Anterior Cruciate Ligament (ACL) Reconstruction Augmentation With Bone Marrow Aspirate, Demineralized Bone Matrix, and Suture Tape Demonstrates No Difference In Outcomes, But Faster Functional Recovery, Versus Non-augmented ACL Reconstruction.

PURPOSE: To compare outcomes after anterior cruciate ligament reconstruction (ACLR) with bone marrow aspirate concentrate (BMAC), demineralized bone matrix (DBM), and suture tape augmentation (STA) vs. ACLR without biologic augmentation or STA. METHODS: A prospective randomized controlled trial at a single institution was performed to compare ACLR with BMAC, DBM, and STA (Group A) vs. ACLR without biologic or STA (Group NA). One hundred patients were required. Skeletally mature patients <25 years old received quadriceps tendon autografts, while patients ≥25 years old received allograft ACLR with an all-inside technique. Concomitant meniscal pathologies were included. Primary outcomes compared were range-of-motion (ROM), limb symmetry, and patient-reported outcomes (PROs). Secondary outcomes included radiographic outcomes and surgical complications. Univariate and mixed-model regression analysis were used to compare outcomes. RESULTS: Fifty-nine patients were included (Group A: 29 patients, 11 females, 38%; Group NA: 30 patients, 15 females, 50%). Early range-of-motion at 6 weeks (125° vs 109° flexion, p<0.0001) and limb symmetry testing at 12 weeks (80.6 % vs. 36.7% [Delta 43.9%], p<0.001) were significantly improved in Group A. At two years, International Knee Documentation (IKDC) scores were similar (91.1 ± 12.7 vs. 85.3 ± 10.8, p=0.109). Knee Injury and Osteoarthritis and Outcome Score (KOOS) Quality of Life (QOL) scores were significantly enhanced in Group A (85.2 ± 20.9 vs. 72.1 ± 20.4, p=0.042). Twenty-two patients (12 Group A, 10 Group NA) underwent CT scans at 6-months to compare bone tunnel healing. Overall, the mean increase in bone tunnel diameter was significantly smaller in Group A vs. NA. No difference in graft re-ruptures or re-operations was observed. Seven of 59 patients (11.9%) underwent re-operation for stiffness (A: 3 (10%) vs. NA: 4 (13%), p=1.0). CONCLUSION: There were no differences in IKDC scores between groups at 2-year follow-up. Functional outcomes including early range-of-motion and limb symmetry were significantly improved in patients who received ACLR with BMAC, DBM, and STA. ACLRACLR.ACLR.

Neurotrophic factor MANF regulates autophagy and lysosome function to promote proteostasis in C. elegans.

The conserved mesencephalic astrocyte-derived neurotrophic factor (MANF) protects dopaminergic neurons but also functions in several other tissues. Previously, we showed that Caenorhabditis elegans manf-1 null mutants have increased ER stress, dopaminergic neurodegeneration, protein aggregation, slower growth, and a reduced lifespan. The multiple requirements of MANF in different systems suggest its essential role in regulating cellular processes. However, how intracellular and extracellular MANF regulates broader cellular function remains unknown. Here, we report a novel mechanism of action for manf-1 that involves the autophagy transcription factor HLH-30/TFEB-mediated signaling to regulate lysosomal function and aging. We generated multiple transgenic strains overexpressing MANF-1 and found that animals had extended lifespan, reduced protein aggregation, and improved neuronal health. Using a fluorescently tagged MANF-1, we observed different tissue localization of MANF-1 depending on the ER retention signal. Further subcellular analysis showed that MANF-1 localizes within cells to the lysosomes. These findings were consistent with our transcriptomic studies and, together with analysis of autophagy regulators, demonstrate that MANF-1 regulates protein homeostasis through increased autophagy and lysosomal activity. Collectively, our findings establish MANF as a critical regulator of the stress response, proteostasis, and aging.

Effect of starvation on electrotaxis response.

