Transition Metal Complexes with Appended Benzimidazole Groups for Sensing Dihydrogenphosphate.

Four new complexes [Ru(bpy)2(bbib)](PF6)2, [Ru(phen)2(bbib)](PF6)2, [Re(CO)3(bbib)(py)](PF6) and [Ir(ppy)2(bbib)](PF6) [where bbib = 4,4'-bis(benzimidazol-2-yl)-2,2'-bipyridine] have been prepared and their photophysical properties determined. Their behaviour has been studied with a variety of anions in acetonitrile, DMSO and 10% aquated DMSO. Acetate and dihydrogenphosphate demonstrate a redshift in the bbib ligand associated absorptions suggesting that the ligand is strongly interacting with these anions. The 3MLCT emissive state is sensitive to the introduction of small quantities of anion (sub-stoichiometric quantities) and significant quenching is typically observed with acetate, although this is less pronounced in the presence of water. The emissive behaviour with dihydrogenphosphate is variable, showing systematic changes as anion concentration increases with several distinct interactions evident . 1H NMR and 31P NMR titrations in a 10% D2O - D6-DMSO mixture suggest that with dihydrogenphosphate, the imidazole group able to act as both a proton acceptor and donor. It appears that all four complexes can form a {[complex]2-H2PO4} "dimer", a one-to-one species (which the X-ray crystallography study suggests is dimeric in the solid-state), and a complex with a combined bis(dihydrogenphosphate) complex anion. The speciation relies on complex equilibria dependent on several factors including the complex charge, the hydrophobicity of the associated ligands, and the solvent.

A New Look at Vertebral Body Tethering (VBT): Through the Modified Clavien-Dindo-Sink (mCDS) Classification.

INTRODUCTION: Anterior vertebral body tethering (AVBT) is increasingly popular as an option for surgical treatment of idiopathic scoliosis (IS). While the technology remains new, it is important for families and patients to be able to compare it to the current standard of care, posterior spinal fusion (PSF). The purpose of this study is to describe the complication rate of AVBT in IS using the mCDS and to compare it to the recently reported complication rate of PSF in IS. METHODS: A multicenter pediatric spine deformity database was queried for all idiopathic scoliosis patients who underwent vertebral body tethering. There were 171 patients with a minimum 9-month follow-up included in this study. Complications were retrospectively graded by 2 attending pediatric spine surgeons using the mCDS classification system. RESULTS: Data from 171 patients with idiopathic scoliosis was available for analysis, with 156/171 (91%) of patients being female and an average age of 12.2 years old at surgery. There were 156 thoracic tethers (1 with an LIV below L2), 5 lumbar tethers, 9 staged double tethers, and only 1 patient with same-day double tether. Fifty-five (55) (32%) patients experienced a total of 69 complications. The most common complication type for VBT by mCDS was Grade IIIb, encompassing 29/69 (42%) of complications. The second most frequent complication grade was Grade I at 23/69 (33%). Thirty-four (34) out of 69 (49%) of the VBT complications reported required either procedural/surgical intervention or admission to the ICU. CONCLUSIONS: This is the first study to directly compare the complication profile of VBT to PSF using the mCDS. Forty-nine percent (49%) of the VBT complications reported were at least Grade III, while only 7% of complications in the control PSF cohort from the literature were Grade III or higher. The mCDS complication classification brings light to the early learning experience of a new technique compared to the widely accepted standard of PSF for IS. LEVEL OF EVIDENCE: III - Retrospective comparative study.

Regional Anesthesia as an Alternative to Procedural Sedation for Forearm Fracture Reductions in the Pediatric Emergency Department.

