s43390-020-00081-wDOI Listing
August 2020

Resource Utilization for Patients With Distal Radius Fractures in a Pediatric Emergency Department.

JAMA Netw Open 2020 02 5;3(2):e1921202. Epub 2020 Feb 5.

Department of Orthopaedic Surgery, Emory University School of Medicine, Atlanta, Georgia.

Importance: Improvement of clinician understanding of acceptable deformity in pediatric distal radius fractures is needed.

Objective: To assess how often children younger than 10 years undergo a potentially unnecessary closed reduction using procedural sedation in the emergency department for distal radial metaphyseal fracture and the associated cost implications for these reduction procedures.

Design, Setting, And Participants: This retrospective cross-sectional study included 258 consecutive children younger than 10 years who presented to a single, level I, pediatric emergency department and who had a distal radius fracture with or without ulna involvement between January 1, 2016, and December 31, 2017. Reductions were deemed to be potentially unnecessary if the coronal and sagittal plane angulation of the radius bone measured less than 20° and shortening measured less than 1 cm on initial injury radiographs. Use of procedural sedation or transfer status to another facility was noted if present. Statistical analysis was performed from April 2019 to June 2019.

Main Outcomes And Measures: Potentially unnecessary reduction was the primary outcome. Radiographic findings were measured to determine reduction necessity. Additional variables measured were age, sex, time in the emergency department, transfer status, required reduction procedure, use of sedation, and cost associated with care.

Results: Of the 258 participants studied, 156 (60%) were male, with a mean (SD) age of 6.7 (2.3) years. Among 142 patients (55%) who underwent closed reduction with procedural sedation in the emergency department, 38 (27%) procedures were determined to be potentially unnecessary. Review of Common Procedural Terminology charges revealed an approximately $7000 difference between the stated cost of a reduction procedure in the emergency department vs a cast application in an outpatient orthopedic clinic for distal radial metaphyseal fractures. The mean (SD) maximal angulation in either plane for fractures that underwent appropriate reduction was 30.6° (10.3°) compared with 13.9° (4.5°) for those unnecessarily reduced (P < .001). Patients who were transfers from other facilities were more than twice as likely to undergo a potentially unnecessary reduction (odds ratio, 2.3; 95% CI, 1.1-5.0; P = .03).

Conclusions And Relevance: The findings suggest that improved awareness of these acceptable deformities in young children may be associated with limiting the number of children requiring reduction with sedation, improving emergency department efficiency, and substantially reducing health care costs.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.21202DOI Listing
February 2020

The Reliability of the AOSpine Thoracolumbar Classification System in Children: Results of a Multicenter Study.

J Pediatr Orthop 2020 May/Jun;40(5):e352-e356

Department of Orthopaedic Surgery, Boston Children's Hospital, Boston, MA.

Background: The purpose of this study was to determine whether the new AOSpine thoracolumbar spine injury classification system is reliable and reproducible when applied to the pediatric population.

Methods: Nine POSNA (Pediatric Orthopaedic Society of North America) member surgeons were sent educational videos and schematic papers describing the AOSpine thoracolumbar spine injury classification system. The material also contained magnetic resonance imaging and computed tomography imaging of 25 pediatric patients with thoracolumbar spine injuries organized into cases to review and classify. The evaluators classified injuries into 3 primary categories: A, B, and C. Interobserver reliability was assessed for the initial reading by Fleiss kappa coefficient (kF) along with 95% confidence interval (CI). For A and B type injuries, subclassification was conducted including A0 to A4 and B1 to B2 subtypes. Interobserver reliability across subclasses was assessed using Krippendorff alpha (αk) along with bootstrapped 95% CI. Imaging was reviewed a second time by all evaluators ~1 month later. All imaging was blinded and randomized. Intraobserver reproducibility was assessed for the primary classifications using Fleiss kappa and subclassification reproducibility was assessed by Krippendorff alpha (αk) along with 95% CI. Interpretations for reliability estimates were based on Landis and Koch (1977): 0 to 0.2, slight; 0.2 to 0.4, fair; 0.4 to 0.6, moderate; 0.6 to 0.8, substantial; and >0.8, almost perfect agreement.

Results: Twenty-five cases were read for a total of 225 initial and 225 repeated evaluations. Adjusted interobserver reliability was almost perfect (kF=0.82; CI, 0.77-0.87) across all raters. Subclassification reliability was substantial (αK=0.79; CI, 0.62-0.90). Adjusted intraobserver reproducibility was almost perfect (kF=0.81; CI, 0.71-0.90) for both primary classifications and for subclassifications (αk=0.81; CI, 0.73-0.86).

Conclusions: The reliability for the AOSpine thoracolumbar spine injury slassification System was high amongst POSNA surgeons when applied to pediatric patients. Given a lack of a uniform classification in the pediatric population, the AOSpine thoracolumbar spine injury classification system has the potential to be used as the first universal spine fracture classification in children.

