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Accurate and efficient diagnosis, as well as a consistent and effective treatment of acute hematogenous osteomyelitis, are paramount to ensure successful clinical outcomes. Noninvasive measures of isolating the causative pathogen from blood cultures have low sensitivity, with published rates often50%. The use of interventional radiology (IR)-guided percutaneous biopsy has gained traction as a nonsurgical means of obtaining tissue cultures with a reported increased sensitivity of90%. This study aims to determine the utility of IR-guided biopsy in the management of pediatric patients with acute hematogenous pediatric osteomyelitis (OM).An IRB-approved retrospective review was completed of children younger than 18 years admitted to a single institution for treatment of magnetic resonance imaging or culture/biopsy-proven acute hematogenous OM. Patients were excluded for the diagnosis of chronic recurrent multifocal OM, incomplete documentation, treatment initiation at an outside institution, open surgical debridement, and concomitant septic arthritis. Patients who underwent IR-guided biopsy were compared with those treated empirically without biopsy.Fifty patients were included for analysis. Fifteen (30%) had IR-guided biopsies; 35 (70%) were treated empirically. The average age at diagnosis was 11.8 years old (SD: 4.9). Of the 15 patients who underwent IR-guided biopsy, a pathogen was identified in 12 cases (80%); 14 of these patients had concomitant blood cultures with only 1 (7%) positive result (P0.01). Of the 11 patients with positive IR-guided biopsy results in the setting of negative blood cultures, 9 (82%) had alterations in their antibiotic regimen as a result of the biopsy. The average time from blood sample collection to definitive antibiotic initiation was nearly double that of time from IR-guided biopsy collection to definitive antibiotic initiation (70.8 vs. 36 h; P0.01).IR-guided biopsy increased pathogen identification by 47% over blood cultures alone and decreased the time to definitive antibiotics. As such, IR-guided biopsy is an effective and safe diagnostic tool for pathogen identification and appropriate antibiotic selection. Orthopaedic surgeons are encouraged to incorporate IR-guided biopsy early in the treatment pathway for patients with acute OM without an indication for open surgical intervention.Level III retrospective comparative study.

Goals of pediatric mandibular reconstruction are restoring form, function, and esthetics while providing platforms for dental restoration. Though many techniques recreate the inferior mandibular border, most fail to address form and function in a manner that optimizes dental rehabilitation. We describe a surgical technique using a novel custom endoprosthesis that recapitulates the native mandibular contour while supporting the bone construct in a cephalad direction with a medial ledge facilitating implant placement and oral rehabilitation. This multi-institutional retrospective review at high-volume pediatric craniofacial surgery departments features patients with large mandibular resections warranting custom constructs. Thirteen patients underwent mandibular resection and endoprosthesis reconstruction with either free fibula osteocutaneous flaps (n = 9), soft tissue free flaps without bone graft (n = 2), rib graft (n = 1), or iliac crest bone graft (n = 1). Five patients required revisions for distal flap necrosis, intraoral granuloma, and orocutaneous fistulas; one endoprosthesis required removal. Excellent esthetic and reconstructive outcomes were achieved; however, only 2 patients completed dental restoration given financial constraints. A custom endoprosthesis represents an untapped avenue toward comprehensive pediatric mandibular reconstruction. It shows compatibility with microvascular flaps while optimizing facial contour and bone height for implant placement. Given these advantages, substantial financial barriers to dental restoration should be addressed.

In melanoma, predicting which tumors will ultimately metastasize guides treatment decisions. Transcriptional signatures of primary tumors have been utilized to predict metastasis, but which among these are driver or passenger events remains unclear. We used data from the adjuvant AVAST-M trial to identify a predictive gene signature in localized tumors that ultimately metastasized. Using a zebrafish model of primary melanoma, we interrogated the top genes from the AVAST-M signature in vivo. This identified GRAMD1B, a cholesterol transfer protein, as a bona fide metastasis suppressor, with a majority of knockout animals rapidly developing metastasis. Mechanistically, excess free cholesterol or its metabolite 27-hydroxycholesterol promotes invasiveness via activation of an AP-1 program, which is associated with increased metastasis in humans. Our data demonstrate that the transcriptional seeds of metastasis are embedded within localized tumors, suggesting that early targeting of these programs can be used to prevent metastatic relapse. Significance: We analyzed human melanoma transcriptomics data to identify a gene signature predictive of metastasis. To rapidly test clinical signatures, we built a genetic metastasis platform in adult zebrafish and identified GRAMD1B as a suppressor of melanoma metastasis. GRAMD1B-associated cholesterol overload activates an AP-1 program to promote melanoma invasion. This article is highlighted in the In This Issue feature, p. 1

