Roxana Beladi

Purpose: Sacroiliac joint (SIJ) dysfunction is a frequently overlooked source of persistent low back pain after lower lumbar surgery. The SIJ is an adjacent joint to the lower lumbar spine and can thus be subject to adjacent segment disease (ASD) after lower lumbar fusion. Spinopelvic imbalance can potentially predispose a patient to ASD in the SIJ, causing SIJ dysfunction. However, the impact of spinopelvic imbalance following minimally invasive (MIS) lower lumbar fusion on SIJ dysfunction and, thus, subsequent fusion remains inconclusive. We sought to determine whether spinopelvic imbalance after lower lumbar fusion predisposes patients to subsequent MIS SIJ fusion (SIJF). Methods: We retrospectively reviewed consecutive elective lower lumbar fusion patients (ending levels L5/S1) to select our cases and controls in a 1:1 match. We included patients who underwent MIS lower lumbar fusion from 10/2005 to 05/2021 at a single institution with an ending level including L5 or S1, a starting level at or below T12, and had at least two years of follow-up. We excluded patients with inadequate or absent postoperative X-rays, those who underwent lumbar fusion for trauma or infection, pelvic fixation, revision lumbar surgery, and prior SIJF. We performed a pilot study to determine the sample size as 190 per group. Confounders, including the number of pregnancies, were collected. Consistent with prior literature, we defined spinopelvic imbalance as a PI-LL mismatch of <-10° or > 10° [1–5]. We compared the groups using univariate analysis. The odds of developing SIJF related to PI-LL mismatch were calculated using Chi-Square. We performed multivariable analysis modeling on SIJF to adjust for covariates. Results: We included 488 patients (203 SIJF vs. 285 control). Between groups, the SIJF patients were significantly younger (52.55 ± 12.81 vs. 55.84 ± 14.71; P = 0.005), had a higher proportion of females (67.5% vs. 55.1%; P = 0.006), and increased levels fused (1.78 ± 0.97 vs. 1.38 ± 0.64; P < 0.001). Interestingly, number of pregnancies was not significantly different (P = 0.791). PI-LL mismatch demonstrated a 3.54 increased odds of requiring subsequent SIJF (p < 0.001). Multiple logistic regression adjusting for age at lumbar fusion, female sex, and number of levels demonstrated that PI-LL mismatch (OR 1.10; 95% CI 1.06–1.15; p < 0.001) and operative levels (OR 1.84; 95% CI 1.42–2.39; p < 0.001) were independently associated with significantly increased odds of requiring SIJF, while age (OR 0.98; 95% CI 0.96–0.99; p < 0.001) and female sex (OR 0.54; 95% CI 0.36–0.81; p = 0.003) were associated with significantly decreased odds of requiring SIJF. Conclusion: PI-LL mismatch following MIS lower lumbar fusion was independently associated with significant odds of requiring subsequent SIJF. Optimizing spinopelvic imbalance can decrease the odds of requiring subsequent SIJF after MIS lower lumbar surgery. Given the biases associated with the retrospective and observational nature of our study design, further prospective studies are needed.

The urokinase-type plasminogen activator receptor (uPAR) is a unique protease binding receptor, now recognized as a key regulator of inflammation. Initially, uPA/uPAR was considered thrombolytic (clot-dissolving); however, recent studies have demonstrated its predominant immunomodulatory functions in inflammation and cancer. The uPA/uPAR complex has a multifaceted central role in both normal physiological and also pathological responses. uPAR is expressed as a glycophosphatidylinositol (GPI)-linked receptor interacting with vitronectin, integrins, G protein-coupled receptors, and growth factor receptors within a large lipid raft. Through protein-to-protein interactions, cell surface uPAR modulates intracellular signaling, altering cellular adhesion and migration. The uPA/uPAR also modifies extracellular activity, activating plasminogen to form plasmin, which breaks down fibrin, dissolving clots and activating matrix metalloproteinases that lyse connective tissue, allowing immune and cancer cell invasion and releasing growth factors. uPAR is now recognized as a biomarker for inflammatory diseases and cancer; uPAR and soluble uPAR fragments (suPAR) are increased in viral sepsis (COVID-19), inflammatory bowel disease, and metastasis. Here, we provide a comprehensive overview of the structure, function, and current studies examining uPAR and suPAR as diagnostic markers and therapeutic targets. Understanding uPAR is central to developing diagnostic markers and the ongoing development of antibody, small-molecule, nanogel, and virus-derived immune-modulating treatments that target uPAR.

Serine protease inhibitors, SERPINS, are a highly conserved family of proteins that regulate serine proteases in the central coagulation and immune pathways, representing 2–10% of circulating proteins in the blood. Serine proteases form cascades of sequentially activated enzymes that direct thrombosis (clot formation) and thrombolysis (clot dissolution), complement activation in immune responses and also programmed cell death (apoptosis). Virus-derived serpins have co-evolved with mammalian proteases and serpins, developing into highly effective inhibitors of mammalian proteolytic pathways. Through interacting with extracellular and intracellular serine and cysteine proteases, viral serpins provide a new class of highly active virus-derived coagulation-, immune-, and apoptosis-modulating drug candidates. Viral serpins have unique characteristics: (1) function at micrograms per kilogram doses; (2) selectivity in targeting sites of protease activation; (3) minimal side effects at active concentrations; and (4) the demonstrated capacity to be modified, or fine-tuned, for altered protease targeting. To date, the virus-derived serpin class of biologics has proven effective in a wide range of animal models and in one clinical trial in patients with unstable coronary disease. Here, we outline the known viral serpins and review prior studies with viral serpins, considering their potential for application as new sources for immune-, coagulation-, and apoptosis-modulating therapeutics.