Showing papers by "Rush University Medical Center published in 2022"

Molecular signaling in temporomandibular joint osteoarthritis

Abstract: Objective Temporomandibular joint (TMJ) osteoarthritis (OA) is a type of TMJ disorders with clinical symptoms of pain, movement limitation, cartilage degeneration and joint dysfunction. This review article is aiming to summarize recent findings on signaling pathways involved in TMJ OA development and progression. Methods Most recent findings in TMJ OA studies have been reviewed and cited. Results TMJ OA is caused by inflammation, abnormal mechanical loading and genetic abnormalities. The molecular mechanisms related to TMJ OA have been determined using different genetic mouse models. Recent studies demonstrated that several signaling pathways are involved in TMJ OA pathology, including Wnt/β-catenin, TGF-β and BMP, Indian Hedgehog, FGF, NF-κB, and Notch pathways, which are summarized in this review article. Alterations of these signaling pathways lead to the pathological changes in TMJ tissues, affecting cartilage matrix degradation, catabolic metabolism and chondrocyte apoptosis. Conclusion Multiple signaling pathways were involved in the pathological process of TMJ OA. New therapeutic strategies, such as stem cell application, gene editing and other techniques may be utilized for TMJ OA treatment. The translational potential of this article TMJ OA is a most important subtype of TMJ disorders and may lead to substantial joint pain, dysfunction, dental malocclusion, and reduced health-related quality of life. This review article summarized current findings of signaling pathways involved in TMJ OA, including Wnt/β-catenin, TGF-β and BMP, Indian Hedgehog, FGF, NF-κB, and Notch pathways, to better understand the pathological mechanisms of TMJ OA and define the molecular targets for TMJ OA treatment.

Kindlin-2 deletion in osteoprogenitors causes severe chondrodysplasia and low-turnover osteopenia in mice

Abstract: Background Our recent studies demonstrate that the focal adhesion protein Kindlin-2 exerts crucial functions in the mesenchymal stem cells, mature osteoblasts and osteocytes in control of early skeletal development and bone homeostasis in mice. However, whether Kindlin-2 plays a role in osteoprogenitors remains unclear. Materials and methods Mice lacking Kindlin-2 expression in osterix (Osx)-expressing cells (i.e., osteoprogenitors) were generated. Micro-computerized tomography (μCT) analyses, histology, bone histomorphometry and immunohistochemistry were performed to determine the effects of Kindlin-2 deletion on skeletal development and bone mass accrual and homeostasis. Bone marrow stromal cells (BMSCs) from mutant mice (Kindlin-2fl/fl; OsxCre) and control littermates were isolated and determined for their osteoblastic differentiation capacity. Results Kindlin-2 was highly expressed in osteoprogenitors during endochondral ossification. Deleting Kindlin-2 expression in osteoprogenitors impaired both intramembranous and endochondral ossifications. Mutant mice displayed multiple severe skeletal abnormalities, including unmineralized fontanel, limb shortening and growth retardation. Deletion of Kindlin-2 in osteoprogenitors impaired the growth plate development and largely delayed formation of the secondary ossification center in the long bones. Furthermore, adult mutant mice displayed a severe low-turnover osteopenia with a dramatic decrease in bone formation which exceeded that in bone resorption. Primary BMSCs isolated from mutant mice exhibited decreased osteoblastic differentiation capacity. Conclusions Our study demonstrates an essential role of Kinlind-2 expression in osteoprogenitors in regulating skeletogenesis and bone mass accrual and homeostasis in mice. The translational potential of this article This study reveals that Kindlin-2 through its expression in osteoprogenitor cells controls chondrogenesis and bone mass. We may define a novel therapeutic target for treatment of skeletal diseases, such as chondrodysplasia and osteoporosis.

