Forty-Six Years of Technological Innovation in Musculoskeletal Medicine: An Analysis of a Patent Database (1973 to 2018).

BACKGROUND: Technological innovation in orthopaedics is key to advancing patient care. As emerging technologies near maturity, clinicians must be able to objectively assess where and when these technologies can be implemented. Patent databases are an underappreciated resource for quantifying innovation, especially within orthopaedic surgery. This study used a patent database to assess patent activity and relative growth of technologies in musculoskeletal medicine and orthopaedics over a period of 46 years. METHODS: A total of 121,471 patent records were indexed from Lens.org , a patent database. These patents were grouped into subspecialty clusters and technology clusters using patent codes. Five-year (2014 to 2018), 10-year (2009 to 2018), and 30-year (1989 to 2018) compound annual growth rates were calculated and compared for each cluster. RESULTS: Annual patent activity increased from one patent in 1973 to 4,866 patents in 2018. Of the eight subspecialty clusters, the largest number of patents were related to 'Inflammation' (n = 63,128; 40.57%). The 'Elbow', 'Shoulder', and 'Knee' clusters experienced increased annual patent activity since 2000. Of the 12 technological clusters, the largest number of patents were related to 'Drugs' (n = 55,324; 39.75%). The 'Custom/patient-specific instrumentation, 'Computer Modeling', 'Robotics', and 'Navigation' clusters saw growth in the average annual patent activity since 2000. DISCUSSION: Innovation, as measured by patent activity in musculoskeletal medicine and orthopaedics, has seen notable growth since 1973. The 'Robotics' cluster seems poised to experience exponential growth in industry investment and technological developments over the next 5 to 10 years. The 'Diagnostics', 'Computer Modeling', 'Navigation', and 'Design and Manufacturing' clusters demonstrate potential for exponential growth in industry investment and technological developments within the next 10 to 20 years.

Identifying Trends and Quantifying Growth for Technological Innovation in Knee Arthroplasty: An Analysis of a Patent Database (1990 to 2020).

Technological innovation is the key for surgical progress in knee arthroplasty and improvement in patient outcomes. Exploring patented technologies can help elucidate trends and growth for numerous innovative technologies. However, patent databases, which contain millions of patents, remain underused in arthroplasty research. Therefore, the present study aimed to: (1) quantify patent activity; (2) group patents related to similar technologies into well-defined clusters; and (3) compare growth between technologies in the field of knee arthroplasty over a 30-year period. An open-source international patent database was queried from January 1990 to January 2020 for all patents related to knee arthroplasty A search strategy identified 70,154 patents, of which 24,425 were unique and included analysis. Patents were grouped into 14 independent technology clusters using Cooperative Patent Classification (CPC) codes. Patent activity was normalized via a validated formula adjusting for exponential growth. Compound annual growth rates (CAGR) were calculated (5-year, 10-year, and 30-year CAGR) and compared for each cluster. Overall yearly patent activity increased by 2,023%, from 104 patents in 1990 to 2,208 patents in 2020. The largest technology clusters were "drugs" (n = 5,347; 23.8%), "components" (n = 4,343; 19.0%), "instruments" (n = 3,130; 13.7%), and "materials" (n = 2,378; 10.4%). The fastest growing technologies with their 5-year CAGR were: "user interfaces for surgical systems" (58.1%); "robotics" (28.6%); "modularity" (21.1%); "navigation" (15.7%); and "computer modeling" (12.5%). Since 1990, overall patent growth rate has been greatest for "computer modeling" (8.4%), "robotics" (8.0%), "navigation" (7.9%), and "patient-specific instrumentation" (6.4%). Most patents in knee arthroplasty for the last 30 years have focused on drugs, components, instruments, and materials. Recent exponential growth was mainly observed for user interfaces for surgical systems, robotics, modularity, navigation, and computer-assisted technologies. Innovation theory would suggest that these rapidly growing technologies are experiencing high innovation output, increased resource investments, growing adoption by providers, and significant clinical impact. Periodic monitoring of technological innovation via patent databases can be useful to establish trends and future directions in the field of knee arthroplasty.

BET Inhibitors Synergize with Carfilzomib to Induce Cell Death in Cancer Cells via Impairing Nrf1 Transcriptional Activity and Exacerbating the Unfolded Protein Response.

Currently, proteasome inhibitors bortezomib, carfilzomib, and ixazomib are successfully used in clinics to treat multiple myeloma. However, these agents show limited efficacy against solid tumors. Identification of drugs that can potentiate the action of proteasome inhibitors could help expand the use of this therapeutic modality to solid tumors. Here, we found that bromodomain extra-terminal (BET) family protein inhibitors such as JQ1, I-BET762, and I-BET151 synergize with carfilzomib in multiple solid tumor cell lines. Mechanistically, BET inhibitors attenuated the ability of the transcription factor Nrf1 to induce proteasome genes in response to proteasome inhibition, thus, impeding the bounce-back response of proteasome activity, a critical pathway by which cells cope with proteotoxic stress. Moreover, we found that treatment with BET inhibitors or depletion of Nrf1 exacerbated the unfolded protein response (UPR), signaling that was initiated by proteasome inhibition. Taken together, our work provides a mechanistic explanation behind the synergy between proteasome and BET inhibitors in cancer cell lines and could prompt future preclinical and clinical studies aimed at further investigating this combination.

Microcalcifications in stone-obstructed human submandibular gland are associated with apoptosis and cell proliferation.

OBJECTIVE: Human submandibular gland (SMG) stones are associated with inflammation, fibrosis and microcalcifications in the surrounding tissues. However, there is little information about the accompanying cell injury-repair process, apoptosis, and cell proliferation. The purpose of this study was to investigate such an association and its clinical significance. DESIGN OF STUDY: Mid-gland paraffin sections of human SMGs ("stone glands") and normal SMGs ("non-stone glands") were subjected to stains for general histology (hematoxylin and eosin), fibrosis (Masson's trichrome), and calcification (alizarin red) and to immunohistochemistry for proliferative activity (Ki-67), and apoptosis (Caspase-3). Tissues were assessed for areas of inflammation, calcium deposition, and fibrosis, and for cycling and apoptotic cells. RESULTS: Acini were atrophic and proportionately fewer in lobules with fibrosis in stone glands. Additionally, stone glands had intraluminal calcifications (microliths) in scattered excretory and striated ducts and blood vessel walls. Areas of inflammation and fibrosis were small and uncommon, and calcifications were not seen in non-stone glands. Proliferating and apoptotic cells were common in the main duct of stone glands where ciliated and mucous cell hyperplasia and stratified squamous metaplasia had occurred, uncommon in the main duct of non-stone glands, and uncommon in all other parenchymal elements of both stone and non-stone glands. CONCLUSION: Stone obstruction in the main excretory ducts of SMG resulted in progressive depletion of acini from proximal to distal lobules via calcification, inflammation, fibrosis, and parenchymal cell atrophy, apoptosis and proliferation. Interlobular duct microliths contributed to this depletion by further provoking intralobular inflammation, fibrosis, and acinar atrophy.