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Introduction: Guidelines for benign prostate hyperplasia (BPH) interventions are volume based. The degree to which different imaging modalities actually correlate to treated volume is not known for BPH. The present study compares the accuracy of preoperative ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), and MRI-transitional zone (TZ) to BPH enucleation weight. Methods: A retrospective review of patients who underwent enucleation for BPH and had preoperative transrectal ultrasound (TRUS), CT, and/or MRI was performed. Total prostate volumes were measured for CT, MRI, and TRUS; MRI-TZ volume was also measured. The primary outcome was difference between enucleated pathology weight in grams and preoperative imaging volume. Differences between enucleation and imaging volume for each modality were calculated with one-way analysis of variance, with Tukey's honest significance test to determine pairwise significance (RStudio V1.2). Results: From January to October 2020, there were 114 preoperative imaging studies available for 95 patients. Thirty-four (30%) of the studies were TRUS, 46 (40%) were CT, and 34 (30%) were MRI. MRI-TZ most accurately predicted enucleation volume on multivariate analysis (F-statistic p -value < 0.001). Preoperative imaging was greater than enucleation volume by a median of 46 cc for TRUS, 51 cc for CT, 53 cc for MRI, and 14 cc for MRI-TZ. Pairwise significance was reached for MRI-TZ over CT ( p -adj < 0.001), MRI-TZ over MRI ( p -adj < 0.001) and MRI-TZ over US ( p -adj = 0.03). Conclusions: Enucleation volume for BPH was most accurately predicted by TZ volume on MRI compared with total prostate volume on CT, TRUS, and MRI. MRI total volume was not superior to CT total volume. Focusing on MRI-TZ volume rather than total prostate volume may more accurately stratify patients for BPH treatment. In experienced hands, median enucleation volume is within 14 cc of MRI-TZ volume.

Background: The medical therapy of prostatic symptoms (MTOPS) trial randomized men with symptoms of benign prostatic hyperplasia (BPH) and followed response of treatment with a 5α-reductase inhibitor (5ARI), an alpha-adrenergic receptor antagonist (α-blocker), the combination of 5ARI and α-blocker or no medical therapy (none). Medical therapy reduced risk of clinical progression by 66% but the reasons for nonresponse or loss of therapeutic response in some patients remains unresolved. Our previous work showed that prostatic glucocorticoid levels are increased in 5ARI-treated patients and that glucocorticoids can increased branching of prostate epithelia in vitro. To understand the transcriptomic changes associated with 5ARI treatment, we performed bulk RNA sequencing of BPH and control samples from patients who received 5ARI versus those that did not. Deconvolution analysis was performed to estimate cellular composition. Bulk RNA sequencing was also performed on control versus glucocorticoid-treated prostate epithelia in 3D culture to determine underlying transcriptomic changes associated with branching morphogenesis., Method: Surgical BPH (S-BPH) tissue was defined as benign prostatic tissue collected from the transition zone (TZ) of patients who failed medical therapy while control tissue termed Incidental BPH (I-BPH) was obtained from the TZ of men undergoing radical prostatectomy for low-volume/grade prostatic adenocarcinoma confined to the peripheral zone. S-BPH patients were divided into four subgroups: men on no medical therapy (none: n = 7), α-blocker alone (n = 10), 5ARI alone (n = 6) or combination therapy (α-blocker and 5ARI: n = 7). Control I-BPH tissue was from men on no medical therapy (none: n = 8) or on α-blocker (n = 6). A human prostatic cell line in 3D culture that buds and branches was used to identify genes involved in early prostatic growth. Snap-frozen prostatic tissue taken at the time of surgery and 3D organoids were used for RNA-seq analysis. Bulk RNAseq data were deconvoluted using CIBERSORTx. Differentially expressed genes (DEG) that were statistically significant among S-BPH, I-BPH, and during budding and branching of organoids were used for pathway analysis., Results: Transcriptomic analysis between S-BPH (n = 30) and I-BPH (n = 14) using a twofold cutoff (p < 0.05) identified 377 DEG (termed BPH377) and a cutoff < 0.05 identified 3377 DEG (termed BPH3377). Within the S-BPH, the subgroups none and α-blocker were compared to patients on 5ARI to reveal 361 DEG (termed 5ARI361) that were significantly changed. Deconvolution analysis of bulk RNA seq data with a human prostate single cell data set demonstrated increased levels of mast cells, NK cells, interstitial fibroblasts, and prostate luminal cells in S-BPH versus I-BPH. Glucocorticoid (GC)-induced budding and branching of benign prostatic cells in 3D culture was compared to control organoids to identify early events in prostatic morphogenesis. GC induced 369 DEG (termed GC359) in 3D culture. STRING analysis divided the large datasets into 20-80 genes centered around a hub. In general, biological processes induced in BPH supported growth and differentiation such as chromatin modification and DNA repair, transcription, cytoskeleton, mitochondrial electron transport, ubiquitination, protein folding, and cholesterol synthesis. Identified signaling pathways were pooled to create a list of DEG that fell into seven hubs/clusters. The hub gene centrality was used to name the network including AP-1, interleukin (IL)-6, NOTCH1 and NOTCH3, NEO1, IL-13, and HDAC/KDM. All hubs showed connections to inflammation, chromatin structure, and development. The same approach was applied to 5ARI361 giving multiple networks, but the EGF and sonic hedgehog (SHH) hub was of particular interest as a developmental pathway. The BPH3377, 5ARI363, and GC359 lists were compared and 67 significantly changed DEG were identified. Common genes to the 3D culture included an IL-6 hub that connected to genes identified in BPH hubs that defined AP1, IL-6, NOTCH, NEO1, IL-13, and HDAC/KDM., Conclusions: Reduction analysis of BPH and 3D organoid culture uncovered networks previously identified in prostatic development as being reinitiated in BPH. Identification of these pathways provides insight into the failure of medical therapy for BPH and new therapeutic targets for BPH/LUTS., (© 2024 Wiley Periodicals LLC.)