Single-stage Xi® robotic radical nephroureterectomy for upper tract urothelial carcinoma: surgical technique and outcomes

Abstract: Radical nephroureterectomy (RNU) represents the standard of care for high grade upper tract urothelial carcinoma (UTUC). Open and laparoscopic approaches are well-established treatments, but evidence regarding robotic RNU is growing. The introduction of the Xi® system facilitates the implementation of this multi-quadrant procedure. The aim of this video-article is to describe the surgical steps and the outcomes of Xi® robotic RNU.Single stage Xi® robotic RNU without patients repositioning and robot re-docking were done between 2015 and 2019 and collected in a large worldwide multi-institutional study, the ROBotic surgery for Upper tract Urothelial cancer STudy (ROBUUST). Institutional review board approval and data share agreement were obtained at each center. Surgical technique is described in detail in the accompanying video. Descriptive statistics of baseline characteristics and surgical, pathological, and oncological outcomes were analyzed.Overall, 148 patients were included in the analysis; 14% had an ECOG >1 and 68.2% ASA ≥3. Median tumor dimension was 3.0 (IQR:2.0-4.2) cm and 34.5% showed hydronephrosis at diagnosis. Forty-eight% were cT1 tumors. Bladder cuff excision and lymph node dissection were performed in 96% and 38.1% of the procedures, respectively. Median operative time and estimated blood loss were 215.5 (IQR:160.5-290.0) minutes and 100.0 (IQR: 50.0-150.0) mL, respectively. Approximately 56% of patients took opioids during hospital stay for a total morphine equivalent dose of 22.9 (IQR:16.0-60.0) milligrams equivalent. Post-operative complications were 26 (17.7%), with 4 major (2.7%). Seven patients underwent adjuvant chemotherapy, with median number of cycles of 4.0 (IQR:3.0-6.0).Single stage Xi® RNU is a reproducible and safe minimally invasive procedure for treatment of UTUC. Additional potential advantages of the robot might be a wider implementation of LND with a minimally invasive approach.

Multicenter Outcomes After Primary Hip Arthroscopy: A Comparative Analysis of Two-Year Outcomes After Labral Repair, Segmental Labral Reconstruction, or Circumferential Labral Reconstruction

Abstract: (1) To report minimum 2-year follow-up patient-reported outcome measures in patients undergoing labral repair (LR), segmental labral reconstruction (SLR), or circumferential labral reconstruction (CLR) in the primary setting; and (2) to compare minimum 2-year follow-up patient-reported outcome measures among these groups.A retrospective review of a prospectively maintained multicenter database of patients undergoing hip arthroscopy was performed. Inclusion criteria were patients undergoing hip arthroscopy for treatment of labral tear and femoroacetabular impingement syndrome between January 2014 and October 2017, and completion of minimum 2-year postoperative outcome scores. Exclusion criteria were patients undergoing revision hip surgery, labral treatment limited to debridement, lateral center-edge angle <20°, osteoarthritis (Tönnis grade > 1), slipped capital femoral epiphysis, workers compensation status, and patients undergoing concomitant gluteus medius and/or minimus repair. Labral reconstruction patients were matched (1:3) with labral repair patients on age, sex, and body mass index. The labral reconstruction group was further stratified into SLR, and CLR groups. Patient demographic characteristics and clinical outcomes including Hip Outcome Score - Activities of Daily Living, Hip Outcome Score - Sport Subscale, modified Harris Hip Score, international Hip Outcome Tool, and visual analog scale for pain were analyzed, as well as achievement of the minimal clinical improvement difference (MCID). A P-value less than .05 indicated statistical significance.A total of 416 patients were included (LR, n = 312; SLR, n = 53; CLR, n = 51). The age, body mass index, and sex of the matched cohort were 42.3 ± 11.2 years, 24.7 ± 3.7, and 55.0% female. At a minimum of 2-year after hip arthroscopic surgery, no differences were found in preoperative, postoperative, or the delta visual analog scale for pain, modified Harris Hip Score, Hip Outcome Score - Activities of Daily Living, Hip Outcome Score - Sport Subscale, or international Hip Outcome Tool. Subsequently, the proportion of patients achieving the MCID and the PASS at latest follow-up were analyzed. This analysis revealed that no significant differences in the rate of MCID or PASS achievement for any outcome measure existed based on labral treatment.In this multicenter study on labral treatment in the primary setting, patients undergoing LR, SLR, and CLR demonstrated no difference in preoperative or postoperative scores, nor the proportion of patients achieving clinically significant outcome improvement.III; therapeutic outcome study with controls.

