Total Knee Arthroplasty After Meniscectomy Is More Likely in Patients With Bicompartmental or Complex Tears.

Purpose: To determine the relationship between meniscus tear morphologies, stratified by location and pattern, and knee arthroplasty rates in a commercial insurance population. Methods: The PearlDiver database was queried for patients ≥35 years old with a meniscus tear of specified laterality and ≥2 years follow-up between 2015 and 2018. Two analyses were conducted with cohorts matched on age, sex, Charlson Comorbidity Index, obesity, osteoarthritis (OA), and treatment (meniscectomy vs conservative): one with equal-sized subgroups by tear location (medial only, lateral only, or both medial and lateral) and another by tear pattern (bucket-handle, complex, or peripheral). The rate of subsequent total knee arthroplasty (TKA) was compared between matched groups. Results: In total, 129,987 patients (mean age: 57.8 ± 10.5 years) were matched by tear location; 1,734 patients with medial-only tears (4.0%), 1,786 with lateral-only tears (4.1%), and 2,611 with medial plus lateral tears (6.0%) underwent a TKA within 5 years (P < .001). Patients with both medial and lateral tears were 1.55-fold more likely to undergo TKA. In total, 24,213 patients (mean age: 56.0 ± 10.5 years) were matched by tear pattern; 296 patients with bucket-handle tears (3.7%), 373 with complex tears (4.6%), and 336 with peripheral tears (4.2%) underwent TKA (P = .01). Patients with complex tears were 1.29-fold more likely to undergo TKA than patients with bucket-handle tears (P = .002). Conclusions: In matched cohorts of patients with degenerative meniscus tears, having both medial plus lateral tears conferred a 1.5-fold risk of TKA, whereas complex tears conferred a 1.3-fold risk within 5 years. Specific meniscal tear patterns and locations harbor varying risk in progressing to end-stage knee OA, and these data may help counsel patients about their likelihood of progressing to end-stage OA warranting an arthroplasty procedure. Level of Evidence: Level III, retrospective comparative study.

No difference in clinical outcomes between operative and nonoperative management of minimally retracted proximal hamstring ruptures.

PURPOSE: The indications for surgical treatment of proximal hamstring ruptures are continuing to be refined. The purpose of this study was to compare patient-reported outcomes (PROs) between patients who underwent operative or nonoperative management of proximal hamstring ruptures. METHODS: A retrospective review of the electronic medical record identified all patients who were treated for a proximal hamstring rupture at our institution from 2013 to 2020. Patients were stratified into two groups, nonoperative or operative management, which were matched in a 2:1 ratio based on demographics (age, gender, and body mass index), chronicity of the injury, tendon retraction, and number of tendons torn. All patients completed a series of PROs including the Perth Hamstring Assessment Tool (PHAT), Visual Analogue Scale for pain (VAS), and the Tegner Activity Scale. Statistical analysis was performed using multi-variable linear regression and Mann-Whitney testing to compare nonparametric groups. RESULTS: Fifty-four patients (mean age = 49.6 ± 12.9 years; median: 49.1; range: 19-73) with proximal hamstring ruptures treated nonoperatively were successfully matched 2:1 to 27 patients who had underwent primary surgical repair. There were no differences in PROs between the nonoperative and operative cohorts (n.s.). Chronicity of the injury and older age correlated with significantly worse PROs across the entire cohort (p < 0.05). CONCLUSIONS: In this cohort of primarily middle-aged patients with proximal hamstring ruptures with less than three centimeters of tendon retraction, there was no difference in patient-reported outcome scores between matched cohorts of operatively and nonoperatively managed injuries. LEVEL OF EVIDENCE: Level III.

RANTES Concentration at the Time of Surgery Is Associated With Postoperative Stiffness in Patients Undergoing ACL Reconstruction.

