A Multicenter Study Validates the WHO 2022 Classification for Conjunctival Melanocytic Intraepithelial Lesions With Clinical and Prognostic Relevance.

Several nomenclature and grading systems have been proposed for conjunctival melanocytic intraepithelial lesions (C-MIL). The fourth "WHO Classification of Eye Tumors" (WHO-EYE04) proposed a C-MIL classification, capturing the progression of noninvasive neoplastic melanocytes from low- to high-grade lesions, onto melanoma in situ (MIS), and then to invasive melanoma. This proposal was revised to the WHO-EYE05 C-MIL system, which simplified the high-grade C-MIL, whereby MIS was subsumed into high-grade C-MIL. Our aim was to validate the WHO-EYE05 C-MIL system using digitized images of C-MIL, stained with hematoxylin and eosin and immunohistochemistry. However, C-MIL cases were retrieved from 3 supraregional ocular pathology centers. Adequate conjunctival biopsies were stained with hematoxylin and eosin, Melan-A, SOX10, and PReferentially expressed Antigen in Melanoma. Digitized slides were uploaded on the SmartZoom platform and independently scored by 4 ocular pathologists to obtain a consensus score, before circulating to 14 expert eye pathologists for independent scoring. In total, 105 cases from 97 patients were evaluated. The initial consensus diagnoses using the WHO-EYE04 C-MIL system were as follows: 28 benign conjunctival melanoses, 13 low-grade C-MIL, 37 high-grade C-MIL, and 27 conjunctival MIS. Using this system resulted in 93% of the pathologists showing only fair-to-moderate agreement (kappa statistic) with the consensus score. The WHO-EYE05 C-MIL system (with high-grade C-MIL and MIS combined) improved consistency between pathologists, with the greatest level of agreement being seen with benign melanosis (74.5%) and high-grade C-MIL (85.4%). Lowest agreements remained between pathologists for low-grade C-MIL (38.7%). Regarding WHO-EYE05 C-MIL scoring and clinical outcomes, local recurrences of noninvasive lesions developed in 8% and 34% of the low- and high-grade cases. Invasive melanoma only occurred in 47% of the cases that were assessed as high-grade C-MIL. This extensive international collaborative study is the first to undertake a comprehensive review of the WHO-EYE05 C-MIL scoring system, which showed good interobserver agreement and reproducibility.

Ultra-sensitive UV solar-blind optical wireless communications with an SiPM.

In this Letter, an SiPM with a dedicated cooling system suitable for receiving ultra-low-power solar-blind wavelengths is reported. This is designed to decrease the temperature of the detector from 21°C to -10°C, and the corresponding dark count rate (DCR) is reduced by approximately 10 dB. A 275 nm optical wireless communication (OWC) system is established using on-off-keying (OOK) modulation. Transmission rates ranging from 100 kbit/s to 2 Mbit/s are demonstrated with this cooled SiPM. The received power is as low as 30 pW (corresponding to 41.5 photons per bit) at a data rate of 1 Mbit/s and a bit error rate of 2.4 × 10-3.

Anion-Dependent Reactivity of Mono- and Dinuclear Boron Cations.

The dinuclear bis(N-heterocyclic carbene) borane adduct 2 rapidly reacts with tritylium salts at room temperature but the outcome is strongly impacted by the respective counter-ion. Using tritylium tetrakis(perfluoro-tert-butoxy)aluminate affords - depending on the solvent - either the bis(boronium) ion 4 or the hydride-bridged dication 5. In case of tritylium hexafluorophosphate, however, H/F exchange occurs between boron and phosphorus yielding the dinuclear BF3 adduct 3 along with phosphorus dihydride trifluoride. H/F exchange also takes place when using the mononuclear N-heterocyclic carbene BH3 adduct 6 and hence provides a facile route to PH2 F3 , which is usually synthesized in more complex reaction sequences regularly involving toxic hydrogen fluoride. DFT calculations shed light on the H/F exchange between the borenium ion and the [PF6 ]- counter-ion and the computed mechanism features only small barriers in line with the experimental observations.

