Citations

Tumor-educated platelets (TEPs) are a potential method of liquid biopsy for the diagnosis and monitoring of cancer. However, the mechanism underlying tumor education of platelets is not known, and transcripts associated with TEPs are often not tumor-associated transcripts. We demonstrated that direct tumor transfer of transcripts to circulating platelets is an unlikely source of the TEP signal. We used CDSeq, a latent Dirichlet allocation algorithm, to deconvolute the TEP signal in blood samples from patients with glioblastoma. We demonstrated that a substantial proportion of transcripts in the platelet transcriptome are derived from nonplatelet cells, and the use of this algorithm allows the removal of contaminant transcripts. Furthermore, we used the results of this algorithm to demonstrate that TEPs represent a subset of more activated platelets, which also contain transcripts normally associated with nonplatelet inflammatory cells, suggesting that these inflammatory cells, possibly in the tumor microenvironment, transfer transcripts to platelets that are then found in circulation. Our analysis suggests a useful and efficient method of processing TEP transcriptomic data to enable the isolation of a unique TEP signal associated with specific tumors.

Abstract Background The aim of this study was to evaluate the safety and efficacy of fecal microbiota, live-jslm (RBL; REBYOTA)—the first single-dose, broad consortia microbiota-based live biotherapeutic approved by the US Food and Drug Administration for preventing recurrent Clostridioides difficile infection (rCDI) in adults following standard-of-care (SOC) antibiotic treatment. Methods PUNCH CD3-OLS was a prospective, phase 3, open-label study, conducted across the US and Canada. Participants were aged ≥18 years with documented rCDI and confirmed use of SOC antibiotics. Participants with comorbidities including inflammatory bowel disease and mild-to-moderate immunocompromising conditions could be enrolled. A single dose of RBL was rectally administered within 24–72 hours of antibiotic completion. The primary endpoint was the number of participants with RBL- or administration-related treatment-emergent adverse events (TEAEs). Secondary endpoints included treatment success and sustained clinical response, at 8 weeks and 6 months after RBL administration, respectively. Results Overall, 793 participants were enrolled, of whom 697 received RBL. TEAEs through 8 weeks after administration were reported by 47.3% of participants; most events were mild or moderate gastrointestinal disorders. Serious TEAEs were reported by 3.9% of participants. The treatment success rate at 8 weeks was 73.8%; in participants who achieved treatment success, the sustained clinical response rate at 6 months was 91.0%. Safety and efficacy rates were similar across demographic and baseline characteristic subgroups. Conclusions RBL was safe and efficacious in participants with rCDI and common comorbidities. This is the largest microbiota-based live biotherapeutic study to date, and findings support use of RBL to prevent rCDI in a broad patient population. Clinical Trials Registration NCT03931941.

