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The United States Veterans Affairs (VA) Health Care System has a strong history of conducting impactful oncology randomized clinical trials (RCTs). We developed a phase II/III RCT to test the use of metastasis-directed therapy in Veterans with oligometastatic prostate cancer (OMPC)—the first VA RCT in OMPC that leverages novel imaging and advanced radiotherapy techniques. To accomplish this, we developed a clinical trial network to conduct the study. In this manuscript, we describe several challenges we encountered in study development/conduct and our strategies to address them, with the goal of helping investigators establish robust study networks to conduct clinical trials. In the study start-up, we encountered challenges in timely site activation, and leveraged project management to maximize efficiency. Additionally, there were several changes in the clinical paradigms in imaging and treatment that led to protocol amendments to ensure maximum equipoise, recruitment, and impact of the study. Specifically, we amended the trial to add de novo OMPC patients (from initially only recurrent OMPC) and expanded the study to allow up to 10 metastases (from initially five). Finally, in order to maintain local study team engagement, we developed initiatives to maximize collaboration and add value to the overall clinical program through study participation. [ABSTRACT FROM AUTHOR]

Simple Summary: Given the prevalence of COVID-19 infection, assessment of sequelae is critical to public health. Recent studies revealed a higher incidence of resistant hypertension after COVID-19 recovery. Presently, there is limited data and ability to clinically ascribe mechanisms using traditional techniques. Literature-based discovery (LBD) leverages artificial intelligence to stitch together multi-scalar relationships from millions of journal articles. Identified related concepts are ranked according to their predicted relevance in ascribing the shared etiology of hypertension and COVID-19. The dominant LBD-identified ascribed physiology included: altered endocrine function, inflammation, lipid dysfunction, altered nerve input for blood pressure, and altered COVID-19 viral entry. Multiple studies have reported new or exacerbated persistent or resistant hypertension in patients previously infected with COVID-19. We used literature-based discovery to identify and prioritize multi-scalar explanatory biology that relates resistant hypertension to COVID-19. Cross-domain text mining of 33+ million PubMed articles within a comprehensive knowledge graph was performed using SemNet 2.0. Unsupervised rank aggregation determined which concepts were most relevant utilizing the normalized HeteSim score. A series of simulations identified concepts directly related to COVID-19 and resistant hypertension or connected via one of three renin–angiotensin–aldosterone system hub nodes (mineralocorticoid receptor, epithelial sodium channel, angiotensin I receptor). The top-ranking concepts relating COVID-19 to resistant hypertension included: cGMP-dependent protein kinase II, MAP3K1, haspin, ral guanine nucleotide exchange factor, N-(3-Oxododecanoyl)-L-homoserine lactone, aspartic endopeptidases, metabotropic glutamate receptors, choline-phosphate cytidylyltransferase, protein tyrosine phosphatase, tat genes, MAP3K10, uridine kinase, dicer enzyme, CMD1B, USP17L2, FLNA, exportin 5, somatotropin releasing hormone, beta-melanocyte stimulating hormone, pegylated leptin, beta-lipoprotein, corticotropin, growth hormone-releasing peptide 2, pro-opiomelanocortin, alpha-melanocyte stimulating hormone, prolactin, thyroid hormone, poly-beta-hydroxybutyrate depolymerase, CR 1392, BCR-ABL fusion gene, high density lipoprotein sphingomyelin, pregnancy-associated murine protein 1, recQ4 helicase, immunoglobulin heavy chain variable domain, aglycotransferrin, host cell factor C1, ATP6V0D1, imipramine demethylase, TRIM40, H3C2 gene, COL1A1+COL1A2 gene, QARS gene, VPS54, TPM2, MPST, EXOSC2, ribosomal protein S10, TAP-144, gonadotropins, human gonadotropin releasing hormone 1, beta-lipotropin, octreotide, salmon calcitonin, des-n-octanoyl ghrelin, liraglutide, gastrins. Concepts were mapped to six physiological themes: altered endocrine function, 23.1%; inflammation or cytokine storm, 21.3%; lipid metabolism and atherosclerosis, 17.6%; sympathetic input to blood pressure regulation, 16.7%; altered entry of COVID-19 virus, 14.8%; and unknown, 6.5%. [ABSTRACT FROM AUTHOR]