Development of fluorescent peptide G protein-coupled receptor activation biosensors for NanoBRET characterization of intracellular allosteric modulators.

G protein-coupled receptors (GPCRs) are widely therapeutically targeted, and recent advances in allosteric modulator development at these receptors offer further potential for exploitation. Intracellular allosteric modulators (IAM) represent a class of ligands that bind to the receptor-effector interface (e.g., G protein) and inhibit agonist responses noncompetitively. This potentially offers greater selectivity between receptor subtypes compared to classical orthosteric ligands. However, while examples of IAM ligands are well described, a more general methodology for assessing compound interactions at the IAM site is lacking. Here, fluorescent labeled peptides based on the Gα peptide C terminus are developed as novel binding and activation biosensors for the GPCR-IAM site. In TR-FRET binding studies, unlabeled peptides derived from the Gαs subunit were first characterized for their ability to positively modulate agonist affinity at the ß2 -adrenoceptor. On this basis, a tetramethylrhodamine (TMR) labeled tracer was synthesized based on the 19 amino acid Gαs peptide (TMR-Gαs19cha18, where cha = cyclohexylalanine). Using NanoBRET technology to detect binding, TMR-Gαs19cha18 was recruited to Gs coupled ß2 -adrenoceptor and EP2 receptors in an agonist-dependent manner, but not the Gi-coupled CXCR2 receptor. Moreover, NanoBRET competition binding assays using TMR-Gαs19cha18 enabled direct assessment of the affinity of unlabeled ligands for ß2 -adrenoceptor IAM site. Thus, the NanoBRET platform using fluorescent-labeled G protein peptide mimetics offers novel potential for medium-throughput screens to identify IAMs, applicable across GPCRs coupled to a G protein class. Using the same platform, Gs peptide biosensors also represent useful tools to probe orthosteric agonist efficacy and the dynamics of receptor activation.

Eating sustainably: Conviction or convenience?

Environmentally sustainable food consumption is one component of addressing climate change. Previous research has largely approached sustainable food consumption by investigating individual behaviors, without a broader conceptualization of what motivates food consumers to act sustainably. Using a representative sample of Indiana consumers, we explore sustainability across a range of food behaviors through latent class analysis, controlling for environmental attitudes, spatial access to food, and consumer demographics. This approach allows us to go beyond consumer segmentation analysis to explore how consumers conceptualize sustainable food behavior. The largest class of consumers (44% of the sample) appear either unwilling or unable to pay more for sustainability but are more likely to engage in sustainable behaviors that intersect with self-oriented attributes such as health benefits and lower cost. A second class (34%) consists of consumers who seem to be primarily motivated by the single issue of buying organic, are on average higher income, more educated, have better access to food, and are not opposed to paying for sustainability. Consumers in the smallest and most highly motivated group (9%) in terms of sustainability attitudes and self-perceived sustainability focus on local food production and are generally rural dwelling with less income. Only 13% of consumers engage in few to no sustainable behaviors, and these people notably exhibit the least sustainable attitudes. These findings illustrate the ways in which food sustainability is more nuanced than often characterized-much of it is driven by convenience and self-interest rather than reputation with respect to sustainability or conviction about environmental outcomes. This work also highlights how a combination of social, psychological, and spatial barriers exists and shape how different consumer groups conceptualize sustainable food consumption.

Differences in imaging and clinical characteristics are associated with higher rates of decompression-fusion versus decompression-alone in women compared to men for lumbar degenerative spondylolisthesis.