Caenorhabditis elegans is an ideal model for investigating the effects of extrinsic and intrinsic conditions on the behavioral changes of animals. Our group previously showed how different conditions influence the behavior of worms following an electric stimulus in a microfluidic channel, known as electrotaxis. In this study we describe the effect of starvation on the electrotaxis movement of animals. We show that acute starvation did not affect the electrotaxis response or dopaminergic neurons but extended the lifespan of animals.

Partial meniscectomy using needle arthroscopy associated with significantly less pain and improved patient reported outcomes at two weeks after surgery: A comparison to standard knee arthroscopy.

Purpose: to compare immediate post-operative pain and patient-reported outcomes (PROs) after partial meniscectomy with needle (NA) vs. standard (SA) arthroscopy technique. Methods: A retrospective review of a consecutive series of patients who underwent partial meniscectomy before and after adoption of a needle arthroscopic technique was performed. Meniscus repairs, root repairs, and those with ligamentous injuries were excluded. Total milligram morphine equivalents (MMEs) consumed, Visual analog scale (VAS) pain, and Knee Injury and Osteoarthritis Outcome Scores (KOOS) were compared pre-operatively and at 2 and 6-weeks postoperatively. Univariate analysis was used to compare results. Results: Nineteen patients were in each group (NA: 10 females, SA: 11 females). Mean ± SD age (NA 42.8 ± 8.4 vs. SA 47.6 ± 10.4 years, p = 0.13) and body mass index (NA 31.4 ± 5.6 vs. SA 35.1 ± 5.4 m/kg2, p = 0.06) were not significantly different. Seventeen (89%) patients in both groups had medial meniscus tears of the posterior horn. Preoperative Outerbridge score was significantly greater in the SA group (3.4 vs. 1.8, p = 0.002); however, preoperative VAS pain (NA 6.1 ± 1.7 vs. SA 6.1 ± 1.8, p = 0.98) and KOOS pain (NA 44 ± 17% vs. SA 37 ± 12.5%, p = 0.20) were similar. Amount of arthroscopic fluid used was significantly greater in the SA vs. NA group (1.4 ± 0.7 vs. 0.5 ± 0.3 L, p < 0.0001), but tourniquet time was equivalent (NA 20 ± 6 vs.16 ± 6 min, p = 0.11). VAS pain scores (NA 1.0 ± 1.1 vs. SA 2.6 ± 1.5, p = 0.0014), KOOS pain (NA 79 ± 15% vs. 58 ± 19%, p = 0.0006), and Quality of Life (QOL) scores (NA 70 ± 22% vs. SA 43 ± 24%, p = 0.001) were significantly better at 2-weeks post-op in the N group. By 6 weeks post-op, all PROs including VAS pain and KOOS scores were similar between groups. Conclusions: Adoption of a needle arthroscopic technique for partial meniscectomy was associated with significantly improved VAS and KOOS pain scores two-weeks post-operatively. Differences were not sustained at 6 weeks after surgery. Level of evidence: III, Retrospective Comparison Study.

Rotator Cuff Repair Using a Needle Arthroscope Through a Dual-Lumen Flexible Cannula.

The advent of arthroscopy in shoulder surgery has allowed for the development of minimally invasive techniques for the treatment of shoulder pathology. Further developments in needle arthroscopy have continued this trend toward less invasive shoulder surgery, allowing for decreased pain using smaller portals and decreased fluid irrigation through the shoulder joint during surgery. This technique describes a minimally invasive rotator cuff repair using a dual-lumen cannula that provides both direct visualization and direct instrument access to the pathology. This new cannula has the potential to further refine and to simplify needle arthroscopic techniques about the shoulder. With judicious patient selection, needle arthroscopy is a viable option for the treatment of common shoulder pathology.

Economics at the FCC 2021-22: 5G Spectrum Auctions, Affordable Connectivity, Broadband Data Collection, and Merger Review.