Background: Recent work has characterized polysomnographic changes in Alzheimer's Dementia (AD) that correlate with disease severity and precede clinical diagnosis. However, relatively small sample sizes and a paucity of studies examining sleep microarchitecture have been limitations. In this study we examined sleep micro‐ and microarchitectural features in large cohorts of patients with AD and mild cognitive impairment (MCI). Method: Using a database of over 15,000 clinical PSGs with associated clinical metadata, 125 and 173 subjects were identified with mild AD and MCI, respectively. 260 age and sex matched subjects without neurological disease were identified as healthy controls (HC). Sleep staging results were based on AASM criteria, and micro‐architectural features were assessed using an algorithm trained to predict wake (1) or sleep (0) using spectral data from 3 seconds of EEG from a unique healthy adult cohort (Wake EEG Similarity Index, WESI). Result: Sleep fragmentation was apparent in both the MCI and AD cohorts (relative to healthy controls), with AD subjects demonstrating significantly more severe PSG disturbances. Healthy controls demonstrated 400 minutes of total sleep time, in contrast to 374 minutes for MCI subjects and 362 minutes for healthy controls. Healthy subjects demonstrated 33 minutes of wake after sleep onset (WASO), compared to 60 and 67 minutes for MCI and AD subjects, respectively. As has been previously reported in smaller cohorts, wakeful bouts and N1 durations were significantly prolonged for AD and (to a lesser extent) MCI subjects, while N2, N3, and REM durations were reduced (with a pronounced reduction in AD N3 percentage). Sleep microarchitectural features assessed using WESI demonstrated that AD and MCI subjects had markedly higher relative wakefulness in all sleep stages except for N3, which showed the same sleep depth as HC. Conclusion: We confirm increased sleep fragmentation and loss of deeper sleep stages, correlating to disease severity. Spectral features of all sleep stages EXCEPT N3 appear more wakeful in AD and MCI subjects ‐ suggesting microarousals or impaired sleep maintenance contribute to sleep pathology. While N3 duration was markedly reduced, depth of sleep was comparable between populations. PSG findings offer promise as early diagnostic and therapeutic targets. [ABSTRACT FROM AUTHOR]

A variety of intra-articular injections are used for the management of osteoarthritis. A rare complication of intra-articular injections is acute pseudoseptic arthritis, which mimics true septic arthritis. To the authors knowledge, pseudosepsis has not been reported as a complication after platelet-rich plasma (PRP) injections. We present a case report of pseudoseptic arthritis resulting in acute postinjection pain and a joint effusion after an intra-articular PRP injection into the knee. Clinically, pseudosepsis can occur after PRP treatment with significantly elevated white blood cell counts in the synovial fluid, and should be a consideration in cases of post-PRP injection flares. A case report of pseudoseptic arthritis after platelet-rich plasma injections for knee osteoarthritis, a rare complication. [ABSTRACT FROM AUTHOR]

Objective/Hypothesis: To evaluate clinical outcomes following failed endoscopic extraction of salivary calculi and to assess any relation between clinical outcome and calculi location, number, size, and mobility. If sialendoscopy fails to extract the calculus, subsequent spontaneous passage of the calculus out of the ductoglandular system or secondary effects of sialendoscopy could mitigate the clinical impact of a residual sialolithiasis. Study Design: Prospective observational study. Methods: Prospective comparative study of endoscopic procedures for sialolithiasis performed in the Manukau Surgery Center, in Auckland, New Zealand, from 2010 to 2020. The recurrent symptoms and the variables related to the need for additional surgical intervention for salivary calculi were analyzed. Results: Among the 465 sialendoscopy procedures, 154 (33.1%) were for obstructive sialolithiasis. Among these, there were 30 (19.4%) with unsuccessful stone extraction with re‐operation for these failures performed in 14 of the 27 failed submandibular cases (52%) and 2 of the 3 parotids (66.7%). Location of calculi was a significant factor in predicting the need of further surgery. Patients with perihilar stones were 5 times more likely to have a failed procedure (P =.001). If the stone was intraglandular, the likelihood increased to 8.5 times (P =.005). The likelihood for a revision procedure increased almost 11 times if the stone was intraglandular (P =.004). Calculi size, mobility, multiple calculi, and presence of concurrent stenosis did not correlate with need for further surgery. Conclusions: A significant proportion of "failed" sialendoscopy did not require further intervention. Stone location was a significant factor in predicting a failed procedure and the need for re‐intervention. Laryngoscope, 132:1029–1033, 2022 [ABSTRACT FROM AUTHOR]

