Faculty Bibliography

PURPOSE/OBJECTIVE:Workers face a notable risk of musculoskeletal injuries when performing squatting tasks. Knee exoskeletons offer a promising solution to mitigate muscle strain through squat assistance. However, existing studies on knee exoskeletons lack a comprehensive study that meets the multifaceted requirements of squatting assistance in terms of portability, efficiency, and muscle strain mitigation. Furthermore, another open research question pertains to the control strategy of squat assistance, which should be adaptable to various postures and cadences for different individuals. In particular, the effect of controlling negative power assistance during the squat-down phase is not studied. METHODS:To fill these two gaps, first, we develop a simple (computationally efficient and implementable in a microcontroller) and generalizable (for different postures, cadences, and individuals) torque controller for portable knee exoskeletons that delivers both negative and positive power. Our portable knee exoskeleton can benefit users by enhancing efficiency (reducing metabolic cost, heart rate, breathing ventilation), mitigating muscle strain (reducing EMG), and reducing perceived exertion (reducing Borg 6-20 scale) during squatting. Second, we study the effect of three levels of negative power assistance during the squat-down phase. RESULTS:This study integrates comprehensive biomechanics and physiology analyses that evaluate our exoskeleton's effectiveness using four objective and two subjective metrics with a group of able-bodied subjects (n = 7). The exoskeleton reduced metabolic cost by 12.8%, heart rate by 13.8%, breathing ventilation by 8.9%, and reduced extensor muscle activity by 39.4-43.2%, flexor muscle activity by 18.9-20.3%, and Borg perceived exertion rate by 1.8 during squatting compare with not wearing the robot. CONCLUSION/CONCLUSIONS:Different from the musculoskeletal model predictions that suggest increasing benefit with a higher level of negative power assistance, we find that the best performances were achieved with a moderate level of negative power assistance, followed by no assistance and then high assistance.

Rates of cognitive decline in Alzheimer's disease (AD) are extremely heterogeneous. Although biomarkers for amyloid-beta (Aβ) and tau proteins, the hallmark AD pathologies, have improved pathology-based diagnosis, they explain only 20-40% of the variance in AD-related cognitive impairment (CI). To discover novel biomarkers of CI in AD, we performed cerebrospinal fluid (CSF) proteomics on 3,397 individuals from six major prospective AD case-control cohorts. Synapse proteins emerged as the strongest correlates of CI, independent of Aβ and tau. Using machine learning, we derived the CSF YWHAG:NPTX2 synapse protein ratio, which explained 27% of the variance in CI beyond CSF pTau₁₈₁:Aβ₄₂, 11% beyond tau positron emission tomography, and 28% beyond CSF neurofilament, growth-associated protein 43 and neurogranin in Aβ⁺ and phosphorylated tau⁺ (A+T₁+) individuals. CSF YWHAG:NPTX2 also increased with normal aging and 20 years before estimated symptom onset in carriers of autosomal dominant AD mutations. Regarding cognitive prognosis, CSF YWHAG:NPTX2 predicted conversion from A+T₁+ cognitively normal to mild cognitive impairment (standard deviation increase hazard ratio = 3.0, P = 7.0 × 10^-4) and A+T₁+ mild cognitive impairment to dementia (standard deviation increase hazard ratio = 2.2, P = 8.2 × 10^-16) over a 15-year follow-up, adjusting for CSF pTau₁₈₁:Aβ₄₂, CSF neurofilament, CSF neurogranin, CSF growth-associated protein 43, age, APOE4 and sex. We also developed a plasma proteomic signature of CI, which we evaluated in 13,401 samples, which partly recapitulated CSF YWHAG:NPTX2. Overall, our findings underscore CSF YWHAG:NPTX2 as a robust prognostic biomarker for cognitive resilience versus AD onset and progression, highlight the potential of plasma proteomics in replacing CSF measurement and further implicate synapse dysfunction as a core driver of AD dementia.