PURPOSE: The goals were to ascertain if differences in imaging/clinical characteristics between women and men were associated with differences in fusion for lumbar degenerative spondylolisthesis. METHODS: Patients had preoperative standing radiographs, CT scans, and intraoperative fluoroscopic images. Symptoms and comorbidity were obtained from patients; procedure (fusion-surgery or decompression-alone) was obtained from intraoperative records. With fusion surgery as the dependent variable, men and women were compared in multivariable logistic regression models with clinical/imaging characteristics as independent variables. The sample was dichotomized, and analyses were repeated with separate models for men and women. RESULTS: For 380 patients (mean age 67, 61% women), women had greater translation, listhesis angle, lordosis, and pelvic incidence, and less diastasis and disc height (all p ≤ 0.03). The rate of fusion was higher for women (78% vs. 65%; OR 1.9, p = 0.008). Clinical/imaging variables were associated with fusion in separate models for men and women. Among women, in the final multivariable model, less comorbidity (OR 0.5, p = 0.05), greater diastasis (OR 1.6, p = 0.03), and less anterior disc height (OR 0.8, p = 0.0007) were associated with fusion. Among men, in the final multivariable model, opioid use (OR 4.1, p = 0.02), greater translation (OR 1.4, p = 0.0003), and greater diastasis (OR 2.4, p = 0.0002) were associated with fusion. CONCLUSIONS: There were differences in imaging characteristics between men and women, and women were more likely to undergo fusion. Differences in fusion within groups indicate that decisions for fusion were based on composite assessments of clinical and imaging characteristics that varied between men and women.

Oculopharyngeal Muscular Dystrophy Ptosis, Mueller's Muscle Involvement, and a Review of Management Over 34 Years.

PURPOSE: To review the management of the ptosis associated with oculopharyngeal muscular dystrophy (OPMD) from one author's experience over 34 years, demonstrate Mueller's muscle involvement in this disease, and how this impacts the preferred choice of surgery. METHODS: Retrospective, nonrandomized comparative case series. Forty patients with OPMD who underwent primary bilateral ptosis surgery through an anterior eyelid incision and had their Mueller's muscle biopsied (one side) and sent for histopathologic analysis were selected for chart review. The main outcome measure was the presence or absence of dystrophic changes in the biopsied Mueller's muscle. RESULTS: In 29/40 biopsies (72.5%), there were dystrophic changes and fatty infiltration of Mueller's muscle identified histopathologically. CONCLUSIONS: Mueller's muscle is involved in the dystrophic process more often than expected contributing to ptosis in the OPMD syndrome. A combined Mueller's-aponeurotic advancement is more effective at elevating the eyelid than simply advancing the aponeurosis when Mueller's is fatty infiltrated at the time of external levator advancement surgery in our experience. Management strategies for ptosis surgery in OPMD are reviewed. The age of onset, levator muscle function, previous ptosis repair, how debilitated the patient is with their disease process systemically, as well as the presence of other eye problems (e.g., dry eye, prior glaucoma filtering procedures, history of corneal surgery, laser refractive procedure) are important clinical considerations in patients with OPMD.

A rare case of intramuscular angioma involving the medial rectus muscle.

Benign benign vascular tumors (e.g., hemangiomas) and malformations are commonly encountered lesions in all ages of life, especially in infancy and childhood. Hemangiomas are considered to be proliferative vascular lesions while malformations are defects of embryonal vascular morphogenesis. Less than 1% of hemangiomas within the body occur in skeletal muscle and of these approximately 15% have been reported to occur in the head and neck musculature (e.g. masseter, trapezius, sternocleidomastoid, mylohyoid, temporalis muscles) Intramuscular angioma (the preferred term for lesions formerly known as intramuscular hemangiomas by WHO Tumors of Soft Tissue and Bone Classification, 5th edition 2020) (IA) occurring in the extraocular muscles or palpebral muscles (orbicularis oculi) are extremely rare with only a few case reports in the English literature. To date, all the extraocular muscles have reportedly been involved. With the case reported herein, the medial rectus muscle appears to be the most common extraocular muscle involved.

Impact of the Novel Z-Acceptor Ligand Bis{(ortho-diphenylphosphino)phenyl}zinc (ZnPhos) on the Formation and Reactivity of Low-Coordinate Ru(0) Centers.