Introduction: New opioid dependency after urologic surgery is a serious adverse outcome that is well-described in the literature. Patients with stone disease often require multiple procedures because of recurrence of disease and hence are at greater risk for repeat opioid exposures. Despite this, opioid prescribing after urologic surgery remains highly variable and in an emergency setting, opioids are still used commonly in management of acute renal colic. Methods: Two literature searches were performed using PubMed. First, we searched available literature concerning opioid-sparing pathways in acute renal colic. Second, we searched available literature for opioid-sparing pathways in ureteroscopy and percutaneous nephrolithotomy (PCNL). Abstracts were reviewed for inclusion in our narrative review. Results: In the setting of acute renal colic, multiple randomized control trials have shown that nonsteroidal anti-inflammatory drugs (NSAIDs) attain greater reduction in pain scores, decreased need for rescue medications, and decreased vomiting events in comparison with opioids. NSAIDs also form a core component in management of postureteroscopy pain and have been demonstrated in randomized trials to have equivalent to improved pain control outcomes compared with opioids. Multiple opioid-free pathways have been described for postureteroscopy analgesia with need for rescue narcotics falling under 20% in most studies, including in patients with ureteral stents. Enhanced Recovery After Surgery protocols after percutaneous nephrolithotomy are less well described but have yielded a reduction in postoperative opioid requirements. Conclusions: In select patients, both acute renal colic and after kidney stone surgery, adequate pain management can usually be obtained with minimal or no opioid medication. NSAIDs form the core of most described opioid-sparing pathways for both ureteroscopy and PCNL, with the contribution of other components to postoperative pain outcomes limited because of lack of head-to-head comparisons. However, medications aimed specifically at targeting stent-related discomfort form a key component of most multimodal postsurgical pain management pathways. Further investigation is needed to develop pathways in patients unable to tolerate NSAIDs.