Children presenting comorbid attention-deficit/hyperactivity disorder (ADHD) and depression symptoms have higher risks of later suicidal ideation and attempt. However, it is unclear to what extent this risk stems from individual differences in the genetic predisposition for ADHD and/or depression. We investigated the unique and combined contribution of genetic predisposition to ADHD and depression to suicidal ideation and attempt by early adulthood. Data were from two longitudinal population-based birth cohorts, the Quebec Longitudinal Study of Child Development and the Quebec Newborn Twin Study (total N = 1207). Genetic predisposition for ADHD and depression were measured using polygenic scores. Suicidal ideation and attempt by age 20 years were self-reported via questionnaires. Across the two cohorts, suicidal ideation and attempt were reported by 99 (8.2%) and 75 (6.1%) individuals, respectively. A higher polygenic score for depression was associated with significantly higher risk of suicidal ideation and attempt, while no significant associations were found for ADHD polygenic score. However, we found an interaction between polygenic scores for depression and ADHD in the association with suicide attempt (P = 0.012), but not suicidal ideation (P = 0.897). The association between polygenic score for depression and suicide attempt was significantly stronger for individuals with a higher polygenic score for ADHD. Individuals scoring ≥ 1-SD above the mean for both polygenic scores were at increased risk for suicide attempt compared to individuals with lower scores (OR 4.03, CI 1.64-9.90), as well as compared to individuals scoring ≥ 1-SD above the mean in only depression (OR 2.92, CI 1.01-8.50) or only ADHD (OR 4.88, CI 1.56-15.26) polygenic scores. Our findings suggest that genetic predisposition for ADHD and depression contributes to increase the risk of suicide attempt in a multiplicative, rather that additive, way. Our results contribute to our understanding of the etiology of suicide risk and may inform screening and risk stratification.

Pregnancy alters immune responses and clinical manifestations of COVID-19, but its impact on Long COVID remains uncertain. This study investigated Long COVID risk in individuals with SARS-CoV-2 infection during pregnancy compared to reproductive-age females infected outside of pregnancy. A retrospective analysis of two U.S. databases, the National Patient-Centered Clinical Research Network (PCORnet) and the National COVID Cohort Collaborative (N3C), identified 29,975 pregnant individuals (aged 18-50) with SARS-CoV-2 infection in pregnancy from PCORnet and 42,176 from N3C between March 2020 and June 2023. At 180 days after infection, estimated Long COVID risks for those infected during pregnancy were 16.47 per 100 persons (95% CI, 16.00-16.95) in PCORnet using the PCORnet computational phenotype (CP) model and 4.37 per 100 persons (95% CI, 4.18-4.57) in N3C using the N3C CP model. Compared to matched non-pregnant individuals, the adjusted hazard ratios for Long COVID were 0.86 (95% CI, 0.83-0.90) in PCORnet and 0.70 (95% CI, 0.66-0.74) in N3C. The observed risk factors for Long COVID included Black race/ethnicity, advanced maternal age, first- and second-trimester infection, obesity, and comorbid conditions. While the findings suggest a high incidence of Long COVID among pregnant individuals, their risk was lower than that of matched non-pregnant females.

INTRODUCTION/UNASSIGNED:There has been an emergence of evidence in the area of frozen shoulder (FS) within the past decade related to risk factors, etiology, diagnosis, and management. It has become increasingly challenging for clinicians and researchers to stay up to date in these areas, particularly with the clinical practice guidelines that are available being few and outdated. To this end, the aim of this study was to produce an international consensus on the risk factors, etiology, diagnosis and management for individuals with FS. METHODS/UNASSIGNED:During phase one a steering committee was formed in order to identify experts in the area of FS, examine the current evidence related to FS and identify key areas lacking consensus. Phase two consisted of inviting experts to participate in a three-round survey with a priori consensus level set at 80%. Descriptive statistics were utilized to determine the characteristics of the expert panel, response rate, and level of consensus. RESULTS/UNASSIGNED:A total of 14 international experts responded to all three rounds of the Delphi survey with 100% response rate following round one. Consensus was reached for 101 items (57 in the first round, 37 in the second round and 7 in the third and final round). Specific to key topic areas, the following number of items reached consensus; etiology 9 items (diabetes mellitus, trauma, shoulder arthroscopy, thyroid disease, prolonged immobilization, adrenocorticotropic hormone deficiency, metabolic synderome, connective tissue disorders, and hyperlipidemia), risk factors 40 items (including biophysical factors for developing FS and biophysical and psychosocial factors influencing the Management and course of outcomes related to FS), diagnosis 19 items (4 confounding the diagnosis and 15 signs and symptoms associated with FS), Management 33 items overall and categorized into effectiveness for early and later stages of FS). CONCLUSION/UNASSIGNED:The results of this international Delphi study help to provide a consensus on key elements to consider in clinical practice related to etiology, risk factors, diagnosis, and management for those with FS.