G protein–coupled receptors (GPCRs) are the largest family of cell surface receptors and signal through the proximal effectors, G proteins and β-arrestins, to influence nearly every biological process. The G protein and β-arrestin signaling pathways have largely been considered separable; however, direct interactions between Gα proteins and β-arrestins have been described that appear to be part of a distinct GPCR signaling pathway. Within these complexes, Gαi/o, but not other Gα protein subtypes, directly interacts with β-arrestin, regardless of the canonical Gα protein that is coupled to the GPCR. Here, we report that the endogenous biased chemokine agonists of CXCR3 (CXCL9, CXCL10, and CXCL11), together with two small-molecule biased agonists, differentially formed Gαi:β-arrestin complexes. Formation of the Gαi:β-arrestin complexes did not correlate well with either G protein activation or β-arrestin recruitment. β-arrestin biosensors demonstrated that ligands that promoted Gαi:β-arrestin complex formation generated similar β-arrestin conformations. We also found that Gαi:β-arrestin complexes did not couple to the mitogen-activated protein kinase ERK, as is observed with other receptors such as the V2 vasopressin receptor, but did couple with the clathrin adaptor protein AP-2, which suggests context-dependent signaling by these complexes. These findings reinforce the notion that Gαi:β-arrestin complex formation is a distinct GPCR signaling pathway and enhance our understanding of the spectrum of biased agonism. A complex to complicate chemokine signaling: G protein–coupled receptors (GPCRs) represent about 30% of the targets of FDA-approved drugs. GPCRs signal through two pathways that are considered separable: one dependent on direct activation of heterotrimeric G proteins and the other on the recruitment of β-arrestin proteins. Building on their previous work, Zheng et al. showed that some, but not all, of the endogenous agonists of the chemokine receptor CXCR3 induced the formation of a Gαi:β-arrestin complex, which was independent of the relative extent of activation of either G protein or β-arrestin signaling pathways. Signaling downstream of the Gαi:β-arrestin complex was different from that stimulated by β-arrestin alone. Together, these data add to the evidence of crosstalk between G proteins and β-arrestins and may have implications for the development of GPCR-targeting drugs. [ABSTRACT FROM AUTHOR]

Objective: To examine the Manukau Salivary Symptom Score (MSSS) questionnaire as a validated tool to assess obstructive sialadenitis-specific symptoms to both indicate disease severity and assess the outcome after sialendoscopic procedures. Study Design: A prospective observational study was performed from 2010 to 2019 comprising 164 patients undergoing sialendoscopy for nonneoplastic chronic obstructive salivary gland disease (COSGD). Setting: Department of Otolaryngology–Head and Neck Surgery at the Manukau Surgical Centre, Auckland, New Zealand, between June 2010 and September 2019. Methods: A prospective observational study was performed from 2010 to 2019 comprising 164 patients undergoing sialendoscopy for nonneoplastic COSGD. Patients completed the MSSS preoperatively and at postoperative follow-up. Statistical tests were used to compare pre- and postoperative answers. Cronbach's α was used to measure internal consistency. Finally, construct validity was determined by comparing the 5-question MSSS questionnaire to the preexisting 20-question Chronic Obstructive Sialadenitis Symptoms (COSS) questionnaire. Results: Postoperatively, patients had significant improvements in pain, eating, talking, swelling, and quality of life (P <.001). The MSSS questionnaire was found to have high internal consistency (α = 0.938). Questions in the MSSS had a very strong positive correlation with 3 COSS questions, a strong positive correlation with 8, a moderate positive correlation with 4, and a weak positive correlation with 1. Four COSS questions were not considered relevant and were not included in the MSSS questionnaire. Conclusion: The MSSS questionnaire is a simple, validated questionnaire that is useful for assessing the impact of sialendoscopy in patients with COSGD. [ABSTRACT FROM AUTHOR]