The preparation and reactivity with H2 of two Ru complexes of the novel ZnPhos ligand (ZnPhos = Zn(o-C6H4PPh2)2) are described. Ru(ZnPhos)(CO)3 (2) and Ru(ZnPhos)(IMe4)2 (4; IMe4 = 1,3,4,5-tetramethylimidazol-2-ylidene) are formed directly from the reaction of Ru(PPh3)(C6H4PPh2)2(ZnMe)2 (1) or Ru(PPh3)3HCl/LiCH2TMS/ZnMe2 with CO and IMe4, respectively. Structural and electronic structure analyses characterize both 2 and 4 as Ru(0) species in which Ru donates to the Z-type Zn center of the ZnPhos ligand; in 2, Ru adopts an octahedral coordination, while 4 displays square-pyramidal coordination with Zn in the axial position. Under photolytic conditions, 2 loses CO to give Ru(ZnPhos)(CO)2 that then adds H2 over the Ru-Zn bond to form Ru(ZnPhos)(CO)2(µ-H)2 (3). In contrast, 4 reacts directly with H2 to set up an equilibrium with Ru(ZnPhos)(IMe4)2H2 (5), the product of oxidative addition at the Ru center. DFT calculations rationalize these different outcomes in terms of the energies of the square-pyramidal Ru(ZnPhos)L2 intermediates in which Zn sits in a basal site: for L = CO, this is readily accessed and allows H2 to add across the Ru-Zn bond, but for L = IMe4, this species is kinetically inaccessible and reaction can only occur at the Ru center. This difference is related to the strong π-acceptor ability of CO compared to IMe4. Steric effects associated with the larger IMe4 ligands are not significant. Species 4 can be considered as a Ru(0)L4 species that is stabilized by the Ru→Zn interaction. As such, it is a rare example of a stable Ru(0)L4 species devoid of strong π-acceptor ligands.

Histopathological Study on the Proposed Pathogenesis of Intratarsal Keratinous Cysts.

PURPOSE: Intratarsal keratinous cysts (IKCs) are a recently described entity that is frequently misdiagnosed clinically as chalazia and mislabeled in the literature as "intratarsal epidermal inclusion cysts" or "epidermoid cysts." It is important to accurately diagnose IKCs and distinguish them from chalazia because IKCs require a complete surgical excision and can exhibit multiple recurrences following curettage. The authors performed a retrospective case series to further elucidate the pathogenesis of IKCs and to determine the diagnostically optimal panel of stains for diagnosis. METHODS: A study group of 8 specimens of IKCs and control specimens of epidermal inclusion cysts were obtained from their pathology laboratories. The authors compared the histological and immunohistochemical profile of IKCs and epidermal inclusion cysts by staining sections from each specimen with hematoxylin and eosin, periodic acid-Schiff, Masson trichrome, cytokeratin 5, cytokeratin 17, carcinoembryonic antigen, and epithelial membrane antigen. The immunoreactivity data were then analyzed using a 2-tailed Mann-Whitney test, assuming a nonparametric population (p < 0.05 is significant). RESULTS: Histopathologically, IKCs are embedded in the tarsus lined by stratified squamous epithelium with an inner undulating cuticle filled with a compact keratinous-appearing material. The authors demonstrate that IKCs develop progressively from dilated meibomian ducts to the formation of complete cysts with their markers. The most valuable immunochemical stains to diagnose IKC were cytokeratin 17, carcinoembryonic antigen, and epithelial membrane antigen (p < 0.05 with each). CONCLUSIONS: These findings provide a better understanding of the pathogenesis and the immunohistochemical findings of this relatively new entity allowing for more appropriate diagnosis of IKCs aiming to reduce future complications from their management.

Systematic Review of the Yield of Temporal Artery Biopsy for Suspected Giant Cell Arteritis.

PURPOSE: To determine the positive yield (utility rate) of temporal artery biopsy (TAB) in patients with suspected giant cell arteritis (GCA). STUDY DESIGN: Systematic review (CRD42017078508) and meta-regression. MATERIALS AND METHODS: All articles concerning TAB for suspected GCA with English language abstracts from 1998 to 2017 were retrieved. Articles were excluded if they exclusively reported positive TAB, or only cases of known GCA. Where available, the pre-specified predictors of age, sex, vision symptoms, jaw claudication, duration of steroid treatment prior to TAB, specimen length, bilateral TAB, and use of ultrasound/MRI (imaging) were recorded for meta-regression. RESULTS: One hundred and thirteen articles met eligibility criteria. The I 2 was 92%, and with such high heterogeneity, meta-analysis is unsuitable. The median yield of TAB was 0.25 (95% confidence interval 0.21 to 0.27), with interquartile range 0.17 to 0.34. On univariate meta-regression age (coefficient 0.012, p = 0.025) was the only statistically significant patient factor associated with TAB yield. CONCLUSIONS: Systematic review revealed high heterogeneity in the yield of TAB. The median utility rate of 25% and its interquartile range provides a benchmark for decisions regarding the under/overutilization of TAB and aids in the evaluation of non-invasive alternatives for the investigation of GCA.