Objectives: A DFO can be performed via two techniques: a lateral opening wedge (LOW) osteotomy and a medial closing wedge (MCW) osteotomy. Small case series have looked at how leg length is affected by a lateral opening wedge DFO, however, there is a lack of research comparing these leg length changes to medial closing DFO. Additionally, no studies have presented a model for predicting the leg length changes that will occur following DFO of either technique. Given that limb length differences can lead to accelerated osteoarthritis, back pain, hip pain, and other issues, being able to predict which technique can help prevent this pathology without a secondary procedure would be an important finding. Finally, the medial closing wedge osteotomy can allow for immediate weight-bearing while the lateral opening wedge does not and typically has associated cost with bone grafting. Therefore, we designed this study to validate a tool designed to predict leg length changes after distal femoral osteotomy (DFO) and compare changes following medial closing wedge (MCW) and lateral opening wedge (LOW) techniques. Methods: A collaborative retrospective review was performed of patients from Rush and Mayo Clinic databases who received a DFO and had full-length standing radiographs both pre-and postoperatively. For each preoperative radiograph, the region on the medial (for LOW) or lateral (for MCW) distal femur cortex that would be the “hinge point” during DFO was identified. The distances from the center of the femoral head to the hinge point (“A”), from the hinge point to the center of the tibial plafond (“B”), and the resultant angle at the hinge point (“α”) were measured (Figure 1). Figure 2 demonstrates the equation used to plot a graph of the predicted leg length changes corresponding to the change in α angle produced by DFO. Final leg length was calculated on postoperative radiographs, and the difference between predicted and true leg length changes was compared using paired Wilcoxon signed rank exact tests. Results: 10 MCW and 10 LOW patients were included. For both LOW (n=10) and MCW (n=10) osteotomies, the predicted leg length change was equivalent to the true change measured on postoperative radiographs (LOW P=0.16; MCW P=0.85). LOW DFO’s had 5.10 ± 2.77 mm (range: 1.45-10.87 mm) of leg lengthening, compared to 2.61 ± 1.25 mm (range: 0.50-4.56 mm) of leg shortening (p<0.001) for MCW (Figure 3). On average, there was 0.85 mm of lengthening (range 0.5-1.3 mm) for every 1° of mechanical axis correction with LOW DFO, compared to 0.45 mm of shortening (range: 0.1-1.4 mm) per 1° of MCW correction. Conclusions: This study presents a tool to accurately and reliably predict the leg length changes seen after both medial closing and lateral opening wedge DFO’s. Knowing what leg length changes to expect with each DFO technique is a useful tool that surgeons can utilize during surgical planning. Preoperative radiographic imaging can be used to predict leg length change following DFO with high reliability and accuracy. Surgeons can expect approximately 0.85mm of lengthening per 1° of DFO correction when performing LOW, compared to 0.45mm of shortening per 1° correction for MCW osteotomies.

Glioblastoma (GBM) is the most prevalent and aggressive malignant primary brain tumor. GBM proximal to the lateral ventricles (LVs) is more aggressive, potentially because of subventricular zone contact. Despite this, cross-talk between GBM and neural stem/progenitor cells (NSC/NPCs) is not well understood. Using cell-specific proteomics, we show that LV-proximal GBM prevents neuronal maturation of NSCs through induction of senescence. In addition, GBM brain tumor–initiating cells (BTICs) increase expression of cathepsin B (CTSB) upon interaction with NPCs. Lentiviral knockdown and recombinant protein experiments reveal that both cell-intrinsic and soluble CTSB promote malignancy-associated phenotypes in BTICs. Soluble CTSB stalls neuronal maturation in NPCs while promoting senescence, providing a link between LV-tumor proximity and neurogenesis disruption. Last, we show LV-proximal CTSB up-regulation in patients, showing the relevance of this cross-talk in human GBM biology. These results demonstrate the value of proteomic analysis in tumor microenvironment research and provide direction for new therapeutic strategies in GBM.

Objective: This study aims to appraise recommendations from an expert panel of surgical educators on optimizing surgical education and training in the setting of contemporary challenges. Background: The Blue Ribbon Committee (BRC II), a group of surgical educators, was convened to make recommendations to optimize surgical training, considering the current changes in the landscape of surgical education. Surgical trainees were recruited to assess their impressions of the recommendations. Methods: A mixed-methods study design was employed, with a survey, followed by focus group interviews. Participating residents and fellows were recruited through a purposeful sampling approach. Descriptive statistics were applied to analyze the survey data, and a thematic data analysis on interview transcripts was employed. Results: The majority of trainee respondents (n=16) thought that all of the subcommittee recommendations should be included in the final BRC II recommendations and paper. According to the interviews, overall, the feedback from the trainees was positive, with particular excitement around work-life integration, education support and faculty development, and funding pitfalls. Some themes about concerns included a lack of clarity about the recommendations, concern about some recommendations being in conflict with one another, and a disconnect between the initial BRC II survey and the subsequent recommendations. Conclusions: The residents gathered for this focus group were encouraged by the thought, effort, and intention that gathered the surgical leaders across the country to make the recommendations. While the trainees wanted clarity on some areas, the overall opinion was in agreement with the recommendations.