Acute renal failure with severe loin pain and patchy renal ischemia after anaerobic exercise (ALPE) is a rare cause of exertional acute kidney injury. The proposed mechanism of injury in ALPE is renovascular spasm, in the setting of oxidative stress and muscular damage, which creates a characteristic wedge-shaped infarction pattern on delayed imaging. Patients present with nausea, vomiting, loin or abdominal pain, and fatigue within 1-2 days of anaerobic exercise, associated with an acute rise in serum creatinine, which generally plateaus within 3 days. This process is likely exacerbated by dehydration, analgesic usage, and lower baseline fitness levels. This disease process is distinct from rhabdomyolysis, in that creatine kinase levels are not significantly elevated, myoglobinuria is not seen, and aggressive fluid resuscitation is not beneficial. We present three cases of ALPE following participation in the Marine Combat Fitness Test (CFT), an anaerobic evolution. Medical workup demonstrated no additional etiology for acute renal failure. The average peak creatinine in these patients was 2.9 mg/dL, and all demonstrated return to normal renal function, without hemodialysis. One patient experienced recurrent ALPE, after short-interval CFT participation. Military medical providers should be aware of this diagnosis when evaluating service members with acute renal injury after exercise. The clinical course is benign, and affected service members are at increased risk of recurrence, with subsequent intense exercise. Service members should engage in a graduated exercise program, before intense exercise activities, and should be monitored closely for recurrent renal injury., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2023. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Introduction: Holmium laser lithotripsy is a standard energy source used for treatment of kidney stones during flexible ureteroscopy. Efficiency of laser surgery may be affected by patient and operator characteristics or perioperative management. Here, we sought to examine intraoperative data from patients undergoing high frequency dusting with high-powered holmium laser lithotripsy to evaluate surgical and demographic factors associated with lasing efficiency (LE). Methods: A total of 82 intraoperative reports were analyzed from an ongoing laser lithotripsy clinical trial evaluating the Lumenis Pulse™ 120H holmium laser with renal stones up to 20 mm in diameter with and without Moses 2.0 technology. For each case, the total pause time between lasing activations was corrected to remove lengthy pauses and divided by the total lasing time to calculate an efficiency percentage. This was then compared with patient demographics, anesthesia administration, stone burden, postoperative complications, and stone-free rates using both univariate and multivariate analyses. Results: Of the 82 included patients, 36 received endotracheal tube (ETT) intubation and 46 had a laryngeal mask airway (LMA). Patients with ETT had significantly higher LE (78.7%) compared to those with an LMA (73.3%) in our univariate analysis ( p  < 0.01) as well as in the multivariate model that adjusted for maximum stone size, number of stones, stone density, and patient body mass index ( p  < 0.05). There was also significantly higher mean LE in patients with no postoperative complications (76.3%) compared to those with any grade (I-V) Clavien-Dindo complication within 30 days after surgery (70.0%) ( p  < 0.05). Conclusions: Flexible ureteroscopy and laser lithotripsy cases with higher LE are associated with lower rates of postoperative complications. The data also support the use of ETT over LMA to improve overall LE; however, this remains one consideration among many for choosing anesthesia administration. Clinical Trial Registration number: NCT04505956.

Introduction: Recent retrospective literature suggests that the quick sequential organ failure assessment (qSOFA) scoring tool is a potentially superior tool over use of the systemic inflammatory response syndrome (SIRS) criteria to predict septic shock after percutaneous nephrolithotomy (PCNL) surgery. Here we examine use of qSOFA and SIRS to predict septic shock within data series collected prospectively on PCNL patients as part of a greater study of infectious complications. Materials and Methods: We performed a secondary analysis of two prospective multicenter studies including PCNL patients across nine institutions. Clinical signs informing SIRS and qSOFA scores were collected no later than postoperative day 1. The primary outcome was sensitivity and specificity of SIRS and qSOFA (high-risk score of greater-or-equal to two points) in predicting admission to the intensive care unit (ICU) for vasopressor support. Results: A total of 218 cases at 9 institutions were analyzed. One patient required vasopressor support in the ICU. The sensitivity/specificity was 100%/72.4% (McNemar's test p  < 0.001) for SIRS and was 100%/90.8% (McNemar's test p  < 0.001) for qSOFA. Conclusion: Although positive predictive value for both qSOFA and SIRS in prediction of post-PCNL septic shock is low, prospectively collected data demonstrate use of qSOFA may offer greater specificity than SIRS criteria when predicting post-PCNL septic shock.