BACKGROUND: Pediatric forearm fractures are common injuries in the pediatric emergency department (PED). Pediatric procedural sedation (PPS) is often required for forearm fracture reductions and pain control for casting. Bier blocks and hematoma blocks are types of regional anesthesia (RA) procedures that can be performed as a potential alternative to PPS. OBJECTIVE: The objective of this study is to compare the safety of RA with that of PPS. We hypothesized that RA has a safety profile that is equal or superior to PPS as well as a shorter duration of treatment in the PED. METHODS: Pediatric emergency department encounters in patients presenting with a diagnosis of radius fracture, ulna fracture, distal "both-bone" fracture, Monteggia fracture, and/or Galeazzi fracture were included. Outcomes of interest included patient adverse events (AEs), sedation medications used, PED duration of treatment (arrival time to disposition time), sedation failures, and reduction failures. RESULTS: Propensity matching was performed resulting in 632 well-matched RA-PPS pairs. The PPS cohort had 13% of encounters with at least 1 AE compared with 0.2% in the RA cohort, P < 0.001. The most common AE in the PPS group was hypoxia (9.8%), and the only AE in the RA group was an intravenous infiltrate (0.16%). Within the matched cohorts, PPS required more medications than RA (100% vs 60%, P < 0.001). Ketamine alone was more commonly used in the PPS group than the RA group (86% vs 0.2%, P < 0.001). Propofol was used only in the PPS group. The average duration of treatment was 205 (SD, 81) minutes in the PPS group and 178 (SD, 75) minutes in the RA group ( P < 0.001). There were no reduction failures in either group. CONCLUSIONS: Bier blocks and hematoma blocks are an acceptable alternative to PPS for children requiring forearm reductions. The AE rate is low and the reduction success rate is high. Duration of treatment in the PED is shorter for patients receiving RA compared with PPS.

RAFT Polymer-Antibody Conjugation: Squaramide Ester Chemistry Leads to Conjugates with a Therapeutic Anti-EGFR Antibody with Full Retention of Activity and Increased Tumor Uptake In Vivo.

Covalent conjugation of a biologically stable polymer to a therapeutic protein, e.g., an antibody, holds many benefits such as prolonged plasma exposure of the protein and improved tumor uptake. Generation of defined conjugates is advantageous in many applications, and a range of site-selective conjugation methods have been reported. Many current coupling methods lead to dispersity in coupling efficiencies with subsequent conjugates of less-well-defined structure, which impacts reproducibility of manufacture and ultimately may impact successful translation to treat or image diseases. We explored designing stable, reactive groups for polymer conjugation reactions that would lead to conjugates through the simplest and most abundant residue on most proteins, the lysine residue, yielding conjugates in high purity and demonstrating retention of mAb efficacy through surface plasmon resonance (SPR), cell targeting, and in vivo tumor targeting. We utilized squaric acid diesters as coupling agents for selective amidation of lysine residues and were able to selectively conjugate one, or two, high-molecular-weight polymers to a therapeutically relevant antibody, 528mAb, that subsequently retained full binding specificity. Water-soluble copolymers of N-(2-hydroxypropyl) methacrylamide (HPMA) and N-isopropylacrylamide (NIPAM) were prepared by Reversible Addition-Fragmentation chain-Transfer (RAFT) polymerization and we demonstrated that a dual-dye-labeled antibody-RAFT conjugate (528mAb-RAFT) exhibited effective tumor targeting in model breast cancer xenografts in mice. The combination of the precise and selective squaric acid ester conjugation method, with the use of RAFT polymers, leads to a promising strategic partnership for improved therapeutic protein-polymer conjugates having a very-well-defined structure.

Targeted Hyperbranched Nanoparticles for Delivery of Doxorubicin in Breast Cancer Brain Metastasis.