Outcomes of Extubated COVID and Non-COVID Patients Receiving Awake Venovenous Extracorporeal Membrane Oxygenation

Abstract: Cessation of continuous analgesia and sedation in patients with acute respiratory distress syndrome (ARDS) receiving venovenous (VV) extracorporeal membrane oxygenation (ECMO) facilitates early extubation, family, patient and provider engagement, and mobility. Outcomes associated with an awake ECMO strategy have not been well described in the literature. The purpose of this study was to evaluate outcomes in patients receiving this strategy. This was a retrospective review of ARDS patients receiving awake VV ECMO. The primary outcome was survival to hospital discharge. Secondary outcomes included days requiring ECMO, time from cannulation to extubation, complications, patients requiring tracheostomy, hospital and intensive care unit (ICU) length of stay (LOS), and discharge disposition. In a subgroup analysis, outcomes were compared between non-COVID and COVID ECMO patients. Sixty-two patients were included with a survival to hospital discharge of 85.5%. Days requiring ECMO was 33.0 (0.0-75.0) and cannulation to extubation was 6.0 (4.0-11.0). Three patients received a tracheostomy (4.8%). Bleeding and infection were reported in 80.6% and 82.3% of patients, respectively. Intensive care unit length of stay was 46.0 days (29.0-90.0) and hospital LOS was 51.0 days (32.0-91.0). Over half of the patients (51.6%) were discharged to an acute rehabilitation facility and 27.4% were discharged home. There was similar survival to hospital discharge between the COVID and non-COVID awake ECMO patients (85% in both groups, p = 1.000). This study highlights the impact of an awake ECMO approach on survival to hospital discharge. Future studies are needed to evaluate this approach as compared to current practice to determine if this should become the standard.

GABA facilitates spike propagation through branch points of sensory axons in the spinal cord

Abstract: Movement and posture depend on sensory feedback that is regulated by specialized GABAergic neurons (GAD2+) that form axo-axonic contacts onto myelinated proprioceptive sensory axons and are thought to be inhibitory. However, we report here that activating GAD2+ neurons directly with optogenetics or indirectly by cutaneous stimulation actually facilitates sensory feedback to motor neurons in rodents and humans. GABAA receptors located at or near nodes of Ranvier of sensory axons cause this facilitation by preventing spike propagation failure at the many axon branch points, which is otherwise common without GABA. In contrast, GABAA receptors are generally lacking from axon terminals and so cannot inhibit transmitter release onto motor neurons, unlike GABAB receptors that cause presynaptic inhibition. GABAergic innervation near nodes and branch points allows individual branches to function autonomously, with GAD2+ neurons regulating which branches conduct, adding a computational layer to the neuronal networks generating movement and likely generalizing to other central nervous system axons.

Quality of Life for Older Cancer Patients: Relation of Psychospiritual Distress to Meaning-Making During Dignity Therapy.

Abstract: Background:Nearly 500,000 older Americans die a cancer-related death annually. Best practices for seriously ill patients include palliative care that aids in promoting personal dignity. Dignity The...

Product market threats and leverage adjustments

Abstract: This research examines the effect of product market threats on firms’ leverage adjustments. We find that competitive pressures from the product market accelerate the leverage speed of adjustment (SOA) toward the target capital structure. To establish the causal effect of competitive threats on SOA, we exploit a quasi-natural experiment provided by large import tariff reductions in the U.S. manufacturing sector and show a significant increase in firms’ leverage adjustments after large tariff cuts. The impact of product market threats on leverage adjustments is more pronounced for firms with poor governance quality and exposed to product market threats. Finally, to the extent that reaching the target capital structure enhances firm value, we note that the faster SOA following competition translates into higher firm value. Overall, our study highlights the “bright side” of product market competition and suggests that agency conflicts between managers and shareholders are attenuated by intensified competition.

Examining the Efficacy of Medial Meniscus Posterior Root Repair: A Meta-analysis and Systematic Review of Biomechanical and Clinical Outcomes