Background: Residual fragments (RFs) after percutaneous nephrolithotomy (PCNL) have a significant impact on patients' quality of life and clinical course. There is a paucity of studies that evaluate the natural history of RFs after PCNL. The objective of this study is to compare rates of reintervention, complications, stone growth, and passage in patients with RFs >4, ≤4, and ≤2 mm after PCNL. Methods: Sites from the Endourologic Disease Group for Excellence (EDGE) research consortium examined data of PCNL patients from 2015 to 2019 with at least 1-year follow-up. RF passage, regrowth, reintervention, and complications were recorded and RFs were stratified into >4 and ≤4 mm groups, as well as >2 and ≤2 mm groups. Potential predictors for stone-related events after PCNL were determined using multivariable logistic regression analysis. It was hypothesized that larger RF thresholds would result in lower passage rates, faster regrowth, and greater clinically significant events (complications and reinterventions) than smaller RF thresholds. Results: A total of 439 patients with RFs >1 mm on CT postoperative day 1 were included in this study. For RFs >4 mm, rates of reintervention were found to be significantly higher and Kaplan-Meier curve analysis showed significantly higher rates of stone-related events. Passage and RF regrowth were not found to be significantly different compared with RFs ≤4 mm. However, RFs ≤2 mm had significantly higher rates of passage, and significantly lower rates of fragment regrowth (>1 mm), complications, and reintervention compared with RFs >2 mm. On multivariable analysis, older age, body mass index, and RF size were found to be predictive of stone-related events. Conclusions: With the largest cohort to date, this study by the EDGE research consortium further confirms that clinically insignificant residual fragment is problematic for patients after PCNL, particularly in older more obese patients with larger RFs. Our study underscores the importance of complete stone clearance post-PCNL and challenges the use of Clinically insignificant residual fragment (CIFR).

The effect of obstructive sleep apnea (OSA) on 24-h urine parameters and resultant kidney stone risk is unknown. We sought to compare urinary lithogenic risk factors among patients with kidney stone disease with and without OSA. We performed a retrospective cohort study of adult patients with nephrolithiasis undergoing both polysomnography and 24-h urine analysis. Measures of acid load including gastrointestinal alkali absorption, urinary titratable acid, and net acid excretion were calculated from 24-h urine. We performed univariable comparisons of 24-h urine parameters between those with and without OSA and fit a multivariable linear regression model adjusting for age, sex, and BMI. Overall, there were 127 patients who underwent both polysomnography and a 24-h urine analysis from 2006 to 2018. There were 109 (86%) patients with OSA and 18 (14%) without. Patients with OSA were more commonly male, had greater BMI and had higher rates of hypertension. Patients with OSA had significantly higher levels of 24-h urinary oxalate, uric acid, sodium, potassium, phosphorous, chloride, and sulfate; higher supersaturation of uric acid; higher titratable acid, and net acid excretion; and lower urinary pH and supersaturation of calcium phosphate (p < 0.05). The difference in urinary pH and titratable acid, but not net acid excretion, remained significant when adjusting for BMI, age, and gender (both p = 0.02). OSA is associated with changes in urinary analytes that promote kidney stone formation, similar to those observed with obesity. After accounting for BMI, OSA is independently associated with lower urine pH and increased urinary titratable acid., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To compare rates of patient-reported kidney stone disease to Electronic Health Records (EHR) kidney stone diagnosis using a common dataset to evaluate for socio-demographic differences, including between those with and without active care., Methods: From the All of Us research database, we identified 21,687 adult participants with both patient-reported and EHR data. We compared differences in age, sex, race, education, employment status and healthcare access between patients with self-reported kidney stone history without EHR data to those with EHR-based diagnoses., Results: In this population, the self-reported prevalence of kidney stones was 8.6% overall (n = 1877), including 4.6% (n = 1004) who had self-reported diagnoses but no EHR data. Among those with self-reported kidney stone diagnoses only, the median age was 66. The EHR-based prevalence of kidney stones was 5.7% (n = 1231), median age 67. No differences were observed in age, sex, education, employment status, rural/urban status, or ability to afford healthcare between groups with EHR diagnosis or self-reported diagnosis only. Of patients who had a self-reported history of kidney stones, 24% reported actively seeing a provider for kidney stones., Conclusion: Kidney stone prevalence by self-report is higher than EHR-based prevalence in this national dataset. Using either method alone to estimate kidney stone prevalence may exclude some patients with the condition, although the demographic profile of both groups is similar. Approximately 1 in 4 patients report actively seeing a provider for stone disease., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Defining predictors of antigen-binding affinity of antibodies is valuable for engineering therapeutic antibodies with high binding affinity to their targets. However, this task is challenging owing to the huge diversity in the conformations of the complementarity determining regions of antibodies and the mode of engagement between antibody and antigen. In this study, we used the structural antibody database (SAbDab) to identify features that can discriminate high- and low-binding affinity across a 5-log scale. First, we abstracted features based on previously learned representations of protein-protein interactions to derive 'complex' feature sets, which include energetic, statistical, network-based, and machine-learned features. Second, we contrasted these complex feature sets with additional 'simple' feature sets based on counts of contacts between antibody and antigen. By investigating the predictive potential of 700 features contained in the eight complex and simple feature sets, we observed that simple feature sets perform comparably to complex feature sets in classification of binding affinity. Moreover, combining features from all eight feature-sets provided the best classification performance (median cross-validation AUROC and F1-score of 0.72). Of note, classification performance is substantially improved when several sources of data leakage (e.g., homologous antibodies) are not removed from the dataset, emphasizing a potential pitfall in this task. We additionally observe a classification performance plateau across diverse featurization approaches, highlighting the need for additional affinity-labeled antibody-antigen structural data. The findings from our present study set the stage for future studies aimed at multiple-log enhancement of antibody affinity through feature-guided engineering., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Miller, Clark, Raman and Sasisekharan.)