Breast cancer brain metastases (BM) are associated with a dismal prognosis and very limited treatment options. Standard chemotherapy is challenging in BM patients because the high dosage required for an effective outcome causes unacceptable systemic toxicities, a consequence of poor brain penetration, and a short physiological half-life. Nanomedicines have the potential to circumvent off-target toxicities and factors limiting the efficacy of conventional chemotherapy. The HER3 receptor is commonly expressed in breast cancer BM. Here, we investigate the use of hyperbranched polymers (HBP) functionalized with a HER3 bispecific-antibody fragment for cancer cell-specific targeting and pH-responsive release of doxorubicin (DOX) to selectively deliver and treat BM. We demonstrated that DOX-release from the HBP carrier was controlled, gradual, and greater in endosomal acidic conditions (pH 5.5) relative to physiologic pH (pH 7.4). We showed that the HER3-targeted HBP with DOX payload was HER3-specific and induced cytotoxicity in BT474 breast cancer cells (IC50: 17.6 µg/mL). Therapeutic testing in a BM mouse model showed that HER3-targeted HBP with DOX payload impacted tumor proliferation, reduced tumor size, and prolonged overall survival. HER3-targeted HBP level detected in ex vivo brain samples was 14-fold more than untargeted-HBP. The HBP treatments were well tolerated, with less cardiac and oocyte toxicity compared to free DOX. Taken together, our HER3-targeted HBP nanomedicine has the potential to deliver chemotherapy to BM while reducing chemotherapy-associated toxicities.

Pharmacokinetics and Biodistribution of 89Zr-Miltuximab and Its Antibody Fragments as Glypican-1 Targeting Immuno-PET Agents in Glioblastoma.

Glioblastoma (GBM) is the most aggressive form of primary brain cancer, accounting for about 85% of all primary central nervous system (CNS) tumors. With standard treatment strategies like surgery, radiation, and chemotherapy, the median survival time of patients with GBM is only 12-15 months from diagnosis. The poor prognosis of GBM is due to a very high tumor recurrence rate following initial treatment, indicating a dire need for improved diagnostic and therapeutic alternatives for this disease. Antibody-based immunotheranostics holds great promise in treating GBM, combining the theranostic applications of radioisotopes and target-specificity of antibodies. In this study, we developed and validated antibody-based positron emission tomography (PET) tracers targeting the heparan sulfate proteoglycan, glypican-1 (GPC-1), for noninvasive detection of disease using diagnostic molecular imaging. GPC-1 is overexpressed in multiple solid tumor types, including GBM, and is a promising biomarker for novel immunotheranostics. Here, we investigate zirconium-89 (89Zr)-conjugated Miltuximab (a clinical stage anti-GPC-1 monoclonal antibody developed by GlyTherix, Ltd.) and engineered fragments for their potential as immuno-PET tracers to detect GPC-1positive GBM tumors in preclinical models. We explore the effects of molecular size, avidity, and Fc-domain on the pharmacokinetics and biodistribution in vivo, by comparing in parallel the full-length antibody (Miltuximab), Fab'2, Fab, and single-chain variable fragment (scFv) formats. High radiolabeling efficiency (>95%) was demonstrated by all the formats and the stability post-radiolabeling was higher for larger constructs of Miltuximab and the Fab. Receptor-mediated internalization of all 89Zr-labeled formats was observed in a human GBM cell line in vitro, while full-length Miltuximab demonstrated the highest tumor retention (5.7 ± 0.94% ID/g, day-9 postinjection (p.i.)) and overall better tumor-to-background ratios than the smaller Fc-less formats. Results from in vivo PET image quantification and ex vivo scintillation counting were highly correlated. Altogether, 89Zr-DFO-Miltuximab appears to be an effective immuno-PET imaging agent for detecting GPC-1positive tumors such as GBM and the current results support utility of the Fc containing whole mAb format over smaller antibody fragments for this target.

Probing the Biocompatibility and Immune Cell Association of Chiral, Water-Soluble, Bottlebrush Poly(2-oxazoline)s.