The Federal Communications Commission (FCC) is responsible for regulation in the communications marketplace and for management of the nation's non-federal radio spectrum. During the past year, FCC economists continued to work on auctions so as to repurpose mid-band spectrum for advanced wireless services - including 5G - as well as initiatives to close the connectivity gap and make broadband more affordable. FCC economists also evaluated the likely competitive effects of Verizon's proposed acquisition of prepaid competitor TracFone Wireless. Finally, FCC economists helped in setting up the novel Broadband Data Collection.

Cabin1 domain-containing gene picd-1 interacts with pry-1/Axin to regulate multiple processes in Caenorhabditis elegans.

The Axin family of scaffolding proteins control diverse processes, such as facilitating the interactions between cellular components and providing specificity to signaling pathways. While several Axin family members have been discovered in metazoans and shown to play crucial roles, their mechanism of action are not well understood. The Caenorhabditis elegans Axin homolog, pry-1, is a powerful tool for identifying interacting genes and downstream effectors that function in a conserved manner to regulate Axin-mediated signaling. Our lab and others have established pry-1's essential role in developmental processes that affect the reproductive system, seam cells, and a posterior P lineage cell, P11.p. Additionally, pry-1 is crucial for lipid metabolism, stress responses, and aging. In this study, we expanded on our previous work on pry-1 by reporting a novel interacting gene named picd-1 (pry-1-interacting and Cabin1 domain-containing). PICD-1 protein shares sequence conservation with CABIN1, a component of the HUCA complex. Our findings have revealed that PICD-1 is involved in several pry-1-mediated processes, including stress response and lifespan maintenance. picd-1's expression overlapped with that of pry-1 in multiple tissues throughout the lifespan. Furthermore, PRY-1 and PICD-1 inhibited CREB-regulated transcriptional coactivator homolog CRTC-1, which promotes longevity in a calcineurin-dependent manner. Overall, our study has demonstrated that picd-1 is necessary for mediating pry-1 function and provides the basis to investigate whether Cabin-1 domain-containing protein plays a similar role in Axin signaling in other systems.

The FGFR4 Homolog KIN-9 Regulates Lifespan and Stress Responses in Caenorhabditis elegans.

Fibroblast growth factor receptors (FGFRs) regulate diverse biological processes in eukaryotes. The nematode Caenorhabditis elegans is a good animal model for studying the roles of FGFR signaling and its mechanism of regulation. In this study, we report that KIN-9 is an FGFR homolog in C. elegans that plays essential roles in aging and stress response maintenance. kin-9 was discovered as a target of miR-246, a microRNA that is positively regulated by the Axin family member pry-1. We found that animals lacking kin-9 function were long-lived and resistant to chemically induced stress. Furthermore, they showed a reduced expression of endoplasmic reticulum unfolded protein response (ER-UPR) pathway genes, suggesting that kin-9 is required to maintain a normal ER-UPR. The analysis of GFP reporter-based expression in transgenic animals revealed that KIN-9 is localized in the intestine. Overall, our findings demonstrate that kin-9 is regulated by miR-246 and may function downstream of pry-1. This study prompts future investigations to understand the mechanism of miRNA-mediated FGFR function in maintaining aging and stress response processes.

Excision of a Knee Cyclops Lesion Using a Needle Arthroscope.

After anterior cruciate ligament (ACL) reconstruction surgery, achieving full range of motion and strength of the postoperative knee is critical for optimal surgical outcomes. Abnormal tissue growth and scar formation in the postoperative knee can create a block to terminal extension of the knee. Cyclops lesions are areas of granulation tissue with neovascularization and fibrous tissue formation peripherally, most commonly at the anterolateral aspect of the tibial graft site after ACL reconstruction. When these lesions block terminal extension and cause mechanical symptoms, cyclops syndrome is diagnosed, and secondary knee arthroscopy is often performed to remove this tissue to allow for full range of motion. This Technical Note describes a minimally invasive approach with the NanoScope. The NanoScope allows for decreased postoperative pain and swelling with a likely quicker recovery back to normal postoperative therapy.