Purpose: Treatment of struvite kidney stones requires complete surgical stone removal combined with antibiotic therapy to eliminate urinary tract infections and preventive measures to reduce stone recurrence. The optimal duration of antibiotic therapy is unknown. We sought to determine if 2- or 12-weeks of antibiotics post percutaneous nephrolithotomy (PNL) for infection stones resulted in better outcomes for stone recurrence and positive urine cultures., Material and Methods: This multi-center, prospective randomized trial evaluated patients with the clinical diagnosis of infection stones. Patients were randomized to 2- or 12-weeks of postoperative oral antibiotics (nitrofurantoin or culture-specific antibiotic) and included if residual fragments were ≤4 mm on computed tomography imaging after PNL. Imaging and urine analyses were performed at 3-, 6-, and 12-months post-procedure., Results: Thirty-eight patients were enrolled and randomized to either 2-weeks (n = 20) or 12-weeks (n = 18) of antibiotic therapy post-PNL. Eleven patients were excluded due to residual fragments >4 mm, and 3 patients were lost to follow-up. The primary outcome was the stone-free rate (SFR) at 6 months post-PNL. At 3-, 6-, and 12-months follow-up, SFRs were 72.7% versus 80.0%, 70.0% versus 57.1%, 80.0% versus 57.1% (p = ns), between 2- and 12-week-groups, respectively. At 3-, 6-, and 12-months follow-up, positive urine cultures were 50.0% versus 37.5%, 50.0% versus 83.3%, and 37.5% versus 100% between 2- and 12-week groups, respectively (p = ns)., Conclusions: For patients with stone removal following PNL, neither 2-weeks nor 12-weeks of postoperative oral antibiotics is superior to prevent stones and recurrent positive urine cultures., (© 2022 The Japanese Urological Association.)

Background: The development of benign prostatic hyperplasia (BPH) and medication-refractory lower urinary tract symptoms (LUTS) remain poorly understood. This study attempted to characterize the pathways associated with failure of medical therapy for BPH/LUTS., Methods: Transitional zone tissue levels of cholesterol and steroids were measured in patients who failed medical therapy for BPH/LUTS and controls. Prostatic gene expression was measured using qPCR and BPH cells were used in organoid culture to study prostatic branching., Results: BPH patients on 5-α-reductase inhibitor (5ARI) showed low levels of tissue dihydrotestosterone (DHT), increased levels of steroid 5-α-reductase type II (SRD5A2), and diminished levels of androgen receptor (AR) target genes, prostate-specific antigen (PSA), and transmembrane serine protease 2 (TMPRSS2). 5ARI raised prostatic tissue levels of glucocorticoids (GC), whereas alpha-adrenergic receptor antagonists (α-blockers) did not. Nuclear localization of GR in prostatic epithelium and stroma appeared in all patient samples. Treatment of four BPH organoid cell lines with dexamethasone, a synthetic GC, resulted in budding and branching., Conclusions: After failure of medical therapy for BPH/LUTS, 5ARI therapy continued to inhibit androgenesis but a 5ARI-induced pathway increased tissue levels of GC not seen in patients on α-blockers. GC stimulation of organoids indicated that the GC receptors are a trigger for controlling growth of prostate glands. A 5ARI-induced pathway revealed GC activation can serve as a master regulator of prostatic branching and growth., (© 2022 Wiley Periodicals LLC.)