Poly(2-oxazoline)s (POx) have received substantial attention as poly(ethylene glycol) (PEG) alternatives in the biomedical field due to their biocompatibility, high functionality, and ease of synthesis. While POx have demonstrated strong potential as biomaterial constituents, the larger family of poly(cyclic imino ether)s (PCIE) to which POx belongs remains widely underexplored. One highly interesting sub-class of PCIE is poly(2,4-disubstituted-2-oxazoline)s (PdOx), which bear an additional substituent on the backbone of the polymers' repeating units. This allows fine-tuning of the hydrophilic/hydrophobic balance and renders the PdOx chiral when enantiopure 2-oxazoline monomers are used. Herein, we synthesize new water-soluble (R-/S-/RS-) poly(oligo(2-ethyl-4-methyl-2-oxazoline) methacrylate) (P(OEtMeOxMA)) bottlebrushes and compare them to well-established PEtOx- and PEG-based bottlebrush controls in terms of their physical properties, hydrophilicity, and biological behavior. We reveal that the P(OEtMeOxMA) bottlebrushes show a lower critical solution temperature behavior at a physiologically relevant temperature (∼44 °C) and that the enantiopure (R-/S-) variants display a chiral secondary structure. Importantly, we demonstrate the biocompatibility of the chiral P(OEtMeOxMA) bottlebrushes through cellular association and mouse biodistribution studies and show that these systems display higher immune cell association and organ accumulation than the two control polymers. These novel materials possess properties that hold promise for applications in the field of nanomedicine and may be beneficial carriers for therapeutics that require enhanced cellular association and immune cell interaction.

Development and Validation of a Targeted Treatment for Brain Tumors Using a Multi-Drug Loaded, Relapse-Resistant Polymeric Theranostic.

This study aimed to develop a multifunctional polymer platform that could address the issue of treatment resistance when using conventional chemotherapeutics to treat glioblastoma (GBM). An antibody-conjugated, multi-drug loaded hyperbranched polymer was developed that provided a platform to evaluate the role of targeted nanomedicine treatments in overcoming resistant GBM by addressing the various complications with current clinically administered formulations. The polymer was synthesized via reversible addition fragmentation chain transfer polymerization and included the clinical first-line alkylating agent temozolomide (TMZ) which was incorporated as a polymerizable monomer, poly (ethylene glycol) (PEG) units to impart biocompatibility and enable conjugation with αPEG-αEphA2 bispecific antibody (αEphA2 BsAb) for tumor targeting, and hydrazide moieties for attachment of a secondary drug which allows exploration of synergistic therapies. To overcome the resistance to TMZ, the O6 alkylguanine DNA alkyltransferase (AGT, DNA repair protein) inhibitor, dialdehyde O6 benzylguanine (DABG) was subsequently conjugated to the polymer via an acid labile hydrazone linker to facilitate controlled release under conditions encountered within the tumor microenvironment. The prolonged degradation half-life (4-5 h) of the polymer conjugated TMZ in vitro offered a potential avenue to overcome the inability to deliver these drugs in combination at therapeutic doses. Although only 20% of DABG could be released within the studied timeframe (192 h) under conditions mimicking the acidic nature of the tumor environment, cytotoxicity evaluation using cell assays confirmed the improved therapeutic efficacy toward resistant GBM cells after attaching DABG to the polymer delivery vehicle. Of note, when the polymeric delivery vehicle was specifically targeted to receptors (Ephrin A2) on the surface of the GBM cells using our in-house developed EphA2 specific BsAb, the dual-drug-loaded polymer exhibited an improved therapeutic effect on TMZ-resistant cells compared to the free drug combination. Both in vitro and in vivo targeting studies showed high uptake of the construct to GBM tumors with an upregulated EphA2 receptor (T98G and U251) compared to a tumor that had low expression (U87MG), where a dual tumor xenograft model was used to demonstrate the enhanced accumulation in tumor tissue in vivo. Despite the synthetic challenges of developing systems to effectively deliver controlled doses of TMZ and DABG, these studies highlight the potential benefit of this formulation for delivering multi-drug combinations to resistant GBM tumor cells and offer a platform for future optimization in therapeutic studies.

