Virtual Clinical Trials - Implications of Computer Simulations and Artificial Intelligence for Musculoskeletal Research.

ABSTRACT: In silico clinical trials, particularly when augmented with artificial intelligence methods, represent an innovative approach with much to offer, particularly in the musculoskeletal field. They are a cost-effective, efficient, and ethical means of evaluating treatments and interventions by supplementing and/or augmenting traditional randomized controlled trials (RCTs). While they are not a panacea and should not replace traditional RCTs, their integration into the research process promises to accelerate medical advancements and improve patient outcomes. To accomplish this, a multidisciplinary approach is needed, and collaboration is instrumental. With advances in computing and analytical prowess, and by adhering to the tenets of team science, realization of such a novel integrative approach toward clinical trials may not be far from providing far-reaching contributions to medical research. As such, by harnessing the power of in silico clinical trials, investigators can potentially unlock new possibilities in treatment and intervention for ultimately improving patient care and outcomes.

Impact of the COVID-19 pandemic on the productivity and career prospects of musculoskeletal researchers.

Academic researchers faced a multitude of challenges posed by the COVID-19 pandemic, including widespread shelter-in-place orders, workplace closures, and cessation of in-person meetings and laboratory activities. The extent to which these challenges impacted musculoskeletal researchers, specifically, is unknown. We developed an anonymous web-based survey to determine the pandemic's impact on research productivity and career prospects among musculoskeletal research trainees and faculty. There were 116 musculoskeletal (MSK) researchers with varying demographic backgrounds who completed the survey. Of respondents, 48.3% (n = 56) believed that musculoskeletal funding opportunities decreased because of COVID-19, with faculty members more likely to hold this belief compared to nonfaculty researchers (p = 0.008). Amongst MSK researchers, 88.8% (n = 103) reported research activity was limited by COVID-19, and 92.2% (n = 107) of researchers reported their research was not able to be refocused on COVID-19-related topics, with basic science researchers less likely to be able to refocus their research compared to clinical researchers (p = 0.030). Additionally, 47.4% (n = 55) reported a decrease in manuscript submissions since the onset of the pandemic. Amongst 51 trainee researchers, 62.8% (n = 32) reported a decrease in job satisfaction directly attributable to the COVID-19 pandemic. In summary, study findings indicated that MSK researchers struggled to overcome challenges imposed by the pandemic, reporting declines in funding opportunities, research productivity, and manuscript submission. Trainee researchers experienced significant disruptions to critical research activities and worsening job satisfaction. Our findings motivate future efforts to support trainees in developing their careers and target the recovery of MSK research from the pandemic stall.

Discovery of circulating blood biomarkers in patients with and without Modic changes of the lumbar spine: a preliminary analysis.

PURPOSE: The following study aimed to determine the existence of blood biomarkers in symptomatic patients with or without lumbar Modic changes (MC). METHODS: A cross-sectional sub-analyses of a prospective cohort was performed. Fasting blood samples were collected from patients with and without lumbar MC who had undergone spinal fusion or microdiscectomy. An 80-plex panel and CCL5/RANTES were used to assess preoperative plasma cytokine concentrations. Patient demographics and imaging phenotypes were also assessed. RESULTS: Thirty-one subjects were analysed (n = 18 no MC; n = 13 MC). No significant differences were found in age, sex, body mass index, smoking and alcohol history, and surgical procedure (i.e. fusion, decompression) between the two groups (p > 0.05). Several statistically significant blood biomarkers in MC patients were identified, including elevated levels of C-C Motif Chemokine Ligand 5 (CCL5, p = 0.0006), while Macrophage Migration Inhibitory Factor (MIF) was significantly lower (p = 0.009). Additionally, C-X-C Motif Chemokine Ligand 5 (CXCL5, p = 0.052), Pentraxin 3 (PTX3, p = 0.06) and Galectin-3 (Gal-3, p = 0.07) showed potential relevance. Moreover, MC patients exhibited significantly higher levels of disc degeneration (p = 0.0001) and displacement severity (p = 0.020). Based on multivariate analyses and controlling for disc degeneration/displacement, CCL5 (OR 1.02; 95% CI 1.002-1.033; p = 0.028) and MIF (OR 0.60; 95% CI 0.382-0.951; p = 0.030) were independently associated with MC patients. CONCLUSION: This "proof-of-concept" study is the first to identify specific and significantly circulating blood biomarkers associated with symptomatic patients with lumbar MC, independent of disc alterations of degeneration and/or bulges/herniations. Specifically, differences in CCL5 and MIF protein levels were significantly noted in MC patients compared to those without MC.

How Does Resorption Differ Among Single-Level and Multilevel Lumbar Disc Herniations? A Prospective Multi-Imaging and Clinical Phenotype Study.