Proton pump inhibitors (PPIs) are widely prescribed medications that have effects on both enteric and urinary solute handling with an unknown effect on risk of nephrolithiasis. Our objectives were to examine the association between PPI exposure and incident nephrolithiasis and to determine its effect on 24H urine chemistry. We performed a single-center retrospective study on patients diagnosed with gastroesophageal reflux disease (GERD) without a history of kidney stones. Exposure to PPIs was abstracted, and then subsequent kidney stone diagnoses were identified. Multivariable Cox models with time-varying covariates were used to estimate the hazard of PPI use on incident nephrolithiasis. We used multivariable linear regression to analyze a subset of patients who went through 24-h urine analysis. We identified n = 55,765 PPI-naïve GERD patients without prior kidney stone diagnoses of whom 40,866 (73.2%) were exposed to PPI over a median of 3 year follow up. On multivariable analysis, PPI use was associated with higher risk of incident kidney stone diagnoses (HR 1.19, 95% CI 1.06-1.34). Among 593 patients with GERD with 24-H urine data, the PPI-exposed group (n = 307) had significantly lower mean urinary citrate (mean 3.0 vs 3.4 mmol, p = 0.029) and urinary magnesium (mean 3.6 vs 4.3 mmol, p < 0.001) on multivariable analyses. Exposure to PPIs is associated with an increased risk of kidney stones among patients with GERD. Hypomagnesemia and hypocitraturia associated with PPI exposure may contribute to kidney stone risk., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The dynamic interplay between virus and host plays out across many interacting surfaces as virus and host evolve continually in response to one another. In particular, epitope-paratope interactions (EPIs) between viral antigen and host antibodies drive much of this evolutionary race. In this review, we describe a series of recent studies examining aspects of epitope complexity that go beyond two interacting protein surfaces as EPIs are typically understood. To structure our discussion, we present a framework for understanding epitope complexity as a spectrum along a series of axes, focusing primarily on 1) epitope biochemical complexity (e.g., epitopes involving N-glycans) and 2) antigen conformational/dynamic complexity (e.g., epitopes with differential properties depending on antigen state or fold-axis). We highlight additional epitope complexity factors including epitope tertiary/quaternary structure, which contribute to epistatic relationships between epitope residues within- or adjacent-to a given epitope, as well as epitope overlap resulting from polyclonal antibody responses, which is relevant when assessing antigenic pressure against a given epitope. Finally, we discuss how these different forms of epitope complexity can limit EPI analyses and therapeutic antibody development, as well as recent efforts to overcome these limitations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Miller, Raman, Clark and Sasisekharan.)

Complex glycans decorate viral surface proteins and play a critical role in virus-host interactions. Viral surface glycans shield vulnerable protein epitopes from host immunity yet can also present distinct "glycoepitopes" that can be targeted by host antibodies such as the potent anti-HIV antibody 2G12 that binds high-mannose glycans on gp120. Two recent publications demonstrate 2G12 binding to high mannose glycans on SARS-CoV-2 and select Influenza A (Flu) H3N2 viruses. Previously, our lab observed 2G12 binding and functional inhibition of a range of Flu viruses that include H3N2 and H1N1 lineages. In this manuscript, we present these data alongside structural analyses to offer an expanded picture of 2G12-Flu interactions. Further, based on the remarkable breadth of 2G12 N-glycan recognition and the structural factors promoting glycoprotein oligomannosylation, we hypothesize that 2G12 glycoepitopes can be defined from protein structure alone according to N-glycan site topology. We develop a model describing 2G12 glycoepitopes based on N-glycan site topology, and apply the model to identify viruses within the Protein Data Bank presenting putative 2G12 glycoepitopes for 2G12 repurposing toward analytical, diagnostic, and therapeutic applications., (© 2022. The Author(s).)

The Omicron variant features enhanced transmissibility and antibody escape. Here, we describe the Omicron receptor-binding domain (RBD) mutational landscape using amino acid interaction (AAI) networks, which are well suited for interrogating constellations of mutations that function in an epistatic manner. Using AAI, we map Omicron mutations directly and indirectly driving increased escape breadth and depth in class 1-4 antibody epitopes. Further, we present epitope networks for authorized therapeutic antibodies and assess perturbations to each antibody's epitope. Since our initial modeling following the identification of Omicron, these predictions have been realized by experimental findings of Omicron neutralization escape from therapeutic antibodies ADG20, AZD8895, and AZD1061. Importantly, the AAI predicted escape resulting from indirect epitope perturbations was not captured by previous sequence or point mutation analyses. Finally, for several Omicron RBD mutations, we find evidence for a plausible role in enhanced transmissibility via disruption of RBD-down conformational stability at the RBD down -RBD down interface., Competing Interests: R.S. is a board member of Tychan, Singapore, which focuses on infectious diseases., (© 2022 The Author(s).)