Reduced neuronal population in the dorsolateral prefrontal cortex in infant macaques infected with simian immunodeficiency virus (SIV).

Pediatric HIV infection remains a global health crisis with an estimated 150,000 new mother-to-child (MTCT) infections each year. Antiretroviral therapy (ART) has improved childhood survival, but only an estimated 53% of children worldwide have access to treatment. Adding to the health crisis is the neurological impact of HIV on the developing brain, in particular cognitive and executive function, which persists even when ART is available. Imaging studies suggest structural, connectivity, and functional alterations in perinatally HIV-infected youth. However, the paucity of histological data limits our ability to identify specific cortical regions that may underlie the clinical manifestations. Utilizing the pediatric simian immunodeficiency virus (SIV) infection model in infant macaques, we have previously shown that early-life SIV infection depletes the neuronal population in the hippocampus. Here, we expand on these previous studies to investigate the dorsolateral prefrontal cortex (dlPFC). A total of 11 ART-naïve infant rhesus macaques (Macaca mulatta) from previous studies were retrospectively analyzed. Infant macaques were either intravenously (IV) inoculated with highly virulent SIVmac251 at ~1 week of age and monitored for 6-10 weeks or orally challenged with SIVmac251 from week 9 of age onwards with a monitoring period of 10-23 weeks post-infection (19-34 weeks of age), and SIV-uninfected controls were euthanized at 16-17 weeks of age. Both SIV-infected groups show a significant loss of neurons along with evidence of ongoing neuronal death. Oral- and IV-infected animals showed a similar neuronal loss which was negatively correlated to chronic viremia levels as assessed by an area under the curve (AUC) analysis. The loss of dlPFC neurons may contribute to the rapid neurocognitive decline associated with pediatric HIV infection.

C. elegans electrotaxis behavior is modulated by heat shock response and unfolded protein response signaling pathways.

The nematode C. elegans is a leading model to investigate the mechanisms of stress-induced behavioral changes coupled with biochemical mechanisms. Our group has previously characterized C. elegans behavior using a microfluidic-based electrotaxis device, and showed that worms display directional motion in the presence of a mild electric field. In this study, we describe the effects of various forms of genetic and environmental stress on the electrotactic movement of animals. Using exposure to chemicals, such as paraquat and tunicamycin, as well as mitochondrial and endoplasmic reticulum (ER) unfolded protein response (UPR) mutants, we demonstrate that chronic stress causes abnormal movement. Additionally, we report that pqe-1 (human RNA exonuclease 1 homolog) is necessary for the maintenance of multiple stress response signaling and electrotaxis behavior of animals. Further, exposure of C. elegans to several environmental stress-inducing conditions revealed that while chronic heat and dietary restriction caused electrotaxis speed deficits due to prolonged stress, daily exercise had a beneficial effect on the animals, likely due to improved muscle health and transient activation of UPR. Overall, these data demonstrate that the electrotaxis behavior of worms is susceptible to cytosolic, mitochondrial, and ER stress, and that multiple stress response pathways contribute to its preservation in the face of stressful stimuli.

Therapeutic effects of TP5, a Cdk5/p25 inhibitor, in in vitro and in vivo models of Parkinson's disease.

Parkinson's Disease (PD) is a chronic progressive neurodegenerative disease. Current treatments for PD are symptomatic and only increase striatal dopamine levels. Proactive neuroprotective approaches that slow the progression of PD and maintain appropriate dopamine neuron populations are needed to treat the disease. One suggested mechanism contributing to the pathology of PD involves the binding of cyclin-dependent kinase 5 (Cdk5) to p25, creating a hyperactivated complex to induce cell death. The objective of this study is to investigate the neuroprotective and neurorestorative properties of Truncated Peptide 5 (TP5), a derivative of the p35 activator involved in Cdk5 regulation, via the inhibition of Cdk5/p25 complex function. SH-SY5Y cell line and the nematode Caenorhabditis elegans were exposed to paraquat (PQ), an oxidative stressor, to induce Parkinsonian phenotypes. TP5 was administered prior to PQ exposure to determine its neuroprotective effects and, in further experiments, after PQ exposure to examine its neurorestorative effects. In the SH-SY5Y cell line, TP5 was found to have neuroprotective effects using a cell viability assay and demonstrated neuroprotective and neurorestorative effects in C. elegans by examining dopaminergic neurons and dopamine-dependent behaviour. TP5 decreased elevated Cdk5 activation in worms that were exposed to PQ. TP5's inhibition of Cdk5/p25 hyperactivity led to the protection of dopamine neurons in these PD models. This suggests that TP5 can act as a potential therapeutic drug towards PD.