BACKGROUND: Patients undergoing anterior cruciate ligament (ACL) reconstruction have been shown to be at risk for postoperative arthrofibrosis. Diagnostic biomarkers associated with the development of postoperative stiffness are unknown. HYPOTHESIS: Biomarkers found in the synovial fluid at the time of surgery are associated with the development of postoperative arthrofibrosis in a cohort of patients undergoing ACL reconstruction. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: Patients undergoing ACL reconstruction were prospectively enrolled. Synovial fluid was collected before surgical incision. A cohort of patients with postoperative stiffness requiring manipulation under anesthesia (MUA) and/or lysis of adhesions (LOA) was retrospectively identified. Matching of cases to controls was performed using a 1:2 pair matching algorithm. Risk factor-adjusted single-biomarker and multivariable models were used to assess the association of synovial fluid biomarkers with postoperative stiffness requiring MUA/LOA. Stepwise logistic regression controlling for clinical risk factors was used to identify biomarkers that are possible predictors of postoperative stiffness. RESULTS: A total of 11 cases (3 male, 8 female) were identified and matched with 21 controls (6 male, 15 female) with no significant differences in age, sex, smoking history, or days from injury to surgery. Concentrations of the biomarker regulated upon activation, normal T-cell expressed and presumably secreted (RANTES) were significantly higher in patients requiring MUA/LOA versus controls (694.20 pg/mL [interquartile range, 214.75-3428.79] vs 113.04 pg/mL [interquartile range, 32.81-517.91], respectively; P = .034). On single-biomarker models, RANTES (odds ratio, 2.28; 95% CI, 1.29-5.37; P = .019) and basic fibroblast growth factor (bFGF) (odds ratio, 1.91; 95% CI, 1.07-3.99; P = .047) were associated with increased risk of postoperative stiffness requiring MUA/LOA after ACL reconstruction. Stepwise logistic regression identified 3 biomarkers that are possible predictors of postoperative stiffness, which were included in the final model: Interleukin 1 receptor antagonist (IL-1RA) (P = .198), bFGF (P = .157), and RANTES (P = .046). CONCLUSION: Higher concentrations of synovial fluid biomarkers bFGF and RANTES were associated with increased risk for stiffness requiring intervention after ACL reconstruction. Interleukin 6 (IL-6), vascular endothelial growth factor A (VEGF-A), tissue inhibitor of metalloproteinases 1 (TIMP-1), interleukin 1 receptor antagonist (IL-1RA), matrix metalloproteinase 3 (MMP-3), monocyte chemotactic protein 1 (MCP-1), and macrophage inflammatory protein 1B (MIP-1B) were not associated with the development of postoperative arthrofibrosis.

A prospective study on gait dominant normal pressure hydrocephalus.

OBJECT: We characterize idiopathic normal pressure hydrocephalus (NPH) following treatment with lumbar puncture (LP) and shunt placement through clinical evaluation and quantitative ProtoKinetics Zeno walkway assessments. We evaluate the symptomology by determining gait characteristics altered by treatment. METHODS: Patients at Barrow Neurological Institute (BNI) who underwent a LP, removing 30-32 mL cerebrospinal fluid) followed by ventriculoperitoneal shunt placement in February 2015 to February 2017 were analyzed for gait impairments. Inclusion in the study required a diagnosis of NPH, no conflicting comorbidities, and pre-LP, post-LP, and 6-month post-shunt assessments. Analyses of gait and balance data recorded by physical therapists and the ProtoKinetics Zeno Walkway at pre-LP, post-LP, and post-shunt were performed. RESULTS: A total of 28 patients were included and one-way analysis of variance and Tukey-Kramer HSD was performed. Among the 15 clinical assessments, nine were significantly altered. Using the ProtoKinetics Zeno Walkway, 7 out of 10 characteristics recorded were considered significantly different among the three data sets. Furthermore, there were more significant differences between pre-LP assessments and post-shunt assessments in comparison to differences between pre-LP assessments and post-LP assessments. CONCLUSIONS: Our results indicate that certain gait characteristics better fit NPH than others. By focusing on the features that are caused by NPH and alleviated by LP and/or shunt placement, a more definitive NPH diagnosis can be attained. Additionally, our findings confirm a cumulative effect of continuous drainage via shunt placement may lead to increased improvement in NPH symptoms over LP results.

Early Loss of Histone H2B Monoubiquitylation Alters Chromatin Accessibility and Activates Key Immune Pathways That Facilitate Progression of Ovarian Cancer.

Recent insights supporting the fallopian tube epithelium (FTE) and serous tubal intraepithelial carcinomas (STIC) as the tissue of origin and the precursor lesion, respectively, for the majority of high-grade serous ovarian carcinomas (HGSOC) provide the necessary context to study the mechanisms that drive the development and progression of HGSOC. Here, we investigate the role of the E3 ubiquitin ligase RNF20 and histone H2B monoubiquitylation (H2Bub1) in serous tumorigenesis and report that heterozygous loss of RNF20 defines the majority of HGSOC tumors. At the protein level, H2Bub1 was lost or downregulated in a large proportion of STIC and invasive HGSOC tumors, implicating RNF20/H2Bub1 loss as an early event in the development of serous ovarian carcinoma. Knockdown of RNF20, with concomitant loss of H2Bub1, was sufficient to enhance cell migration and clonogenic growth of FTE cells. To investigate the mechanisms underlying these effects, we performed ATAC-seq and RNA-seq in RNF20 knockdown FTE cell lines. Loss of RNF20 and H2Bub1 was associated with a more open chromatin conformation, leading to upregulation of immune signaling pathways, including IL6. IL6 was one of the key cytokines significantly upregulated in RNF20- and H2Bub1-depleted FTE cells and imparted upon these cells an enhanced migratory phenotype. These studies provide mechanistic insight into the observed oncogenic phenotypes triggered by the early loss of H2Bub1. SIGNIFICANCE: Loss of RNF20 and H2Bub1 contributes to transformation of the fallopian tube epithelium and plays a role in the initiation and progression of high-grade serous ovarian cancer.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/4/760/F1.large.jpg.