Spetzler-Martin Grade IV arteriovenous malformations (AVMs) are challenging due to high risks associated with both treatment and natural progression. This study compares the outcomes of microsurgical resection and stereotactic radiosurgery (SRS) in high-grade AVMs, analyzing obliteration rates, complications, and functional outcomes. A retrospective cohort of 96 patients treated with either microsurgical resection (33 patients) or SRS (63 patients) was analyzed. Propensity-score matching was employed to account for baseline variables such as AVM size (cm), preoperative embolization and rupture status. Primary endpoints included AVM obliteration, complication rates, and modified Rankin Scale (mRS) scores. After matching, 31 patients per group were analyzed. Microsurgical resection achieved significantly higher obliteration rates (87.1%) compared to SRS (32.3%, p < 0.001). In the matched SRS cohort (n = 31), the actuarial obliteration rates were 11% (95% CI: 0-22%) at 1 year, 17% (95% CI: 0-31%) at 3 years, and 43% (95% CI: 13-63%) at 5 years post-treatment. Complication rates were similar (32.3% resection, 38.7% SRS, p = 0.6). Functional outcomes in terms of improvement in modified Rankin Scale (mRS) scores were observed in 50.0% of microsurgery patients and 41.4% of SRS patients. However, the absolute number of patients improving was similar (13 vs. 12), and the microsurgery group had more cases of worsening mRS scores compared to the SRS group (4 vs. 2). The difference was not statistically significant (p = 0.4). Microsurgical resection offers superior obliteration rates for high-grade AVMs with comparable complication risks to SRS. SRS remains a valuable alternative for select patients, particularly those ineligible for resection. Future research should focus on optimizing multimodal treatment approaches. Clinical trial number Not applicable.

Background/PurposeAPS ACTION Registry was created to study the natural course of antiphospholipid syndrome (APS) over 10 years in persistently antiphospholipid antibody (aPL) positive patients with or without systemic autoimmune rheumatic diseases (SARDs). Our primary objective was to compare the characteristics of aPL-positive patients with or without thrombocytopenia (TP) and/or autoimmune hemolytic anemia (AIHA).MethodsThe registry inclusion criteria are positive aPL based on the Revised Sapporo APS Classification Criteria, tested at least twice within 1 year prior to enrollment. For the primary comparison of demographic, clinical, and serologic characteristics in this retrospective study, we divided patients into two groups: TP/AIHA ever and never. Thrombocytopenia was defined as a platelet count of <100,000 x 10⁹/L tested twice at least 12 weeks apart, and AIHA was defined as anemia with hemolysis and a positive direct antiglobulin test (DAT). For the secondary analysis, we compared patients with TP versus AIHA, and the immunosuppressive use stratified by systemic lupus erythematosus (SLE) classification.ResultsAs of April 2022, of 1,039 patients (primary aPL/APS: 618 [59%]; SLE classification: 334 [31%]) included in the registry, 228 (22%) had baseline (historical or current) TP and/or AIHA (TP only: 176 [17%]; AIHA only: 35 [3%], and both: 17 [2%]). Thrombocytopenia and/or AIHA was significantly associated with Asian race, SLE classification, cardiac valve disease, catastrophic/microvascular APS, triple aPL (lupus anticoagulant, anticardiolipin antibody, and anti-β₂-glycoprotein-I antibody) positivity, and SLE-related serologic and inflammatory markers. When 101/618 (16%) primary aPL/APS patients and 101/334 (34%) SLE patients with TP and/or AIHA were compared, azathioprine and mycophenolate mofetil were more commonly reported in lupus patients, however corticosteroid, intravenous immunoglobulin, and rituximab use were similar between groups.ConclusionIn our large multi-center international cohort of persistently aPL-positive patients, approximately one-fifth had active or historical TP and/or AIHA at registry entry; half of these patients had additional SLE. Cardiac valve disease, catastrophic/microvascular APS, and triple aPL-positivity were aPL-related clinical and laboratory manifestations associated with TP and/or AIHA, suggesting a more severe APS clinical phenotype in aPL-patients with TP and/or AIHA.