The Reliability of the AO Spine Upper Cervical Classification System in Children: Results of a Multi-Center Study.

BACKGROUND: There is no uniform classification system for traumatic upper cervical spine injuries in children. This study assesses the reliability and reproducibility of the AO Upper Cervical Spine Classification System (UCCS), which was developed and validated in adults, to children. METHODS: Twenty-six patients under 18 years old with operative and nonoperative upper cervical injuries, defined as from the occipital condyle to the C2-C3 joint, were identified from 2000 to 2018. Inclusion criteria included the availability of computed tomography and magnetic resonance imaging at the time of injury. Patients with significant comorbidities were excluded. Each case was reviewed by a single senior surgeon to determine eligibility. Educational videos, schematics describing the UCCS, and imaging from 26 cases were sent to 9 pediatric orthopaedic surgeons. The surgeons classified each case into 3 categories: A, B, and C. Inter-rater reliability was assessed for the initial reading across all 9 raters by Fleiss's kappa coefficient (kF) along with 95% confidence intervals. One month later, the surgeons repeated the classification, and intra-rater reliability was calculated. All images were de-identified and randomized for each read independently. Intra-rater reproducibility across both reads was assessed using Fleiss's kappa. 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-six cases were read by 9 raters twice. Sub-classification agreement was moderate to substantial with α κ estimates from 0.55 for the first read and 0.70 for the second read. Inter-rater agreement was moderate (kF 0.56 to 0.58) with respect to fracture location and fair (kF 0.24 to 0.3) with respect to primary classification (A, B, and C). Krippendorff's alpha for intra-rater reliability overall sub-classifications ranged from 0.41 to 0.88, with 0.75 overall raters. CONCLUSION: Traumatic upper cervical injuries are rare in the pediatric population. A uniform classification system can be vital to guide diagnosis and treatment. This study is the first to evaluate the use of the UCCS in the pediatric population. While moderate to substantial agreement was found, limitations to applying the UCCS to the pediatric population exist, and thus the UCCS can be considered a starting point for developing a pediatric classification. LEVEL OF EVIDENCE: Level III.

Modulating Macrophage Clearance of Nanoparticles: Comparison of Small-Molecule and Biologic Drugs as Pharmacokinetic Modifiers of Soft Nanomaterials.

Nanomedicines show benefits in overcoming the limitations of conventional drug delivery systems by reducing side effects, toxicity, and exhibiting enhanced pharmacokinetic (PK) profiles to improve the therapeutic window of small-molecule drugs. However, upon administration, many nanoparticles (NPs) prompt induction of host innate immune responses, which in combination with other clearance pathways such as renal and hepatic, eliminate up to 99% of the administered dose. Here, we explore a drug predosing strategy to transiently suppress the mononuclear phagocyte system (MPS), subsequently improving the PK profile and biological behaviors exhibited by a model NP system [hyperbranched polymers (HBPs)] in an immunocompetent mouse model. In vitro assays allowed the identification of five drug candidates that attenuated cellular association. Predosing of lead compounds chloroquine (CQ) and zoledronic acid (ZA) further showed increased HBP retention within the circulatory system of mice, as shown by both fluorescence imaging and positron emission tomography-computed tomography. Flow cytometric evaluation of spleen and liver tissue cells following intravenous administration further demonstrated that CQ and ZA significantly reduced HBP association with myeloid cells by 23 and 16%, respectively. The results of this study support the use of CQ to pharmacologically suppress the MPS to improve NP PKs.

Antibody-Based Formats to Target Glioblastoma: Overcoming Barriers to Protein Drug Delivery.