P63 Positive Mucoepidermoid Tumor of the Lacrimal Sac with Associated Papilloma.

We report a case of a 44-year-old man who presented with a left medial canthal mass and epiphora. Imaging was suggestive of a mass continuous with the nasolacrimal sac. Subsequent surgical exploration revealed a mass adherent to bone with invasion of the lacrimal system. Histological examination revealed a squamous/transitional cell papilloma overlying a low-grade mucoepidermoid carcinoma (MEC). Complete surgical resection was completed and pathology confirmed the diagnosis. This is the first case in which a MEC has been reported concurrently with an overlying papilloma, providing support for the hypothesis that MECs arise from papillomas in the lacrimal sac. Additionally, the tissue stained positive for p63, which is congruent with MEC immunoreactivity in the salivary gland. The description of these unique histopathological findings may assist in definitive diagnosis and improve our understanding of the pathophysiology underlying lacrimal sac MEC tumors.

Anti-inflammatory therapy after selective laser trabeculoplasty: a randomized, double-masked, placebo-controlled clinical trial.

PURPOSE: To investigate the effect of anti-inflammatory therapy on selective laser trabeculoplasty (SLT) outcomes. DESIGN: Randomized, double-masked, placebo-controlled trial. PARTICIPANTS: Patients with primary open-angle or pseudo-exfoliation glaucoma. METHODS: Patients undergoing SLT were randomized to receive placebo (artificial tears), prednisolone acetate 1%, or ketorolac tromethamine 0.5% eye drops 4 times per day for 5 days commencing immediately after SLT. MAIN OUTCOME MEASURES: Change in intraocular pressure (IOP) from baseline to the 1-month post-SLT visit. RESULTS: Mean change in IOP at the 1-month primary outcome time point, as well as all other time points, was not significantly different among groups (P = 0.99). Likewise, a repeated-measures, mixed-effects model did not find significant differences in IOP outcome at the 1-month time point (P = 0.95). The IOP was reduced in all groups at the 1-month post-SLT time point and all other time points, and no significant differences were found between groups using separate unadjusted cross-sectional analyses of variance (P > 0.15 for analyses at all time points). Treatment failure rates were not different among groups (P = 0.75), and at 1 year after SLT, the percentage of patients maintaining a 20% IOP reduction ranged from 18% to 22% in the 3 study groups. CONCLUSIONS: Anti-inflammatory therapy after SLT does not seem to substantially influence the IOP-lowering effect of SLT. In this study of patients with low baseline IOP, SLT showed limited efficacy in achieving a sustained reduction in IOP.

Think globally, research locally: paradigms and place in agroecological research.

Conducting science for practical ends implicates scientists, whether they wish it or not, as agents in social-ecological systems, raising ethical, economic, environmental, and political issues. Considering these issues helps scientists to increase the relevance and sustainability of research outcomes. As we rise to the worthy call to connect basic research with food production, scientists have the opportunity to evaluate alternative food production paradigms and consider how our research funds and efforts are best employed. In this contribution, we review some of the problems produced by science conducted in service of industrial agriculture and its associated economic growth paradigm. We discuss whether the new concept of "ecological intensification" can rescue the industrial agriculture/growth paradigm and present an emerging alternative paradigm of decentralized, localized, biodiversity-promoting agriculture for a steady-state economy. This "custom fit" agriculture engages constructively with complex and highly localized ecosystems, and we draw from examples of published work to demonstrate how ecologists can contribute by using approaches that acknowledge local agricultural practices and draw on community participation.