Background: Osteochondral allograft (OCA) transplantation is an important surgical technique for full-thickness chondral defects in the knee. For patients undergoing this procedure, topography matching between the donor and recipient sites is essential to limit premature wear of the OCA. Currently, there is no standardized process of donor and recipient graft matching. Purpose: To evaluate a novel topography matching technique for distal femoral condyle OCA transplantation using 3-dimensional (3D) laser scanning to create 3D-printed patient-specific instrumentation in a human cadaveric model. Study Design: Descriptive laboratory study. Methods: Human cadaveric distal femoral condyles (n = 12) underwent 3D laser scanning. An 18-mm circular osteochondral recipient defect was virtually created on the medial femoral condyle (MFC), and the position and orientation of the best topography-matched osteochondral graft from a paired donor lateral femoral condyle (LFC) were determined using an in silico analysis algorithm minimizing articular step-off distances between the edges of the graft and recipient defect. Distances between the entire surface of the OCA graft and the underneath surface of the MFC were evaluated as surface mismatch. Donor (LFC) and recipient (MFC) 3D-printed patient-specific guides were created based on 3D reconstructions of the scanned condyles. Through use of the guides, OCAs were harvested from the LFC and transplanted to the reamed recipient defect site (MFC). The post-OCA recipient condyles were laser scanned. The 360° articular step-off and cartilage topography mismatch were measured. Results: The mean cartilage step-off and graft surface mismatch for the in silico OCA transplant were 0.073 ± 0.029 mm (range, 0.005-0.113 mm) and 0.166 ± 0.039 mm (range, 0.120-0.243 mm), respectively. Comparatively, the cadaveric specimens postimplant had significantly larger step-off differences (0.173 ± 0.085 mm; range, 0.082-0.399 mm; P = .001) but equivalent graft surface topography matching (0.181 ± 0.080 mm; range, 0.087-0.396 mm; P = .678). All 12 OCA transplants had mean circumferential step-off differences less than a clinically significant cutoff of 0.5 mm. Conclusion: These findings suggest that the use of 3D-printed patient-specific guides for OCA transplantation has the ability to reliably optimize cartilage topography matching for LFC to MFC transplantation. This study demonstrated substantially lower step-off values compared with previous orthopaedic literature when also evaluating LFC to MFC transplantation. Using this novel technique in a model performing MFC to MFC transplantation has the potential to yield further enhanced results due to improved radii of curvature matching. Clinical Relevance: Topography-matched graft implantation for focal chondral defects of the knee in patients improves surface matching and has the potential to improve long-term outcomes. Efficient selection of the allograft also allows improved availability of the limited allograft sources.

AbstractObjectiveNeuromodulation is a viable option for patients with drug‐resistant epilepsies. We reviewed the management of patients with two deep brain neurostimulators. In addition, patients implanted with a device targeting the centromedian‐parafascicular (CM‐Pf) nuclear complex supplements this report to provide an illustrative case to implantation and programming a patient with three active devices.MethodsA narrative review using PubMed and Embase identified patients with drug‐resistant epilepsy implanted with more than one neurostimulator was performed. Combinations of vagus nerve stimulation (VNS), deep brain stimulation (DBS), and responsive neurostimulation (RNS) were identified. We provide a background of a newly reported case of an adult with a triple implant eventually responding to CM‐Pf DBS as the third implant following suboptimal benefit from VNS and RNS.ResultsIn review of the literature, dual‐device therapy is increasing in reports of use with combinations of VNS, RNS, and DBS to treat patients with drug‐resistant epilepsy. We review dual‐device implants with thalamic DBS device combinations, functional neural networks, and programming patients with dual devices. CM‐Pf is a new target for DBS and has shown a variable response in focal epilepsy. We report the unique case of 28‐year‐old male with drug‐resistant focal epilepsy who experienced a 75% seizure reduction with CM‐Pf DBS as his third device after suboptimal responses to VNS and RNS. After 9 months, he also experienced seizure freedom from recurrent focal to bilateral tonic–clonic seizures. No medical or surgical complications or safety issues were encountered.ConclusionWe demonstrate safety and feasibility in an adult combining active VNS, RNS, and CM‐Pf DBS. Patients with dual‐device therapy who experience a suboptimal response to initial device use at optimized settings should not be considered a neuromodulation “failure.” Strategies to combine devices require a working knowledge of brain networks.