Amyloid-ß Increases Tau by Mediating Sirtuin 3 in Alzheimer's Disease.

Increasing evidence indicates that sirtuin 3 (Sirt3) has neuroprotective effects in regulating oxidative stress and energy metabolism, both of which are involved in the pathogenesis of Alzheimer's disease (AD). However, it is unclear whether Sirt3 is associated with cognitive performance and pathological changes in AD. We conducted a case-control study of the postmortem brains of AD (n = 16), mild cognitive impairment (n = 13), and age- and education-matched cognitively normal (CN, n = 11) subjects. We measured the mRNA and protein levels of Sirt3 and assessed their association with cognitive performance and AD pathology. In an ex vivo model of cortical neurons from transgenic mice that carry human tau protein, we modified Sirt3 expression by genetic knockdown and knock-in to investigate the cause-effect relationship between Sirt3 and tau. Sirt3 levels were reduced in the entorhinal cortex, the middle temporal gyrus, and the superior frontal gyrus of AD subjects compared to those of CN. This reduction was associated with poorer test scores of neuropsychological evaluation and the severity of tau pathology. Further study with genetic manipulation of Sirt3 revealed that amyloid-ß increased levels of total tau acetylated tau through its modulation of Sirt3. These data suggest that reduction of Sirt3 is critically involved in pathogenesis of AD.

The Impact of Aging on Brain Pituitary Adenylate Cyclase Activating Polypeptide, Pathology and Cognition in Mice and Rhesus Macaques.

Pituitary adenylate cyclase activating polypeptide (PACAP) is associated with Alzheimer's disease (AD), but its age-related effects are unknown. We chose the rhesus macaque due to its closeness to human anatomy and physiology. We examined four variables: aging, cognitive performance, amyloid plaques and PACAP. Delayed nonmatching-to-sample recognition memory scores declined with age and correlated with PACAP levels in the striatum, parietal and temporal lobes. Because amyloid plaques were the only AD pathology in the old rhesus macaque, we further studied human amyloid precursor protein (hAPP) transgenic mice. Aging was associated with decreased performance in the Morris Water Maze (MWM). In wild type (WT) C57BL/6 mice, the performance was decreased at age 24-26 month whereas in hAPP transgenic mice, it was decreased as early as 9-12 month. Neuritic plaques in adult hAPP mice clustered in hippocampus and adjacent cortical regions, but did not propagate further into the frontal cortex. Cerebral PACAP protein levels were reduced in hAPP mice compared to age-matched WT mice, but the genetic predisposition dominated cognitive decline. Taken together, these data suggest an association among PACAP levels, aging, cognitive function and amyloid load in nonhuman primates, with both similarities and differences from human AD brains. Our results suggest caution in choosing animal models and in extrapolating data to human AD studies.

Cryopreservation of umbilical cord blood with a novel freezing solution that mimics intracellular ionic composition.

BACKGROUND: Cryopreservation protocols have remained relatively unchanged since the first umbilical cord blood banking program was established. This study evaluated the preservation efficacy of a novel intracellular-like cryopreservation solution (CryoStor, BioLife Solutions, Inc.), the rate of addition of two cryopreservation solutions to cord blood units (CBUs), and reduced final dimethyl sulfoxide (DMSO) concentration of 5%. STUDY DESIGN AND METHODS: Split-sample CBUs were cryopreserved with either an in-house 20% DMSO-based cryopreservation solution or CryoStor CS10 at a rate of 1 mL/min (n = 10; i.e., slow addition) or as a bolus injection (n = 6; i.e., fast addition). Infrared images of exothermic effects of the cryopreservation solutions were monitored relative to the rate of addition. Prefreeze and postthaw colony-forming unit assays, total nucleated cells, and CD34+ cell counts were compared. RESULTS: Maximum temperature excursions observed were less than 6°C, regardless of the rate of solution addition. Fast addition resulted in peak excursions approximately twice that of slow addition but the magnitude and duration were minimal and transient. Slow addition of CryoStor CS10 (i.e., final concentration ≤ 5% DMSO) resulted in significantly better postthaw CD34+ cell recoveries; no other metrics were significantly different. Fast addition of CryoStor resulted in similar postthaw metrics compared to slow addition of the in-house solution. CONCLUSION: Slow and fast addition of cryopreservation solutions result in mean temperature changes of approximately 3.3 to 4.45°C. Postthaw recoveries with CryoStor were equivalent to or slightly better than with the in-house cryopreservation solution. CryoStor also provides several advantages including reduced processing time, formulation consistency, and reduced DMSO in the frozen product (≤ 5%).