Level Of Evidence: Level III.
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http://dx.doi.org/10.1097/BPO.0000000000001521DOI Listing
September 2020

Fusions ending at the thoracolumbar junction in adolescent idiopathic scoliosis: comparison of lower instrumented vertebrae.

Spine Deform 2020 04 5;8(2):205-211. Epub 2020 Feb 5.

Department of Orthopedics, Emory University, 201 Dowman Drive, Atlanta, GA, 30322, USA.

Study Design: Retrospective cohort study.

Objective: To compare clinical outcomes and radiographic parameters between patients treated with a posterior spinal fusion that had a lower instrumented vertebra at T11, T12, and L1.

Background: Posterior instrumented fusions are well established for treating patients with adolescent idiopathic scoliosis (AIS). Fusions limited to the thoracic spine can adequately correct a spinal deformity while preserving lumbar segmental mobility. However, fusions that end at the thoracolumbar junction have been proposed to cause adjacent segment complications. Studies comparing outcomes between patients who were treated with fusions that end at the thoracolumbar junction with varying LIVs are limited.

Methods: A multicenter database was queried for patients with AIS that had Lenke Type 1 and 2 curves treated with a fusion that had an LIV at T11, T12, or L1. Coronal curve magnitude, degree of junctional kyphosis, C7-central sacral line, thoracic apical translation, and sagittal stable vertebrae were measured. Clinical and functional outcomes were assessed using the Scoliosis Research Society-22 (SRS-22) questionnaire and lumbar flexibility testing.

Results: The lower instrumented level was below the sagittal stable vertebrae in 22.7%, 40%, and 66.2% of patients in the LIV-T11, T12, and L1 groups, respectively (p < 0.001). The 5-year postoperative lumbar curve magnitudes were 20.3°, 16.3°, and 14.0° for T11, T12, and L1-LIV, respectively (p < 0.001). No patients in the T11 group (0%), two patients in the T12 group (2.5%), and one patient in the L1 (0.8%) group developed distal junctional kyphosis (p = 0.5). The 5-year postoperative total SRS-22 scores were 4.21, 4.50, and 4.38 (p = 0.029). Lumbar flexion decreased by 0.78 cm in the T11-LIV group, increased by 0.01 cm in the T12-LIV group, and decreased by 0.15 cm in the L1-LIV group (p = 0.434).

Conclusion: There was no significant difference in SRS-22 scores, development of distal junctional kyphosis or loss of lumbar mobility between patients treated with a spinal fusion that had an LIV at T11, T12, or L1.

Level Of Evidence: Level III.
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http://dx.doi.org/10.1007/s43390-020-00044-1DOI Listing
April 2020

Glacial cycles drive rapid divergence of cryptic field vole species.

Ecol Evol 2019 Dec 23;9(24):14101-14113. Epub 2019 Nov 23.

Department of Ecology and Evolutionary Biology Cornell University Ithaca NY USA.

Understanding the factors that contribute to the generation of reproductively isolated forms is a fundamental goal of evolutionary biology. Cryptic species are an especially interesting challenge to study in this context since they lack obvious morphological differentiation that provides clues to adaptive divergence that may drive reproductive isolation. Geographical isolation in refugial areas during glacial cycling is known to be important for generating genetically divergent populations, but its role in the origination of new species is still not fully understood and likely to be situation dependent. We combine analysis of 35,434 single-nucleotide polymorphisms (SNPs) with environmental niche modeling (ENM) to investigate genomic and ecological divergence in three cryptic species formerly classified as the field vole (). The SNPs demonstrate high genomic divergence (pairwise values of 0.45-0.72) and little evidence of gene flow among the three field vole cryptic species, and we argue that genetic drift may have been a particularly important mechanism for divergence in the group. The ENM reveals three areas as potential glacial refugia for the cryptic species and differing climatic niches, although with spatial overlap between species pairs. This evidence underscores the role that glacial cycling has in promoting genetic differentiation and reproductive isolation by subdivision into disjunct distributions at glacial maxima in areas relatively close to ice sheets. Future investigation of the intrinsic barriers to gene flow between the field vole cryptic species is required to fully assess the mechanisms that contribute to reproductive isolation. In addition, the Portuguese field vole () shows a high inbreeding coefficient and a restricted climatic niche, and warrants investigation into its conservation status.
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http://dx.doi.org/10.1002/ece3.5846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953675PMC
December 2019

Use of an Accelerated Discharge Pathway in Patients With Severe Cerebral Palsy Undergoing Posterior Spinal Fusion for Neuromuscular Scoliosis.

Spine Deform 2019 09;7(5):804-811

Emory University Department of Orthopaedics, 59 Executive Park South, NE, Suite 2000, Atlanta, GA 30329, USA. Electronic address:

Background: Implementation of a coordinated multidisciplinary postoperative pathway has been shown to reduce length of stay after posterior spinal fusion (PSF) for adolescent idiopathic scoliosis. This study sought to compare the outcomes of nonambulatory cerebral palsy (CP) patients treated with PSF and cared for using an accelerated discharge (AD) pathway with those using a more traditional discharge (TD) pathway.