The breakdown of the ventricular zone with the presence of blood in cerebrospinal fluid has been shown to increase shunt catheter obstruction in the treatment of hydrocephalus, but the mechanisms by which this occurs are generally unknown. Using a custom‐built incubation chamber, we immunofluorescently assayed cell attachment and morphology on shunt catheters with and without blood after 14 days. Samples exposed to blood showed significantly increased cell attachment (average total cell count 392.0 ± 317.1 vs. control of 94.7 ± 44.5, p < 0.0001). Analysis of the glial fibrillary acidic protein expression showed similar trends (854.4 ± 450.7 vs. control of 174.3 ± 116.5, p < 0.0001). An in vitro model was developed to represent the exposure of astrocytes to blood following an increase in blood–brain barrier permeability. Exposure of astrocytes to blood increases the number of cells and their spread on the shunt. [ABSTRACT FROM AUTHOR]

Context: Focal sympathetic nerve blocks of the ganglion impar are often effective treatments for coccydynia (coccyx pain) and other pelvic pain syndromes. These injections are generally performed under contrast-enhanced fluoroscopic guidance. Vascular uptake may potentially occur during the injection and vascular uptake rates have been reported for other spinal injections, but never for ganglion impar blocks. Aims: The purpose of the study was to determine vascular uptake rates during fluoroscopy-guided ganglion impar blocks. Settings and Design: An academic/University-based Coccyx Pain Center. Methods and Materials: A total of 78 consecutive trans-coccygeal ganglion impar blocks were analyzed for vascular uptake of contrast as determined by intermittent fluoroscopy. Statistical Analysis Used: Direct calculation of incidence. Results: Only one patient (1.3%) demonstrated a vascular uptake pattern, which was readily recognized and corrected by slightly adjusting the position of the needle tip and thereby subsequently obtaining the desired contrast pattern at the ganglion impar. Conclusions: Vascular uptake incidence is low during ganglion impar blocks. This information can be one of the multiple factors considered when a physician is deciding whether or not to use contrast in an individual patient. [ABSTRACT FROM AUTHOR]

Among bacterial toxin-antitoxin systems, to date no antitoxin has been identified that functions by cleaving toxin mRNA. Here we show that YjdO (renamed GhoT) is a membrane lytic peptide that causes ghost cell formation (lysed cells with damaged membranes) and increases persistence (persister cells are tolerant to antibiotics without undergoing genetic change). GhoT is part of a new toxin-antitoxin system with YjdK (renamed GhoS) because in vitro RNA degradation studies, quantitative real-time reverse-transcription PCR and whole-transcriptome studies revealed that GhoS masks GhoT toxicity by cleaving specifically yjdO (ghoT) mRNA. Alanine substitutions showed that Arg28 is important for GhoS activity, and RNA sequencing indicated that the GhoS cleavage site is rich in U and A. The NMR structure of GhoS indicates it is related to the CRISPR-associated-2 RNase, and GhoS is a monomer. Hence, GhoT-GhoS is to our knowledge the first type V toxin-antitoxin system where a protein antitoxin inhibits the toxin by cleaving specifically its mRNA. [ABSTRACT FROM AUTHOR]

Background: Diabetes is associated with factors such as physical activity, diet, and the environment. Previous studies have shown the use of deep learning and satellite imagery to predict community-level health outcomes. However, no studies have assessed whether these deep learning tools can extract information distinct from demography and socioeconomic status, or can be integrated together for a more robust approach. Objective: To utilize satellite-imagery based deep learning and traditional survey-based statistical methods to examine the relationship between built environment and diabetes prevalence. Methods: A convolutional neural network (CNN), a deep learning approach, was used to extract features of built environment from 100,000+ satellite images of Seattle (SEA), Los Angeles (LA), San Antonio (SA), and Memphis (MEM). Diabetes prevalence and population data were retrieved from the CDC PLACES Project and American Community Surveys (ACS). Elastic net and ordinary least squares (OLS) regressions were used to quantify the associations of 1) environmental features and diabetes rates, 2) ACS covariates and diabetes rates, and 3) environmental features and the residuals of the ACS data model. Results: The all-cities environment CNN model explained 68.2% of variation, while single-city models explained 90.3% (MEM), 81% (SA), 70.5% (SEA), and 46.2% (LA) of variation. ACS OLS models explained 81.2% (all-cities), 84.4% (MEM), 74.1% (SA), 78.1% (SEA), and 76.5% (LA) of variation. The integrated model explained 91.3% (all-cities), 91.5% (MEM), 90.1% (SA), 85.9% (SEA), and 85.9% (LA). Conclusion: Superior performance of the multimodal analysis, conjoining environmental and population data, demonstrates the capability of CNNs in capturing features of built environment absent from ACS data. Such combined models may enable better understanding of the effects of built environment on diabetes, and guide policymakers in implementing community changes to reduce diabetes prevalence. Disclosure: K. Zheng: None. R. Lawton: None. D. Z. Zheng: None. E. Huang: Other Relationship; Self; Stratus Medicine, kelaHealth, MedBlue Data. Funding: National Center for Advancing Translational Sciences (UL1TR002553) [ABSTRACT FROM AUTHOR]

