Citations

Abstract Mass spectrometry (MS) is a technique widely employed for the identification and characterization of proteins, with personalized medicine, systems biology, and biomedical applications. The application of MS-based proteomics advances our understanding of protein function, cellular signaling, and complex biological systems. MS data analysis is a critical process that includes identifying and quantifying proteins and peptides and then exploring their biological functions in downstream analyses. To address the complexities associated with MS data analysis, we developed ProtPipe to streamline and automate the processing and analysis of high-throughput proteomics and peptidomics datasets with DIA-NN preinstalled. The pipeline facilitates data quality control, sample filtering, and normalization, ensuring robust and reliable downstream analyses. ProtPipe provides downstream analyses, including protein and peptide differential abundance identification, pathway enrichment analysis, protein–protein interaction analysis, and major histocompatibility complex (MHC)–peptide binding affinity analysis. ProtPipe generates annotated tables and visualizations by performing statistical post-processing and calculating fold changes between predefined pairwise conditions in an experimental design. It is an open-source, well-documented tool available at https://github.com/NIH-CARD/ProtPipe, with a user-friendly web interface.

BACKGROUND: While initial data for transcatheter aortic valve replacement (TAVR) in aortic stenosis patients with mitral stenosis (MS) suggested a poor short-term prognosis, outcomes for contemporary balloon-expandable valves remain unknown. The aim of this retrospective multicenter registry study was to compare the potential impact of MS on TAVR outcomes with balloon-expandable valves. METHODS: Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapies Registry and Centers for Medicare & Medicaid Services claims data were used to obtain a cohort of 327 925 patients who underwent TAVR with current balloon-expandable valves (SAPIEN 3, SAPIEN 3 Ultra, or SAPIEN 3 Ultra Resilia) between June 2015 and December 2022 across 791 sites. Severe MS (defined as >10 mm Hg mean gradient or <1.5 cm 2 area) was compared with mild or less MS (defined as <5 mm Hg mean gradient and >2 cm 2 area) using propensity matching to minimize confounding variables. RESULTS: Patients with severe MS (n=8500; 2.6%) had a higher number of comorbid conditions, Society of Thoracic Surgeons risk scores, and were more often women than patients with mild or less MS at the time of index TAVR. While patients with severe MS had worse outcomes at 30 days, when propensity-matched, patients exhibited similar 30-day rates of death (3.2% versus 3.0%), stroke (2.4% versus 2.2%), major vascular complications (1.6% versus 1.6%), device implant success (98.9% versus 99.2%), and new dialysis (0.7% versus 0.5%), with higher rates of pacemaker implantation (11.3% versus 9.4%; P <0.001). By 1 year, there was no difference in the change in the KCCQ (Kansas City Cardiomyopathy Questionnaire) overall score from baseline to 1 year (30.7±27.0 versus 31.9±27.0; P =0.07). By 3 years, an increase in the mortality rate (45.1% versus 40.9%; P <0.001) of patients with severe MS was observed. CONCLUSIONS: MS in isolation is not associated with worsened short-term outcomes among patients undergoing contemporary TAVR with balloon-expandable valves.

AimThis study aimed to evaluate the impact of intraoperative direct sonication on the yield of traditional culture and the time to positivity (TTP) of cultures obtained for periprosthetic joint infection (PJI), thereby assessing its potential to improve diagnostic efficiency and reduce contamination risk.MethodA prospective cohort study was conducted at a tertiary care center, involving 190 patients undergoing revision surgery for PJI from August 2021 to January 2024. Patients were included based on the 2018 International Consensus Meeting definition of PJI. The study utilized a novel sonication protocol, which involved direct intraoperative sonication of the implant and tissue, followed by incubation in a BACT/ALERT 3D system. The primary outcomes measured were the number and percentage of positive culture samples, identified microorganisms, and the TTP of each culture. Statistical analysis was performed using R software, with various tests applied to assess the significance of findings.ResultsThe study included 510 positive cultures from 190 patients, demonstrating that sonication significantly improved the positivity rate for both tissue and prosthesis specimens (p < 0.05). The median TTP for all samples was 3.13 days, with sonicated samples showing a significantly shorter TTP compared to non-sonicated samples (p < 0.05). Specifically, the shortest median TTP was observed in prosthesis post-sonication samples. Furthermore, the study found that Gram-positive organisms had a shorter TTP than gram-negative organisms, and specific microorganisms like Staphylococcus aureus and MRSE showed the fastest TTP. The analysis also revealed higher positivity rates in chronic PJIs compared to acute PJIs for sonicated tissue samples.ConclusionsThe study demonstrates that intraoperative direct sonication combined with the BACT/ALERT 3D system can significantly enhance the diagnostic yield of cultures and reduce the TTP for common PJI pathogens. This novel technique not only improves pathogen detection, facilitating the tailoring of antibiotic therapy, but also potentially reduces the risk of contamination associated with sonication. These findings suggest that direct intraoperative sonication could be a valuable addition to the current diagnostic protocols for PJI, contributing to more effective management and treatment of this complex condition. Further research is necessary to explore the clinical significance of TTP and its correlation with patient outcomes in PJI.