Methods: A total of 74 patients with Gross Motor Function Classification System (GMFCS) class 4/5 CP undergoing PSF were reviewed. Thirty consecutive patients were cared for using a TD pathway, and 44 patients were subsequently treated using an AD pathway. The cohorts were then evaluated for postoperative complications and length of stay.

Results: Length of stay (LOS) was 19% shorter in patients managed with the AD pathway (AD 4.0 days [95% CI 2.5-5.5] vs. TD 4.9 days [95% CI 3.5-6.3], p = .01). There was no difference between groups with respect to age at surgery, GMFCS class, preoperative curve magnitude, pelvic obliquity, kyphosis, postoperative curve correction, fusion to the pelvis, or length of fusion between groups. Length of stay remained significantly shorter in the AD group by 0.9 days when controlling for estimated blood loss (EBL) and length of surgery. Complication rates trended lower in the AD group (33% AD vs. 52% TD, p = .12), including pulmonary complications (21% AD vs. 38% TD, p = .13). There was no significant difference in wound complications, return to the operating room, or medical readmissions between groups.

Conclusions: Adoption of a standardized postoperative pathway reduced LOS by 19% in nonambulatory CP patients. Overall, complications, including pulmonary, trended lower in the AD group. Early discharge appears to be possible in this challenging patient population. Although the AD pathway may not be appropriate for all patients, the utility of the AD pathway in optimizing care for more routine PSF for this patient subset appears to be worthwhile.

Level Of Evidence: Level III, therapeutic.
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http://dx.doi.org/10.1016/j.jspd.2019.02.002DOI Listing
September 2019

Polymer design and component selection contribute to uptake, distribution & trafficking behaviours of polyethylene glycol hyperbranched polymers in live MDA-MB-468 breast cancer cells.

Biomater Sci 2019 Nov 30;7(11):4661-4674. Epub 2019 Aug 30.

Centre for Advanced Imaging (CAI), The University of Queensland, Brisbane, QLD 4072, Australia. and Australian Institute for Bioengineering & Nanotechnology (AIBN), The University of Queensland, Brisbane, QLD 4072, Australia and ARC Centre of Excellence for Convergent Bio-Nano Science & Technology and ARC Training Centre for Innovation in Biomedical Imaging Technology, The University of Queensland, Brisbane, QLD 4072, Australia.

As polymeric nanomedicines grow increasingly complex in design, an effective therapeutic release is often inherently tied to localisation to specific intracellular compartments or microenvironments. The inclusion of environmentally-sensitive moieties links the functionality of such materials to the trafficking behaviours exhibited once materials have obtained access to the cellular milieu. In order to perform their designed function, such materials often need to encounter specific biological cues or stimuli. As such, there is an increased need to improve our understanding of how the physicochemical properties of nanomaterials influence post-internalisation behaviours. Amongst the unknown factors that may contribute to the trafficking behaviours and distribution of polymers within the cellular environment, is the influence of the components selected in the development of such materials. To examine whether composition and arrangement of components within small polymeric nanomaterials contribute to their ability to navigate the intracellular space, here we utilise fluorophores to model component selection, varying the fluorescent handle selected and its method of incorporation. We explore the intracellular behaviours of well-characterised hyperbranched polymers in live MDA-MB-468 breast cancer cells in vitro. Changes in distribution as a function of both fluorophore selection and placement are reported, and our data suggest that the individual components used to produce potential nanomedicines are critical to their overall functioning and efficacy. Further to this, through the use of a novel non-conjugated targeting ligand, we demonstrate that there is inherent competition between component-directing factors and cellular influences on the ultimate fate of the polymers. The behaviours reported here suggest that not only does component selection contribute to intracellular processing, but these factors could potentially be harnessed when designing polymers to ensure improved functionality of future materials for therapeutic delivery.
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http://dx.doi.org/10.1039/c9bm00957dDOI Listing
November 2019

The Walton Centre neurology network - an equitable, sustainable and deliverable model for a large-scale neurology service.

Future Healthc J 2019 Jun;6(2):123-128

Walton Centre NHS Foundation Trust, Liverpool, UK.

UK neurology has many different models of provision and a shortage of essential clinical staff. Services are sometimes unsatisfactory and there is much variation and inequality, especially in areas outside London where there are far fewer consultants. Some hospitals have much better staffed and resourced neurological services than others which may have far less provision or even no neurology service at all. There is no national strategy or agreed model of service delivery - local areas have evolved individual arrangements, often dictated by consultant availability. We describe, with clear operational details, a neurology network model in a large population, with outcomes. In many areas with limited resources it could, by re-organisation of current services, be considered instead of existing separate, variable and potentially inequitable local arrangements.
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http://dx.doi.org/10.7861/futurehosp.6-2-123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6616178PMC
June 2019