Abstract: Medial meniscus posterior root (MMPR) injuries accelerate the progression of osteoarthritis. While partial meniscectomy was once considered the gold standard for treatment, meniscus root repair has become increasingly utilized with reported improvements in clinical and biomechanical outcomes.To perform a systematic review of biomechanical outcomes and a meta-analysis of clinical and radiographic outcomes after MMPR repair.Meta-analysis and systematic review; Level of evidence, 4.The PubMed, Embase, and Cochrane databases were queried in August 2021 for studies reporting biomechanical, clinical, and radiographic outcomes after MMPR repair. Biomechanical studies were assessed for main results and conclusions. Data including study characteristics, cohort demographics, and outcomes were extracted. Included clinical studies were analyzed with a random-effects meta-analysis of proportions for binary outcomes or continuous outcomes for mean differences between preoperative and postoperative time points. Subgroup analysis for studies reporting repair outcomes with concomitant high tibial osteotomy (HTO) was performed where appropriate.A total of 13 biomechanical studies were identified and reported an overall improvement in mean and peak contact pressures after MMPR repair. There were 24 clinical studies, consisting of 876 patients (877 knees), identified, with 3 studies (106 knees) reporting outcomes with concomitant HTO. The mean patient age was 57.1 years (range, 23-74 years), with a mean follow-up of 27.7 months (range, 2-64 months). Overall, clinical outcomes (Lysholm, Hospital for Special Surgery, International Knee Documentation Committee, visual analog scale for pain, Tegner, and Knee injury and Osteoarthritis Outcome Score scores) were noted to improve postoperatively compared with preoperatively, with improved Lysholm scores in patients undergoing concomitant HTO versus MMPR repair alone. Meniscal extrusion was not significantly improved after MMPR repair compared with preoperative measurements. The progression in Kellgren-Lawrence grades from grade 0 to grades 1 to 3 occurred in 5.9% (21/354) of patients after repair, with no patients progressing from grades 1 to 3 to grade 4.MMPR repair generally improved biomechanical outcomes and led to improved patient-reported outcomes with greater improvements noted in patients undergoing concomitant HTO. Repair did not significantly improve meniscal extrusion, while only 5.9% of patients were noted to progress to low-grade osteoarthritis. The high level of heterogeneity in the included biomechanical and clinical investigations emphasizes the need for more well-designed studies that evaluate outcomes after MMPR repair.

Anti-HIV Drugs Cause Mitochondrial Dysfunction in Monocyte-Derived Macrophages

Abstract: Combination antiretroviral therapy (cART) dramatically changed the face of the HIV/AIDS pandemic, making it one of the most prominent medical breakthroughs of the past 3 decades. However, as the life span of persons living with HIV (PLWH) continues to approach that of the general population, the same cannot be said regarding their quality of life. PLWH are affected by comorbid conditions such as high blood pressure, diabetes, and neurocognitive impairment at a higher rate and increased severity than their age-matched counterparts. PLWH also have higher levels of inflammation, the drivers of which are not entirely clear. As cART treatment is lifelong, we assessed here the effects of cART, independent of HIV, on primary human monocyte-derived macrophages (MDMs). MDMs were unskewed or skewed to an alternative phenotype and treated with Atripla or Triumeq, two first-line cART treatments. We report that Triumeq skewed alternative MDMs toward an inflammatory nonsenescent phenotype. Both Atripla and Triumeq caused mitochondrial dysfunction, specifically efavirenz and abacavir. Additionally, transcriptome sequencing (RNA-seq) demonstrated that both Atripla and Triumeq caused differential regulation of genes involved in immune regulation and cell cycle and DNA repair. Collectively, our data demonstrate that cART, independent of HIV, alters the MDM phenotype. This suggests that cART may contribute to cell dysregulation in PLWH that subsequently results in increased susceptibility to comorbidities.

Patients With a High Femoroepiphyseal Roof With Concomitant Borderline Hip Dysplasia and Femoroacetabular Impingement Syndrome Do Not Demonstrate Inferior Outcomes Following Arthroscopic Hip Surgery