Context.— Genomic reports are primarily organized in a narrative and unstructured format with variations in content and format. Regulatory requirements and professional guidelines for genetic test reporting exist but provide little guidance for effective communication of information. Objective.— To assess clinical genomic reporting practices across 5 disciplines within molecular diagnostics, including germline, somatic solid tumors, somatic hematologic malignancies, pharmacogenomics, and prenatal cell-free DNA screening. Design.— Reporting practices were assessed by using a structured review of clinical genomic reports from multiple laboratories in 5 molecular disciplines spanning different practice settings. Report content was reviewed by the presence/absence of from 27 to 44 elements, including 23 elements required by the College of American Pathologists and/or the Clinical Laboratory Improvement Amendments of 1988 (CLIA). If present, the element’s location on the report was recorded. Results.— A total of 69 genomics reports from 31 laboratories were reviewed. Overall, the reports were compliant with regulatory requirements but showed variability in both format and content. Six of 7 required reporting elements (per CLIA, 42 CFR [Code of Federal Regulations] 493.1291) were included in 90% of the reports. However, these elements were often located in different report sections. Only patient demographics were always found in a specific report section (header). Conclusions.— These results show that reports are overall compliant with regulatory requirements, despite some reporting elements being less consistently reported. The lack of consistent presentation of the data elements presents an opportunity to improve the communication of molecular testing results to clinicians and patients.

Abstract Ageing‐related neuromuscular dysfunction is associated with reduced tropomyosin‐related kinase receptor subtype B (TrkB) signalling and accumulation of damaged cytoplasmic aggregates in motor neurons. Autophagy functions to remove these damaged aggregates, and we previously reported increased cervical motor neuron expression of LC3 and p62 in old age. We hypothesized that inhibition of TrkB kinase activity results in an increase in the relative expression of both LC3 and p62 in cervical motor neurons, consistent with impaired progression of autophagy. TrkB F616A mice, which possess a mutation that renders TrkB kinase activity susceptible to rapid inhibition by 1NMPP1, were treated at 6, 18 or 24 months of age with vehicle or 1NMPP1 for 7 days. Immunofluorescence intensity was measured to determine LC3 and p62 expression in choline acetyltransferase‐positive motor neurons in the cervical spinal cord. The effect of inhibiting TrkB kinase activity on progression of autophagy was age dependent. In 6‐month‐old mice, inhibiting TrkB kinase activity increased cervical motor neuron expression of LC3 by 11% ( P < 0.001) and p62 by 8% ( P = 0.019) compared with vehicle treatment. In 18‐ and 24‐month‐old mice, there was no effect of inhibiting TrkB kinase activity on motor neuron LC3 or p62 expression. We provide evidence that inhibition of TrkB signalling impairs progression of autophagy in motor neurons of young mice, similar to the response to ageing. Accordingly, a reduction of TrkB signalling in old age might contribute to neuromuscular dysfunction by impairing progression of autophagy in motor neurons.

Objective: Lateral condyle fractures are the second most common pediatric elbow fracture after supracondylar humeral fractures. Early complications are frequent which can lead to development of long-term problems. Current literature has evaluated short-term outcomes, but few studies have investigated long-term outcomes into adulthood. Our hypothesis is that the majority of pediatric patients with a lateral condyle fracture will have minimal complications and few surgeries as they age. Methods: A population-based database was used to identify patients who sustained a lateral condyle fracture before the age of 18 between 1966 and 2012. Electronic medical records from all treatment centers in the county were reviewed for clinical and radiographic data. Analysis was performed to determine incidence and long term outcomes based on fracture type and treatment. Results: From 1966 to 2012, 227 pediatric lateral condyle fractures were identified. One hundred seventy-seven fractures (78%) had at least 10 year clinical follow up. Incidence was found to be 13.97 per 100,000. We identified 80 (45%) Weiss type 1, 61 (34%) type 2, and 37 (21%) type 3 fractures. The overall complication rate was 17%, of which 47% were identified >10 years from injury. There was no significant difference in complication rates based on fracture type (P = 0.18) or treatment type (P = 0.55). The most common complication was malunion (n = 15), followed by fishtail deformity (n = 4), stiffness (n = 3), lateral epicondylitis (n = 3), nonunion (n = 2), osteoarthritis (n = 2), and tardy ulnar nerve palsy (n = 1). Five patients underwent revision surgery for nonunion, cubitus valgus, malunion with loose bodies, capitellar osteochondral dessicans with malalignment, and ulnar nerve palsy. Conclusions: This population-based study estimated the overall incidence of pediatric lateral condyle fractures to be 14 per 100,000. Displaced fractures had a higher incidence than undisplaced fractures. Complications beyond 10 years are rare, but the need for future revision surgery is possible, therefore, proper patient and family education is necessary at the time of injury. This is the largest study with the longest follow-up for pediatric lateral condyle fractures. Complications were rare but resulted in a 17% complication rate and a 3% reoperation rate at a minimum. Level of Evidence: Level III.