Intravenous Ketorolac Substantially Reduces Opioid Use and Length of Stay After Lumbar Fusion: A Randomized Controlled Trial.

STUDY DESIGN: A randomized, double-blinded, placebo-controlled trial. OBJECTIVE: To examine the effect of intravenous ketorolac (IV-K) on hospital opioid use compared with IV-placebo (IV-P) and IV acetaminophen (IV-A). SUMMARY OF BACKGROUND DATA: Controlling postoperative pain while minimizing opioid use after lumbar spinal fusion is an important area of study. PATIENTS AND METHODS: Patients aged 18 to 75 years undergoing 1 to 2 level lumbar fusions between April 2016 and December 2019 were included. Patients with chronic opioid use, smokers, and those on systemic glucocorticoids or contraindications to study medications were excluded. A block randomization scheme was used, and study personnel, hospital staff, and subjects were blinded to the assignment. Patients were randomized postoperatively. The IV-K group received 15 mg (age > 65) or 30 mg (age < 65) every six hours (q6h) for 48 hours, IV-A received 1000 mg q6h, and IV-P received normal saline q6h for 48 hours. Demographic and surgical details, opioid use in morphine milliequivalents, opioid-related adverse events, and length of stay (LOS) were recorded. The primary outcome was in-hospital opioid use up to 72 hours. RESULTS: A total of 171 patients were included (58 IV-K, 55 IV-A, and 58 IV-P) in the intent-to-treat (ITT) analysis, with a mean age of 57.1 years. The IV-K group had lower opioid use at 72 hours (173 ± 157 mg) versus IV-A (255 ± 179 mg) and IV-P (299 ± 179 mg; P = 0.000). In terms of opiate use, IV-K was superior to IV-A ( P = 0.025) and IV-P ( P = 0.000) on ITT analysis, although on per-protocol analysis, the difference with IV-A did not reach significance ( P = 0.063). When compared with IV-P, IV-K patients reported significantly lower worst ( P = 0.004), best ( P = 0.001), average ( P = 0.001), and current pain ( P = 0.002) on postoperative day 1, and significantly shorter LOS ( P = 0.009) on ITT analysis. There were no differences in opioid-related adverse events, drain output, clinical outcomes, transfusion rates, or fusion rates. CONCLUSIONS: By reducing opioid use, improving pain control on postoperative day 1, and decreasing LOS without increases in complications or pseudarthrosis, IV-K may be an important component of "enhanced recovery after surgery" protocols.

Complications and Revisions After Spine Surgery in Patients With Skeletal Dysplasia: Have We Improved?

STUDY DESIGN: Retrospective case series. OBJECTIVE: To report contemporary rates of complications and subsequent surgery after spinal surgery in patients with skeletal dysplasia. METHODS: A case series of 25 consecutive patients who underwent spinal surgery between 2007 and 2017 were identified from a single institution's skeletal dysplasia registry. Patient demographics, medical history, surgical indication, complications, and subsequent surgeries (revisions, extension to adjacent levels, or for pathology at a non-contiguous level) were collected. Charlson comorbidity indices were calculated as a composite measure of overall health. RESULTS: Achondroplasia was the most common skeletal dysplasia (76%) followed by spondyloepiphyseal dysplasia (20%); 1 patient had diastrophic dysplasia (4%). Average patient age was 53.2 ± 14.7 years and most patients were in excellent cardiovascular health (88% Charlson Comorbidity Index 0-4). Mean follow up after the index procedure was 57.4 ± 39.2 months (range). Indications for surgery were mostly for neurologic symptoms. The most commonly performed surgery was a multilevel thoracolumbar decompression without fusion (57%). Complications included durotomy (36%), neurologic complication (12%), and infection requiring irrigation and debridement (8%). Nine patients (36%) underwent a subsequent surgery. Three patients (12%) underwent a procedure at a non-contiguous anatomic zone, 3 (12%) underwent a revision of the previous surgery, and another 3 (12%) required extension of their previous decompression or fusion. CONCLUSIONS: Surgical complication rates remain high after spine surgery in patients with skeletal dysplasia, likely attributable to inherent characteristics of the disease. Patients should be counseled on their risk for complication and subsequent surgery.