Purpose Opportunities exist to meaningfully reduce suboptimal prescription opioid use among older adults. Deprescribing is one possible approach to reducing suboptimal use. Appropriate interventions should outline how to carefully taper opioids, closely monitor adverse events, substitute viable alternative and affordable nonopioid pain treatments, and initiate medications for opioid use disorder to properly manage use disorders, as needed. We sought to document and understand provider perceptions to begin developing effective and safe opioid deprescribing interventions. Methods We conducted 3 semistructured focus groups that covered topics such as participant perspectives on opioid deprescribing in older adults, how to design an ideal intervention, and how to identify potential barriers or facilitators in implementing an intervention. Focus group transcripts were double coded and qualitatively analyzed to identify overarching themes. Results Healthcare providers (n = 17), including physicians, pharmacists, nurses, social workers, and administrative staff, participated in 3 focus groups. We identified 4 key themes: (1) involve pharmacists in deprescribing and empower them as leaders of an opioid deprescribing service; (2) ensure tight integration and close collaboration throughout the deprescribing process from the inpatient to outpatient settings; (3) more expansive inclusion criteria than age alone; and (4) provision of access to alternative pharmacological and nonpharmacological pain management modalities to patients. Conclusion Our findings, which highlight various healthcare provider beliefs about opioid deprescribing interventions, are expected to serve as a framework for other organizations to develop and implement interventions. Future studies should incorporate patients’ and family caregivers’ perspectives.

During the coronavirus disease pandemic, audio-only and video telehealth visits became more widely available, but the relative patient satisfaction between telehealth and in-person modalities is not well-described.Our objective was to compare patient satisfaction with audio-only, video, and in-person adult primary care visits at a large, urban public healthcare system.In this cross-sectional study, we used aggregated data from Press Ganey patient satisfaction surveys at 17 primary care facilities at New York City Health + Hospitals for visits between 1 June 2021 to 30 November 2021. We compared mean scores for questions common to surveys for each modality in domains of Access, Care Provider, and Overall Assessment using pairwise comparisons with two-tailed t-tests.There were 7,183/79,562 (9.0%) respondents for in-person visits and 1,009/15,092 (6.7%) respondents for telehealth visits. Compared to respondents for in-person visits, respondents for telehealth visits were more likely to be aged 35-64 years, Asian, and speak English as their primary language, and less likely to be ≥65 years old, Black or other race, and speak Spanish or another language as their primary language (p 0.001). Patients reported higher mean satisfaction for Access measures for telehealth visits than in-person visits (p 0.001). For Care Provider satisfaction questions, video visits generally had higher mean scores than in-person and, in turn, audio-only visits. For Overall Assessment questions, video visits had higher mean scores than in-person and, subsequently, audio-only visits.Of the visit modalities, video visits had the highest mean satisfaction scores across all domains. Telehealth may improve experiences with access, but audio-only visits may provide poorer visit experiences.

With numerous nodes on online heterogeneous networks, how to reach and extract target nodes of our specic interests is a pressing problem. In this paper, we propose a novel heterogeneous network crawler, MCrawl. It addresses the problem via iterative online heterogeneous network crawling by navigating its available APIs, starting from a set of target nodes, i.e., seed nodes. We are facing two challenges towards addressing the problem. First, to navigate within a vast network, how do we start from a small set of target nodes In other words, which nodes in the current frontier and which direction shall we expand, to reach promising target nodes quickly We propose motif-based crawling to exploit the complex structures and rich semantics of heterogeneous networks. Second, in many scenarios, we do not have a classier to assess the quality of the harvested nodes and thus the motifs to expand. We develop a probabilistic inference framework to estimate the yield and harvest rates of motifs, achieving principled bootstrapping for crawling. Our experiment on real networks of MCrawl achieves signicant margins over baselines.