Glioblastoma (GB) is recognized as the most aggressive form of primary brain cancer. Despite advances in treatment strategies that include surgery, radiation, and chemotherapy, the median survival time (∼15 months) of patients with GB has not significantly improved. The poor prognosis of GB is also associated with a very high chance of tumor recurrence (∼90%), and current treatment measures have failed to address the complications associated with this disease. However, targeted therapies enabled through antibody engineering have shown promise in countering GB when used in combination with conventional approaches. Here, we discuss the challenges in conventional as well as future GB therapeutics and highlight some of the known advantages of using targeted biologics to overcome these impediments. We also review a broad range of potential alternative routes that could be used clinically to administer anti-GB biologics to the brain through evasion of its natural barriers.

Surviving Bad Meetings: Efficiencies to Thwart This Increasingly Common Administrative Time Vortex.

Meetings have become a near-constant presence in the practicing pediatric orthopaedist's day. While many meetings are productive and efficient, others may represent a time vortex that take precious hours away from other meaningful pursuits. Organizers and participants in meetings have an obligation to optimize these gatherings whenever possible. Selecting optimal times, ensuring that the minutes together are spent efficiently, creating an agenda and presenting ideas to be discussed in an effective manner, actively listening to other participants, and debriefing are all ways that meetings can be made more productive and enjoyable.

Best Practice Guidelines for Surgical Site Infection in High-risk Pediatric Spine Surgery: Definition, Prevention, Diagnosis, and Treatment.

BACKGROUND: Prior "best practice guidelines" (BPG) have identified strategies to reduce the risk of acute deep surgical site infection (SSI), but there still exists large variability in practice. Further, there is still no consensus on which patients are "high risk" for SSI and how SSI should be diagnosed or treated in pediatric spine surgery. We sought to develop an updated, consensus-based BPG informed by available literature and expert opinion on defining high-SSI risk in pediatric spine surgery and on prevention, diagnosis, and treatment of SSI in this high-risk population. MATERIALS AND METHODS: After a systematic review of the literature, an expert panel of 21 pediatric spine surgeons was selected from the Harms Study Group based on extensive experience in the field of pediatric spine surgery. Using the Delphi process and iterative survey rounds, the expert panel was surveyed for current practices, presented with the systematic review, given the opportunity to voice opinions through a live discussion session and asked to vote regarding preferences privately. Two survey rounds were conducted electronically, after which a live conference was held to present and discuss results. A final electronic survey was then conducted for final voting. Agreement ≥70% was considered consensus. Items near consensus were revised if feasible to achieve consensus in subsequent surveys. RESULTS: Consensus was reached for 17 items for defining high-SSI risk, 17 items for preventing, 6 for diagnosing, and 9 for treating SSI in this high-risk population. After final voting, all 21 experts agreed to the publication and implementation of these items in their practice. CONCLUSIONS: We present a set of updated consensus-based BPGs for defining high-risk and preventing, diagnosing, and treating SSI in high-risk pediatric spine surgery. We believe that this BPG can limit variability in practice and decrease the incidence of SSI in pediatric spine surgery. LEVEL OF EVIDENCE: Not applicable.

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

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 (λem = 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.

Surgical care practitioners: an audit across the surgical specialties.

INTRODUCTION: The Royal College of Surgeons of England (RCS), when devising their curriculum for surgical care practitioners (SCPs), aimed to provide a level of training to produce a practitioner able to work across the surgical patient's journey, providing care to, arguably, an advanced level. This audit planned to examine the reality of this. METHOD: SCPs from a closed group, on the Facebook social media platform were invited to complete an online questionnaire about their role as an SCP. RESULTS: A total of 92 responses were gathered from across the surgical specialty SCP community and from around the UK. Data were collected on the breakdown of the SCP's role and working practices. CONCLUSION: The data collected demonstrated the multifunctional nature of the SCP and their ability to work at a level as envisioned by the RCS curriculum.

Indications for Lumbar Fusion in the Skeletally Mature Adolescent: How to Address Oblique Takeoff and Limb Length Discrepancy.