Substrate-Selective Adhesion of Metal Nanoparticles to Graphene Devices.

Nanostructured electronic devices, such as those based on graphene, are typically grown on top of the insulator SiO2. Their exposure to a flux of small size-selected silver nanoparticles has revealed remarkably selective adhesion: the graphene channel can be made fully metallized, while the insulating substrate remains coverage-free. This conspicuous contrast derives from the low binding energy between the metal nanoparticles and a contaminant-free passivated silica surface. In addition to providing physical insight into nanoparticle adhesion, this effect may be of value in applications involving deposition of metallic layers on device working surfaces: it eliminates the need for masking the insulating region and the associated extensive and potentially deleterious pre- and postprocessing.

Design, Synthesis, and Application of Fluorescent Ligands Targeting the Intracellular Allosteric Binding Site of the CXC Chemokine Receptor 2.

The inhibition of CXC chemokine receptor 2 (CXCR2), a key inflammatory mediator, is a potential strategy in the treatment of several pulmonary diseases and cancers. The complexity of endogenous chemokine interaction with the orthosteric binding site has led to the development of CXCR2 negative allosteric modulators (NAMs) targeting an intracellular pocket near the G protein binding site. Our understanding of NAM binding and mode of action has been limited by the availability of suitable tracer ligands for competition studies, allowing direct ligand binding measurements. Here, we report the rational design, synthesis, and pharmacological evaluation of a series of fluorescent NAMs, based on navarixin (2), which display high affinity and preferential binding for CXCR2 over CXCR1. We demonstrate their application in fluorescence imaging and NanoBRET binding assays, in whole cells or membranes, capable of kinetic and equilibrium analysis of NAM binding, providing a platform to screen for alternative chemophores targeting these receptors.

Instability Missed by Flexion-Extension Radiographs Subsequently Identified by Alternate Imaging in L4-L5 Lumbar Degenerative Spondylolisthesis.

STUDY DESIGN: Cross-sectional preoperative and intraoperative imaging study of L4-L5 lumbar degenerative spondylolisthesis (LDS). OBJECTIVE: To determine if alternate imaging modalities would identify LDS instability that did not meet the criteria for instability based on comparison of flexion and extension radiographs. SUMMARY OF BACKGROUND DATA: Pain may limit full flexion and extension maneuvers and thereby lead to underreporting of true dynamic translation and angulation in LDS. Alternate imaging pairs may identify instability missed by flexion-extension. MATERIALS AND METHODS: Consecutive patients scheduled for surgery for single-level L4-L5 LDS had preoperative standing radiographs in the lateral, flexion, and extension positions, supine computed tomography (CT) scans, and intraoperative fluoroscopic images in the supine and prone positions after anesthesia but before incision. Instability was defined as translation ≥3.5 mm or angulation ≥11° between the following pairs of images: (1) flexion-extension; (2) CT-lateral; (3) lateral-intraoperative supine; (4) lateral-intraoperative prone; and (5) intraoperative supine-prone. RESULTS: Of 240 patients (mean age 68 y, 54% women) 15 (6%) met the criteria for instability by flexion-extension, and 225 were classified as stable. Of these 225, another 84 patients (35% of total enrollment) were reclassified as unstable by comparison of CT-lateral images (21 patients) and by lateral-intraoperative images (63 patients). Nine of the 15 patients diagnosed with instability by flexion-extension had fusion (60%), and 68 of the 84 patients reclassified as unstable by other imaging pairs had fusion (81%) ( P =0.07). The 84 reclassified patients were more likely to undergo fusion compared with the 141 patients who persistently remained classified as stable (odds ratio=2.6, 95% CI: 1.4-4.9, P =0.004). CONCLUSIONS: Our study provides evidence that flexion and extension radiographs underreport the dynamic extent of LDS and therefore should not be solely relied upon to ascertain instability. These findings have implications for how instability should be established and the extent of surgery that is indicated.