Large Language Models (LLMs) bring transformative benefits alongside unique challenges, including intellectual property (IP) and ethical concerns. This position paper explores a novel angle to mitigate these risks, drawing parallels between LLMs and established web systems. We identify "citation" as a crucial yet missing component in LLMs, which could enhance content transparency and verifiability while addressing IP and ethical dilemmas. We further propose that a comprehensive citation mechanism for LLMs should account for both non-parametric and parametric content. Despite the complexity of implementing such a citation mechanism, along with the inherent potential pitfalls, we advocate for its development. Building on this foundation, we outline several research problems in this area, aiming to guide future explorations towards building more responsible and accountable LLMs.

When answering complex questions, large language models (LLMs) may produce answers that do not satisfy all criteria of the question. While existing self-evaluation techniques aim to detect if such answers are correct, these techniques are unable to determine which criteria of the question are satisfied by the generated answers. To address this issue, we propose answer-based claim decomposition (ABCD), a prompting strategy that decomposes questions into a series of true/false claims that can be used to verify which criteria of the input question an answer satisfies. Using the decomposed ABCD claims, we perform fine-grained self-evaluation. Through preliminary experiments on three datasets, including a newly-collected challenge dataset ObscureQA, we find that GPT-3.5 has some ability to determine to what extent its answer satisfies the criteria of the input question, and can give insights into the errors and knowledge gaps of the model., In progress preprint

We propose and study Complementary Concept Generation (CCGen): given a concept of interest, e.g., "Digital Cameras", generating a list of complementary concepts, e.g., 1) Camera Lenses 2) Batteries 3) Camera Cases 4) Memory Cards 5) Battery Chargers. CCGen is beneficial for various applications like query suggestion and item recommendation, especially in the e-commerce domain. To solve CCGen, we propose to train language models to generate ranked lists of concepts with a two-step training strategy. We also teach the models to generate explanations by incorporating explanations distilled from large teacher models. Extensive experiments and analysis demonstrate that our model can generate high-quality concepts complementary to the input concept while producing explanations to justify the predictions.

Recent advancements in Large Language Models, such as ChatGPT, have demonstrated significant potential to impact various aspects of human life. However, ChatGPT still faces challenges in aspects like truthfulness, e.g. providing accurate and reliable outputs. Therefore, in this paper, we seek to understand why ChatGPT falls short in providing truthful answers. For this purpose, we first analyze the failures of ChatGPT in complex open-domain question answering and identifies the abilities under the failures. Specifically, we categorize ChatGPT's failures into four types: comprehension, factualness, specificity, and inference. We further pinpoint three critical abilities associated with QA failures: knowledge memorization, knowledge recall, and knowledge reasoning. Additionally, we conduct experiments centered on these abilities and propose potential approaches to enhance truthfulness. The results indicate that furnishing the model with fine-grained external knowledge, hints for knowledge recall, and guidance for reasoning can empower the model to answer questions more truthfully., Preprint in progress

Purpose To study the types of uveitis examined in a hospital serving indigent populations in need of low-cost care. Methods A retrospective chart review examined the electronic medical records of all patients with uveitis-related at Drexel Eye Physicians. Data collected included demographics, anatomic location of the uveitis, systemic disease associations, treatment modalities and insurance. Statistical analysis was performed using χ² or Fischer exact tests. Results 270 patients (366 eyes) were included for analysis, 67% of patients identified as African American. Most eyes (95.3%, N = 349) were treated with topical corticosteroid drops, and only 6 (1.6%) received an intravitreal implant. Immunosuppressive medications were started in 24 patients (8.9%). Nearly 80% depended to some extent on Medicare or Medicaid Assistance for treatment coverage. There was no association between insurance type and use of biologics or difluprednate. Conclusion We found no association between insurance type and the prescription of medications for uveitis that should be used at home. There was a minimal number of patients prescribed medications for implantation in the office. The adherence of use of medications at home should be investigated.

CRISPR Sequencing of MAS2X tumors.

Supplementary Table S2. David GO analysis of AVAST-M signature

Supplementary Table S5. Normalized Counts of transcripts in GRAMD1B KO and NT cells.

Supp. Fig. S5 shows that GRAMD1B is a metastasis suppressor in human melanoma

Supp Table S4 has a list of antibodies and other resources

An in vivo screen identifies metastasis suppressors in melanoma.