BACKGROUND: Indications for posterior spinal fusion (PSF) with segmental spinal instrumentation (SSI) of a scoliotic deformity in a skeletally mature individual are based on the balance between the anticipated benefit of stopping future curve progression and the potential downside of loss of spinal mobility. The dilemma regarding PSF with SSI in the adolescent population is exacerbated by the patient's participation in athletics requiring flexibility and motion of the spine, the location of the curve, the presence of pelvic obliquity, and the impact of a limb length discrepancy. The purpose of this review is to discuss the potential advantages and disadvantages of PSF with SSI in a hypothetical skeletally mature adolescent with a 45-degree lumbar curve, pelvic obliquity, and limb length discrepancy. DISCUSSION: Natural history studies of untreated adolescent idiopathic scoliosis (AIS) have shown that slow curve progression throughout adulthood is likely. Adults with untreated AIS may also have more back pain and dissatisfaction with their appearance. Although the clinical and radiographic outcomes of PSF with SSI are excellent, patients should be counseled about the impact of fusing the lumbar spine on back pain, decreased spinal mobility, and potential inability to return to athletics at the same level. Adults who undergo surgery for AIS have greater operative morbidity and number of levels fused compared with adolescents. CONCLUSION: These factors should be presented when discussing observation versus PSF with SSI with patients and families. Delaying surgery until formal athletic participation is complete should be considered.

Surgical Outcomes of Obese Patients With Adolescent Idiopathic Scoliosis From Endemic Areas of Obesity in the United States.

BACKGROUND: Obesity rates continue to rise among children and adolescents across the globe. A multicenter research consortium composed of institutions in the Southern US, located in states endemic for childhood obesity, was formed to evaluate the effect of obesity on pediatric musculoskeletal disorders. This study evaluates the effect of body mass index (BMI) percentile and socioeconomic status (SES) on surgical site infections (SSIs) and perioperative complications in patients with adolescent idiopathic scoliosis (AIS) treated with posterior spinal fusion (PSF). METHODS: Eleven centers in the Southern US retrospectively reviewed postoperative AIS patients after PSF between 2011 and 2017. Each center contributed data to a centralized database from patients in the following BMI-for-age groups: normal weight (NW, 5th to <85th percentile), overweight (OW, 85th to <95th percentile), and obese (OB, ≥95th percentile). The primary outcome variable was the occurrence of an SSI. SES was measured by the Area Deprivation Index (ADI), with higher scores indicating a lower SES. RESULTS: Seven hundred fifty-one patients were included in this study (256 NW, 235 OW, and 260 OB). OB and OW patients presented with significantly higher ADIs indicating a lower SES (P<0.001). In addition, SSI rates were significantly different between BMI groups (0.8% NW, 4.3% OW, and 5.4% OB, P=0.012). Further analysis showed that superficial and not deep SSIs were significantly different between BMI groups. These differences in SSI rates persisted even while controlling for ADI. Wound dehiscence and readmission rates were significantly different between groups (P=0.004 and 0.03, respectively), with OB patients demonstrating the highest rates. EBL and cell saver return were significantly higher in overweight patients (P=0.007 and 0.002, respectively). CONCLUSION: OB and OW AIS patients have significantly greater superficial SSI rates than NW patients, even after controlling for SES. LEVEL OF EVIDENCE: Level III.

Workforce issues: the blurring of boundaries in surgical care.

Bradley Russell and Nicholas Fletcher discuss the need for clear boundaries for those nurses practising at an advanced level in surgical specialties.

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

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 CD68hi and CD11bhi macrophages showed similar levels of polymer association, despite CD11bhi 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 CD68hi 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.

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

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-(N-(S-penicillaminylacetyl)amino) phenylarsenonous acid (PENAO) was reported. The anticancer drug 4-(N-(S-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-co- 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-co-PENAO-coated nanoparticles were found to accumulate in the liver, making this particle system unfeasible for future biological studies.