PURPOSE/OBJECTIVE:Robotic-assisted spine surgery (RASS) has increased in prevalence over recent years, and while much work has been done to analyze differences in outcomes when compared to the freehand technique, little has been done to characterize the potential pitfalls associated with using robotics. This study's goal was to leverage expert opinion to develop a classification system of potential sources of error that may be encountered when using robotics in spine surgery. This not only provides practitioners, particularly those in the early stages of robotic adoption, with insight into possible sources of error but also provides the community at large with a more standardized language through which to communicate. METHODS:The Delphi method, which is a validated system of developing consensus, was utilized. The method employed an iterative presentation of classification categories that were then edited, removed, or elaborated upon during several rounds of discussion. Voting took place to accept or reject the individual classification categories with consensus defined as ≥ 80% agreement. RESULTS:After a three-round iterative survey and video conference Delphi process, followed by an in-person meeting at the Safety in Spine Surgery Summit, consensus was achieved on a classification system that includes four key types of potential sources of error in RASS as well as a list of the most commonly identified sources within each category. Initial sources of error that were considered included: cannula skidding/skive, penetration, screw misplacement, registration failure, and frame shift. After completion of the Delphi process, the final classification included four major types of pitfalls including: Reference/Navigation, Patient Factors, Technique, and Equipment Factors (available at https://safetyinspinesurgery.com/ ). CONCLUSION/CONCLUSIONS:This work provides expert insight into potential sources of error in the setting of robotic spine surgery. The working group established four discrete categories while providing a standardized language to unify communication.

This study investigated the potential of combining multiple MR parameters to enhance the characterization of myelin in the mouse brain. We collected ex vivo multiparametric MR data at 7 T from control and Gli1^-/- mice; the latter exhibit enhanced myelination at Postnatal Day 10 (P10) in the corpus callosum and cortex. The MR data included relaxivity, magnetization transfer, and diffusion measurements, each targeting distinct myelin properties. This analysis was followed by and compared to myelin basic protein (MBP) staining of the same samples. Although a majority of the MR parameters included in this study showed significant differences in the corpus callosum between the control and Gli1^-/- mice, only T₂, T₁/T₂, and radial diffusivity (RD) demonstrated a significant correlation with MBP values. Based on data from the corpus callosum, partial least square regression suggested that combining T₂, T₁/T₂, and inhomogeneous magnetization transfer ratio could explain approximately 80% of the variance in the MBP values. Myelin predictions based on these three parameters yielded stronger correlations with the MBP values in the P10 mouse brain corpus callosum than any single MR parameter. In the motor cortex, combining T₂, T₁/T₂, and radial kurtosis could explain over 90% of the variance in the MBP values at P10. This study demonstrates the utility of multiparametric MRI in improving the detection of myelin changes in the mouse brain.

Therapeutic anticoagulation is essential to prevent and treat venous and arterial thromboembolism. The available agents target coagulation factors involved in thrombus formation but are associated with an increased risk of bleeding. Factor XI plays a minor role in haemostasis but contributes substantially to thrombus expansion, making it an attractive target to mitigate bleeding while maintaining antithrombotic efficacy. Various novel inhibitors, including antisense oligonucleotides, monoclonal antibodies and small molecules, have been developed. Phase II trials in orthopaedic surgery showed dose-dependent reductions in venous thromboembolism without significantly increasing bleeding compared with enoxaparin. In the first phase III trial of a small-molecule inhibitor of activated factor XI in patients with atrial fibrillation, asundexian was associated with a reduction in bleeding but also a higher risk of stroke, compared with apixaban. Factor XI inhibitors appear safe and hold promise for secondary prevention in myocardial infarction and ischaemic stroke, with ongoing phase III trials assessing their broader efficacy and safety. This Review discusses the rationale, pharmacology, evidence and future directions of factor XI inhibitors across various clinical settings.