Supp Table S6 Differentially Expressed Genes

Supp Table S3 has a List of Oligonucleotides Sequences

Supplementary Table S1. List of genes predictive of metastasis from AVAST-M trial.

Validation of gramd1b depletion in zebrafish cells and tumors.

Loss of GRAMD1B suppresses de novo cholesterol synthesis in melanoma cells.

The AVAST-M trial identifies a signature predictive of metastatic relapse

In melanoma, predicting which tumors will ultimately metastasize guides treatment decisions. Transcriptional signatures of primary tumors have been utilized to predict metastasis, but which among these are driver or passenger events remains unclear. We used data from the adjuvant AVAST-M trial to identify a predictive gene signature in localized tumors that ultimately metastasized. Using a zebrafish model of primary melanoma, we interrogated the top genes from the AVAST-M signature in vivo. This identified GRAMD1B, a cholesterol transfer protein, as a bona fide metastasis suppressor, with a majority of knockout animals rapidly developing metastasis. Mechanistically, excess free cholesterol or its metabolite 27-hydroxycholesterol promotes invasiveness via activation of an AP-1 program, which is associated with increased metastasis in humans. Our data demonstrate that the transcriptional seeds of metastasis are embedded within localized tumors, suggesting that early targeting of these programs can be used to prevent metastatic relapse.Significance:We analyzed human melanoma transcriptomics data to identify a gene signature predictive of metastasis. To rapidly test clinical signatures, we built a genetic metastasis platform in adult zebrafish and identified GRAMD1B as a suppressor of melanoma metastasis. GRAMD1B-associated cholesterol overload activates an AP-1 program to promote melanoma invasion.This article is highlighted in the In This Issue feature, p. 1

Cholesterol overload activates AP-1 via ERK signaling to mediate invasion upon GRAMD1B loss in melanoma.

Purpose:Chemoradiotherapy for locally advanced cervical cancer fails in over a third of patients. Biomarkers with therapeutic implications are therefore needed. We investigated the relationship between an established prognostic marker, maximum standardized uptake value (SUVmax) on 18F-fluorodeoxyglucose positron emission tomography, and the inflammatory and immune state of cervical cancers.Experimental Design:An SUVmax most prognostic for freedom from progression (FFP) was identified and compared with known prognostic clinical variables in a cohort of 318 patients treated with definitive radiation with prospectively collected clinical data. Gene set enrichment analysis (GSEA) and CIBERSORT of whole-transcriptome data from 68 patients were used to identify biological pathways and immune cell subpopulations associated with high SUVmax. IHC using a tissue microarray (TMA, N = 82) was used to validate the CIBERSORT findings. The impact of macrophages on cervical cancer glucose metabolism was investigated in coculture experiments.Results:SUVmax P = 0.001). The GSEA showed that high SUVmax is associated with increased gene expression of inflammatory pathways, including JAK/STAT3 signaling. CIBERSORT and CD68 staining of the TMA showed high SUVmax tumors are characterized by a monocyte-predominant immune infiltrate. Coculture of cervical cancer cells with macrophages or macrophage-conditioned media altered glucose uptake, and IL6 and JAK/STAT3 signaling contribute to this effect.Conclusions:SUVmax is a prognostic marker in cervical cancer that is associated with activation of inflammatory pathways and tumor infiltration of myeloid-derived immune cells, particularly macrophages. Macrophages contribute to changes in cervical cancer glucose metabolism.See related commentary by Williamson et al., p. 4136

For IL-10, Granzyme B and IFN-γ quantification, bulk TIL were stimulated in vitro with anti-CD3/CD28 beads and protein transport inhibitor (BD GolgiPlugTM) for 6h.Cells were then stained for intracellular cytokine expression by flow cytometry. Summary data were showing IL-10 MFI (P>0.05), IL-10 percentage (p=0.0508), IFN-γ (P>0.05), Granzyme B (P0.05) and Ki67 (P>0.05) by flow cytometry, gated on Tim-3- Tregs and Tim-3+ Tregs from HNSCC TILs (n=4-11 patients per marker, as indicated).