Abstract Introduction The Geriatric Emergency Care Applied Research Network 2.0‐Advancing Dementia Care (GEAR 2.0‐ADC) aims to advance research efforts to improve the emergency care of persons living with dementia (PLWDs). Objective To support this objective, GEAR 2.0‐ADC convened a virtual consensus conference to prioritize emergency care research opportunities for PLWDs inclusive of perspectives of PLWDs to ensure identification of research gaps in response to their experiences and priorities. Inclusion of PLWDs as research partners is increasingly recognized as a best practice, however, approaches to facilitating consensus participation are lacking. Methods Best practices for supporting the engagement of PLWDs in a consensus conference, applied across its three phases (pre‐conference, during the conference, and post‐conference), include: establishing a learning environment focused on research priorities before the event, presenting information in ways that align with participants' learning preferences while accommodating cognitive impairments, and providing multiple opportunities and methods for gathering post‐conference feedback from PLWDs. Results These strategies were identified by PLWDs and care partners (CPs) through semi‐structured interviews, who were involved in the convening process, aimed at exploring ways to enhance facilitation techniques for participants. Conclusion Additionally, these summarized insights aim to encourage the use of community‐engaged approaches in discussions and consensus‐building around research priorities in emergency care, particularly for PLWDs and their CPs.

Background: The microvasculature of the human meniscus has been previously described by Arnoczky and Warren. However, to date, the qualitative and quantitative extra-articular vascular anatomy of the medial meniscus has not been characterized. Purposes: To perform a qualitative and quantitative anatomic study of the extra-articular medial meniscal vasculature and to introduce the novel “medial meniscal artery” (MMA), potentially providing future guidelines for the treatment of meniscal abnormalities. Study Design: Descriptive laboratory study. Methods: A total of 33 unpaired, frozen human cadaveric knees were dissected. The femoral artery was identified and cannulated using an angiocatheter. The arteries were perfused with a red acrylic paint solution, allowing for improved visualization. Artery dimensions and distances were measured using a digital caliper. Perfused specimens were imaged using computed tomography and segmented using 3D reconstruction software to identify vessels and repeat artery measurements digitally. Results: The MMA was consistently identified in all specimens. In 27 (82%) of 33 specimens, the MMA branched directly from the popliteal artery; in 5 (15%), the MMA shared a common trunk with the inferior medial genicular artery; and in 1 specimen (3%), the MMA shared a common branch with the inferior lateral genicular artery. The MMA was easily distinguishable from the superior, inferior, and middle genicular arteries, given its direct course to the medial joint line with terminal branches to the posterior horn of the medial meniscus and deep to the semimembranosus tendon. The MMA exhibited a consistently smaller vessel diameter relative to the genicular arteries. Conclusion: This is the first study to identify and quantitatively describe the MMA in the human knee. The MMA can be identified consistently on gross anatomic dissection in cadaveric donors of varying demographics. Further research is needed to identify and characterize the artery in vivo and to determine the MMA’s role in meniscus preservation surgery. Clinical Relevance: The findings of this study will provide future avenues of research toward understanding medial meniscus vascularization and the genesis of potential degenerative changes when vascularization is poor. This will help to further refine diagnostic and treatment options for meniscus revascularization and compartment preservation. Additionally, this study may help define safe zones in the knee during posterior approaches and expand the base of knowledge for emerging vascular procedures such as genicular artery embolization.

Lung cancer is a leading cause of cancer-related mortality worldwide, characterized by its aggressive nature and poor prognosis. Matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases, play a pivotal role in the progression of lung cancer. They contribute to tumor invasion, metastasis, angiogenesis, and the modulation of the tumor microenvironment by degrading extracellular matrix components and regulating various cellular signaling pathways. Elevated levels of specific MMPs, such as MMP-2, MMP-9, and MMP-14, have been associated with advanced disease stages and reduced survival rates. As such, MMPs have emerged as valuable biomarkers for the diagnosis, prognosis, and prediction of treatment responses in lung cancer. This review aims to provide a comprehensive overview of the current understanding of MMPs in lung cancer, highlighting their diagnostic and prognostic significance, as well as their potential as therapeutic targets. Despite the initial setbacks in developing broad-spectrum MMP inhibitors, recent advancements have spurred interest in more selective inhibitors that minimize off-target effects and enhance therapeutic efficacy. Furthermore, combining MMP-targeted therapies with conventional treatments, such as chemotherapy and immunotherapy, holds promise for improving clinical outcomes. Future research directions include exploring novel MMP inhibitors, understanding the regulatory mechanisms of MMP activity, and integrating MMP biomarkers into personalized medicine approaches. As the field progresses, targeting MMPs may offer new therapeutic avenues and improve the prognosis for lung cancer patients, making this a promising area of investigation.