Summary FANCA is a component of the Fanconi anemia (FA) core complex that activates DNA interstrand crosslink repair by monoubiquitination of FANCD2. Here, we report that purified FANCA protein catalyzes bidirectional single-strand annealing (SA) and strand exchange (SE) at a level comparable to RAD52, while a disease-causing FANCA mutant, F1263Δ, is defective in both activities. FANCG, which directly interacts with FANCA, dramatically stimulates its SA and SE activities. Alternatively, FANCB, which does not directly interact with FANCA, does not stimulate this activity. Importantly, five other patient-derived FANCA mutants also exhibit deficient SA and SE, suggesting that the biochemical activities of FANCA are relevant to the etiology of FA. A cell-based DNA double-strand break (DSB) repair assay demonstrates that FANCA plays a direct role in the single-strand annealing sub-pathway (SSA) of DSB repair by catalyzing SA, and this role is independent of the canonical FA pathway and RAD52. [ABSTRACT FROM AUTHOR]

Abstracts: Lacertus fibrosus Syndrome (LFS) is a rare cause of persistent medial elbow pain in baseball players, often not considered in the initial diagnostic considerations. This case report details a 19-year-old collegiate baseball player who presented with insidious left anterior medial elbow pain, initially diagnosed as biceps tendonitis. The patient did not experience pain relief after six months of conservative management. Sonopalpation during diagnostic ultrasound localized the source of pain to the median nerve at the level of the lacertus fibrosus, and the decision was made to perform ultrasound-guided hydrodissection of the median nerve at this level. The procedure resulted in rapid and sustained symptom relief without the scarring that has been associated with traditional surgical techniques. To date, there has been no study investigating the use of ultrasound-guided hydrodissection targeting lacertus fibrosus. This report highlights the importance of considering LFS in throwing athletes with persistent elbow pain, and advocates for considering ultrasound-guided hydrodissection as a management option for patients with clinical suspicion of LFS., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors and signal through the proximal effectors, G proteins and β-arrestins, to influence nearly every biological process. The G protein and β-arrestin signaling pathways have largely been considered separable; however, direct interactions between Gα proteins and β-arrestins have been described that appear to be part of a distinct GPCR signaling pathway. Within these complexes, Gα i/o , but not other Gα protein subtypes, directly interacts with β-arrestin, regardless of the canonical Gα protein that is coupled to the GPCR. Here, we report that the endogenous biased chemokine agonists of CXCR3 (CXCL9, CXCL10, and CXCL11), together with two small-molecule biased agonists, differentially formed Gα i :β-arrestin complexes. Formation of the Gα i :β-arrestin complexes did not correlate well with either G protein activation or β-arrestin recruitment. β-arrestin biosensors demonstrated that ligands that promoted Gα i :β-arrestin complex formation generated similar β-arrestin conformations. We also found that Gα i :β-arrestin complexes did not couple to the mitogen-activated protein kinase ERK, as is observed with other receptors such as the V2 vasopressin receptor, but did couple with the clathrin adaptor protein AP-2, which suggests context-dependent signaling by these complexes. These findings reinforce the notion that Gα i :β-arrestin complex formation is a distinct GPCR signaling pathway and enhance our understanding of the spectrum of biased agonism.

Heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) are common drug targets and canonically couple to specific G α protein subtypes and β-arrestin adaptor proteins. G protein-mediated signaling and β-arrestin-mediated signaling have been considered separable. We show here that GPCRs promote a direct interaction between G αi protein subtype family members and β-arrestins regardless of their canonical G α protein subtype coupling. G αi :β-arrestin complexes bound extracellular signal-regulated kinase (ERK), and their disruption impaired both ERK activation and cell migration, which is consistent with β-arrestins requiring a functional interaction with G αi for certain signaling events. These results introduce a GPCR signaling mechanism distinct from canonical G protein activation in which GPCRs cause the formation of G αi :β-arrestin signaling complexes., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)