After sorting Tim-3+ CD4+CD25hiCD127- and Tim-3- CD4+CD25hiCD127- cells from HNSCC TIL, they were treated with IL-2 (200 IU/ml) with or without IFN- γ (200ng/ml) for 48 hours. Viability factor (A), Foxp3 (A) and ki-67 expression (B) were tested by flow cytometry.

Prognostic significance of SUVmax for local (cervix) recurrence (A) and any pelvic recurrence (B).

Number of patients in each of the patient cohorts used, and overlap between the cohorts.

Supplemental Material and Methods

Complete Supplemental Figures 1-8 and Supplemental Tables 1-2 are embedded in this file. Each item contains its respective legend.

Tissue microarray staining for CD163, a marker for M2 polarized macrophages.

Representative image of an auto-contoured metabolic tumor volume on simulation CT scan fused with a diagnostic PET scan.

Purpose: Regulatory T (Treg) cells are important suppressive cells among tumor-infiltrating lymphocytes (TIL). Treg cells express the well-known immune checkpoint receptor PD-1, which is reported to mark “exhausted” Treg with lower suppressive function. T-cell immunoglobulin mucin (Tim)-3, a negative regulator of Th1 immunity, is expressed by a sizeable fraction of TIL Tregs, but the functional status of Tim-3+ Tregs remains unclear.Experimental Design: CD4+CTLA-4+CD25high Treg cells were sorted from freshly excised head and neck squamous cell carcinoma (HNSCC) TIL based on Tim-3 expression. Functional and phenotypic features of these Tim-3+ and Tim-3− TIL Tregs were tested by in vitro suppression assays and multi-color flow cytometry. Gene-expression profiling and NanoString analysis of Tim-3+ TIL Treg were performed. A murine HNSCC tumor model was used to test the effect of anti-PD-1 immunotherapy on Tim-3+ Treg.Results: Despite high PD-1 expression, Tim-3+ TIL Treg displayed a greater capacity to inhibit naïve T-cell proliferation than Tim-3− Treg. Tim-3+ Treg from human HNSCC TIL also displayed an effector-like phenotype, with more robust expression of CTLA-4, PD-1, CD39, and IFN-γ receptor. Exogenous IFN-γ treatment could partially reverse the suppressive function of Tim-3+ TIL Treg. Anti-PD-1 immunotherapy downregulated Tim-3 expression on Tregs isolated from murine HNSCC tumors, and this treatment reversed the suppressive function of HNSCC TIL Tregs.Conclusions: Tim-3+ Treg are functionally and phenotypically distinct in HNSCC TIL, and are highly effective at inhibiting T-cell proliferation despite high PD-1 expression. IFN-γ induced by anti–PD-1 immunotherapy may be beneficial by reversing Tim-3+ Treg suppression. Clin Cancer Res; 24(18); 4529–38. ©2018 AACR.

Bootstrap multivariate analysis results.

Tumors are heterogeneous and composed of cells with different dissemination abilities. Despite significant effort, there is no universal biological marker that serves as a metric for metastatic potential of solid tumors. Common to disseminating cells from such tumors, however, is the need to modulate their adhesion as they detach from the tumor and migrate through stroma to intravasate. Adhesion strength is heterogeneous even among cancer cells within a given population, and using a parallel plate flow chamber, we separated and sorted these populations into weakly and strongly adherent groups; when cultured under stromal conditions, this adhesion phenotype was stable over multiple days, sorting cycles, and common across all epithelial tumor lines investigated. Weakly adherent cells displayed increased migration in both two-dimensional and three-dimensional migration assays; this was maintained for several days in culture. Subpopulations did not show differences in expression of proteins involved in the focal adhesion complex but did exhibit intrinsic focal adhesion assembly as well as contractile differences that resulted from differential expression of genes involved in microtubules, cytoskeleton linkages, and motor activity. In human breast tumors, expression of genes associated with the weakly adherent population resulted in worse progression-free and disease-free intervals. These data suggest that adhesion strength could potentially serve as a stable marker for migration and metastatic potential within a given tumor population and that the fraction of weakly adherent cells present within a tumor could act as a physical marker for metastatic potential.Significance:Cancer cells exhibit heterogeneity in adhesivity, which can be used to predict metastatic potential.

Supplementary Figure Legends. Legend for Supplementary Figures S1-S5.