Abstract: The purpose of this study was to compare outcomes after hip arthroscopy for femoroacetabular impingement syndrome (FAIS) in patients with borderline hip dysplasia and hip instability defined radiographically using the femoroepiphyseal acetabular roof (FEAR) index and in patients without radiographic evidence of hip instability.Data from consecutive patients with borderline hip dysplasia (lateral center edge angle between 18˚-25˚) who underwent primary hip arthroscopy between April 2012 and June 2017 for the treatment of FAIS were analyzed. Baseline demographic data, radiographic parameters, preoperative, and 2-year postoperative patient-reported outcome measures were collected. The FEAR index was measured by 3 different observers. Patients with an average FEAR index ≥2˚ were categorized as having radiographic evidence of instability as previously published. The analysis was powered to detect a minimal clinically important difference (MCID) for each outcome score. Statistical analysis was performed as appropriate to compare patients with FEAR index ≥2 and <2°.A total of 140 patients met the inclusion criteria. The average age and body mass index of included patients was 31.7 ± 13.2 (P < .325) years and 25.1 ± 5.6 kg/m2 (P < .862). There were no statistically significant demographic differences between the groups. Nineteen (13.0%) patients were found to have a FEAR index of over 2˚. The FEAR index <2° and FEAR index ≥2° groups had a mean preoperative FEAR index (standard deviation, range) of -7.0 (5.2, -26.8 to 1.9) and 4.8 (2.5, 2.0-11.8), respectively. The interrater intraclass correlation coefficient was 0.96. Postoperative patient-reported outcomes and rates of MCID and patient-acceptable symptomatic state achievement were not statistically different between the radiographically stable and unstable groups. (p>0.05 for all).Patients with borderline hip dysplasia and radiographic evidence of hip instability, as measured by the FEAR index (≥2°), achieve similar improvement in 2-year outcomes compared to those with radiographically stable hips after arthroscopic treatment of FAIS.Retrospective Level III cohort study.

Mechanism of carvedilol induced action potential and calcium alternans

Abstract: Carvedilol is a nonspecific β-blocker clinically used for the treatment of cardiovascular diseases but has also been shown to have profound effects on excitation-contraction coupling and Ca signaling at the cellular level. We investigate the mechanism by which carvedilol facilitates Ca transient (CaT) and action potential duration (APD) alternans in rabbit atrial myocytes. Carvedilol lowered the frequency threshold for pacing-induced CaT alternans and facilitated alternans in a concentration-dependent manner. Carvedilol prolonged the sarcoplasmic reticulum (SR) Ca release refractoriness by significantly increasing the time constant τ of recovery of SR Ca release; however, no changes in L-type calcium current recovery from inactivation or SR Ca load were found after carvedilol treatment. Carvedilol enhanced the degree of APD alternans nearly two-fold. Carvedilol slowed the APD restitution kinetics and steepened the APD restitution curve at the pacing frequency (2 Hz) where alternans were elicited. No effect on the CaT or APD alternans ratios was observed in experiments with a different β-blocker (metoprolol), excluding the possibility that the carvedilol effect on CaT and APD alternans was determined by its β-blocking properties. These data suggest that carvedilol contributes to the generation of CaT and APD alternans in atrial myocytes by modulating the restitution of CaT and APD.

Comparison of saline versus air for identifying endotracheal intubation with ultrasound

Abstract: After intubation has been performed, it is important to rapidly confirm the correct location of the endotracheal tube (ETT). Multiple techniques have been described, each with different limitations. Ultrasound has been increasingly recognized as an alternate modality for identifying the ETT location. However, it can be challenging to visualize the air-filled ETT cuff. Saline insufflation of the ETT cuff has been suggested to improve visualization of the ETT but data are limited. Our study sought to compare the diagnostic accuracy of air versus saline ETT cuff inflation on the diagnostic accuracy of intubation.This was a randomized trial comparing air versus saline cuff inflation using a cadaver model. Adult cadavers were intubated in a random sequence with respect to both the location of intubation (i.e., tracheal vs esophageal) and air versus saline. Blinded sonographers assessed the location of the ETT using the static technique. Outcomes included accuracy of sonographer identification, time to identification, and operator confidence.480 total assessments were performed. When using air, ultrasound was 95.8% sensitive (95% CI 90.5% to 98.6%) and 100% specific (95% CI 97.0% to 100%) with a mean time to confirmation of 8.5 s (95% CI 7.6 s to 9.4 s) and a mean operator confidence of 4.32/5.0 (95% CI 4.21 to 4.42). When using saline, ultrasound was 100% sensitive (95% CI 97.0% to 100%) and 100% specific (95% CI 97.0% to 100%) with a mean time to confirmation of 6.3 s (95% CI 5.9 s to 6.8 s) and a mean operator confidence of 4.52/5.0 (95% CI 4.44 to 4.60).There was no statistically significant difference between air versus saline for intubation confirmation. However, saline was associated with fewer false negatives. Additionally, time to confirmation was faster and operator confidence was higher with the saline group. Further studies should determine if the outcomes would change with more novice sonographers or in specific patient populations.