STUDY DESIGN: Prospective, case series. OBJECTIVE: To identify and characterize any differences in specific patient factors, MRI findings, features of spontaneous disc resorption, and outcomes between patients with single-level and multilevel LDH. BACKGROUND: Lumbar disc herniation (LDH) is one of the most common spinal pathologies worldwide. Though many cases of LDH resolve by spontaneous resorption, the mechanism underlying this "self-healing" phenomenon remains poorly understood, particularly in the context of multilevel herniations. METHODS: A one-year prospective study was conducted of patients presenting with acute symptomatic LDH between 2017 and 2019. Baseline demographics, herniation characteristics, and MRI phenotypes were recorded before treatment, which consisted of gabapentin, acupuncture, and the avoidance of inflammatory-modulating medications. MRIs were performed approximately every three months after the initial evaluation to determine any differences between patients with single-level and multilevel LDH. RESULTS: Ninety patients were included, 17 demonstrated multilevel LDH. Body mass index was higher among patients with multilevel LDH ( P <0.001). Patients with multilevel LDH were more likely to exhibit L3/L4 inferior endplate defects ( P =0.001), L4/L5 superior endplate defects ( P =0.012), and L4/L5 inferior endplate defects ( P =0.020) on MRI. No other differences in MRI phenotypes ( e.g. Modic changes, osteophytes, etc .) existed between groups. Resorption rate and time to resolution did not differ between those with single-level and multilevel LDH. CONCLUSIONS: Resorption rates were similar between single-level and multilevel LDH at various time points throughout one prospective assessment, providing insights that disc healing may have unique programmed signatures. Compared with those with single-level LDH, patients with multilevel herniations were more likely to have a higher BMI, lesser initial axial and sagittal disc measurements, and endplate defects at specific lumbar levels. In addition, our findings support the use of conservative management in patients with LDH, regardless of the number of levels affected. LEVEL OF EVIDENCE: Level 3.

The efficacy and safety of oral antibiotic treatment in patients with chronic low back pain and Modic changes: A systematic review and meta-analysis.

Background: This systematic review and meta-analysis aimed to summarize evidence regarding the effectiveness and safety of oral antibiotic intervention for chronic low back pain (CLBP) patients with/without type-1 Modic changes (MC1). Methods: AMED, CINAHL, Cochrane Library, Embase, and Medline were searched from inception to March 3, 2023. Randomized controlled trials (RCTs) or non-RCTs that investigated the effectiveness or safety of oral antibiotics in treating CLBP patients were eligible for inclusion. Two independent reviewers screened abstracts, full-text articles, and extracted data. The methodological quality of each included article were evaluated by RoB2 and NIH quality assessment tools. The quality of evidence was appraised by GRADE. Meta-analyses were performed, where applicable. A subgroup analysis was conducted to evaluate the RCTs and case series separately, and to evaluate the effect of removing a low-quality RCT. Results: Three RCTs and four case series were included. All Amoxicillin-clavulanate/Amoxicillin treatments lasted for approximately 3 months. Moderate- and low-quality evidence suggested that antibiotic was significantly better than placebo in improving disability and quality of life in CLBP patients with MC1 at 12-month follow-up, respectively. Low-quality evidence from meta-analyses of RCTs showed that oral antibiotic was significantly better than placebo in improving pain and disability in CLBP patients with MC1 immediately post-treatment. Very low-quality evidence from the case series suggested that oral Amoxicillin-clavulanate significantly improved LBP/leg pain, and LBP-related disability. Conversely, low-quality evidence found that oral Amoxicillin alone was not significantly better than placebo in improving global perceived health in patients with CLBP at the 12-month follow-up. Additionally, oral antibiotic users had significantly more adverse effects than placebo users. Conclusions: Although oral antibiotics were statistically superior to placebo in reducing LBP-related disability in patients with CLBP and concomitant MC1, its clinical significance remains uncertain. Future large-scale high-quality RCTs are warranted to validate the effectiveness of antibiotics in individuals with CLBP.

The impact of novel inflammation-preserving treatment towards lumbar disc herniation resorption in symptomatic patients: a prospective, multi-imaging and clinical outcomes study.

PURPOSE: We performed a prospective one-year multi-imaging study to assess the clinical outcomes and rate of disc resorption in acute lumbar disc herniation (LDH) patients undergoing inflammation-preserving treatment (i.e. no NSAIDS, steroids). METHODS: All patients received gabapentin to relieve leg pain, 12 sessions of acupuncture. Repeat MRI was performed, every 3 months, after 12 sessions of treatment continued for those without 40% reduction in herniated disc sagittal area. Disc herniations sizes were measured on sagittal T2W MRI sequences, pre-treatment and at post-treatment intervals. Patients were stratified to fast, medium, slow, and prolonged recovery groups in relation to symptom resolution and disc resorption. RESULTS: Ninety patients (51% females; mean age: 48.6 years) were assessed. Mean size of disc herniation was 119.54 ± 54.34 mm2, and the mean VAS-Leg score was 6.12 ± 1.13 at initial presentation. A total of 19 patients (21.1%) improved at the time of the repeat MRI (i.e. within first 3 months post-treatment). 100% of all patient had LDH resorption within one year (mean: 4.4. months). There was no significant difference at baseline LDH between fast, medium, slow, and prolonged resorption groups. Initial LDH size was weakly associated with degree of leg pain at baseline and initial gabapentin levels. Surgery was avoided in all cases. CONCLUSION: This is the first study to note inflammation-preserving treatment, without conventional anti-inflammatory and steroid medications, as safe and effective for patients with an acute LDH. Rate of disc resorption (100%) was higher than comparative recent meta-analysis findings (66.7%) and no patient underwent surgery.