Fecal Microbiota Transfer Attenuates Gut Dysbiosis and Functional Deficits After Traumatic Brain Injury

Abstract: Background: Traumatic brain injury (TBI) is an underrecognized public health threat. Survivors of TBI often suffer long-term neurocognitive deficits leading to the progressive onset of neurodegenerative disease. Recent data suggests that the gut-brain axis is complicit in this process. However, no study has specifically addressed whether fecal microbiota transfer (FMT) attenuates neurologic deficits after TBI. Hypothesis: We hypothesized that fecal microbiota transfer would attenuate neurocognitive, anatomic, and pathologic deficits after TBI. Methods: C57Bl/6 mice were subjected to severe TBI (n = 20) or sham-injury (n = 20) via an open-head controlled cortical impact. Post-injury, this cohort of mice underwent weekly oral gavage with a slurry of healthy mouse stool or vehicle alone beginning 1 h post-TBI followed by behavioral testing and neuropathologic analysis. 16S ribosomal RNA sequencing of fecal samples was performed to characterize gut microbial community structure pre- and post-injury. Zero maze and open field testing were used to evaluate post-traumatic anxiety, exploratory behavior, and generalized activity. 3D, contrast enhanced, magnetic resonance imaging was used to determine differences in cortical volume loss and white matter connectivity. Prior to euthanasia, brains were harvested for neuropathologic analysis. Results: Fecal microbiome analysis revealed a large variance between TBI, and sham animals treated with vehicle, while FMT treated TBI mice had restoration of gut dysbiosis back to levels of control mice. Neurocognitive testing demonstrated a rescue of normal anxiety-like and exploratory behavior in TBI mice treated with FMT. FMT treated TBI mice spent a greater percentage of time (22%, P = 0.0001) in the center regions of the Open Field as compared to vehicle treated TBI mice (13%). Vehicle-treated TBI animals also spent less time (19%) in the open areas of zero maze than FMT treated TBI mice (30%, P = 0.0001). Comparing in TBI mice treated with FMT, MRI demonstrated a marked attenuation in ventriculomegaly (P < 0.002) and a significant change in fractional anisotropy (i.e., loss of white matter connectivity) (P < 0.0001). Histologic analysis of brain sections revealed a FMT- injury dependent interaction in the microglia/macrophage-specific ionized calcium-binding protein, Iba1 (P = 0.002). Conclusion: These data suggest that restoring a pre-injury gut microbial community structure may be a promising therapeutic intervention after TBI.

Neuropathology of Dementia Disorders

Abstract: This article provides an overview of the neuropathology of common age-related dementing disorders, focusing on the pathologies that underlie Alzheimer disease (AD) and related dementias, including Lewy body dementias, frontotemporal dementia, vascular dementia, limbic-predominant age-related transactive response DNA-binding protein 43 (TDP-43) encephalopathy (LATE), and mixed-etiology dementias. This article also discusses the underlying proteinopathies of neurodegenerative diseases (eg, amyloid-β, paired helical filament tau, α-synuclein, and TDP-43 pathology) and vascular pathologies, including tissue injury (eg, infarcts, hemorrhages) with or without vessel disease.New criteria for AD pathologic diagnosis highlight amyloid-β as the sine qua non of AD; they require molecular markers of amyloid and establish a minimum threshold of Braak neurofibrillary tangle stage 3. Pathologic diagnosis is separated from clinical disease (ie, pathologic diagnosis no longer requires dementia). TDP-43 pathology, a major pathology in a frontotemporal dementia subtype, was found as a central pathology in LATE, a newly named amnestic disorder. Multiple pathologies (often co-occurring with AD) contribute to dementia and add complexity to the clinical picture. Conversely, Lewy body, LATE, and vascular dementias often have accompanying AD pathology. Pathology and biomarker studies highlight subclinical pathologies in older people without cognitive impairment. This resilience to brain pathology is common and is known as cognitive reserve.The pathologies of dementia in aging are most commonly amyloid, tangles, Lewy bodies, TDP-43, hippocampal sclerosis, and vascular pathologies. These pathologies often co-occur (mixed pathologies), which may make specific clinical diagnoses difficult. In addition, dementia-related pathologies are often subclinical, suggesting varying levels of resilience in older people.