Axin Family of Scaffolding Proteins in Development: Lessons from C. elegans.

Scaffold proteins serve important roles in cellular signaling by integrating inputs from multiple signaling molecules to regulate downstream effectors that, in turn, carry out specific biological functions. One such protein, Axin, represents a major evolutionarily conserved scaffold protein in metazoans that participates in the WNT pathway and other pathways to regulate diverse cellular processes. This review summarizes the vast amount of literature on the regulation and functions of the Axin family of genes in eukaryotes, with a specific focus on Caenorhabditis elegans development. By combining early studies with recent findings, the review is aimed to serve as an updated reference for the roles of Axin in C. elegans and other model systems.

A review of the literature pertaining to the efficacy, safety, educational requirements, uses and usage of mechanical adjusting devices: Part 1 of 2.

Over the past decade, mechanical adjusting devices (MADs) were a major source of debate within the Chiropractors' Association of Saskatchewan (CAS). Since Saskatchewan was the only jurisdiction in North America to prohibit the use of MADs, the CAS established a committee in 2001 to review the literature on MADs. The committee evaluated the literature on the efficacy, safety, and uses of moving stylus instruments within chiropractic practice, and the educational requirements for chiropractic practice. Following the rating criteria for the evaluation of evidence, as outlined in the Clinical Guidelines for Chiropractic Practice in Canada (1994), the committee reviewed 55 articles - all of which pertained to the Activator. Of the 55 articles, 13 were eliminated from the final study. Of the 42 remaining articles, 6 were rated as class 1 evidence; 11 were rated as class 2 evidence and 25 were rated as class 3 evidence. In this article - the first in a series of two - the background and the methods utilized by the MAD committee's activities are described, as well as the results for the review of the literature on efficacy. Of the 21 articles related to efficacy, five were identified as Class 1 evidence; 4 were identified as Class 2 evidence; and 12 were identified as Class 3. Overall, the committee reached consensus that the MAD procedures using the Activator were as effective as manual (HVLA) procedures in producing clinical benefit and biological change. A minority report was also written, arguing that there was not enough evidence to support or refute the efficacy of MADs.

A review of the literature pertaining to the efficacy, safety, educational requirements, uses and usage of mechanical adjusting devices: Part 2 of 2.

Over the past decade, mechanical adjusting devices (MADs) were a major source of debate within the Chiropractors' Association of Saskatchewan (CAS). Since Saskatchewan was the only jurisdiction in North America to prohibit the use of MADs, the CAS established a committee in 2001 to review the literature on MADs. The committee evaluated the literature on the efficacy, safety, and uses of moving stylus instruments within chiropractic practice, and the educational requirements for chiropractic practice. Following the rating criteria for the evaluation of evidence, as outlined in the Clinical Guidelines for Chiropractic Practice in Canada (1994), the committee reviewed 55 articles - all of which pertained to the Activator. Of the 55 articles, 13 were eliminated from the final study. Of the 42 remaining articles, 6 were rated as class 1 evidence; 11 were rated as class 2 evidence and 25 were rated as class 3 evidence. In this article - the second in a series of two - we review the results of uses and usage, safety and educational requirements. Of the 30 articles designated under the category of usage, 3 were rated as Class 1 evidence; 9 studies were classified as Class 2 evidence and 18 were rated as Class 3 evidence. Overall the committee reached consensus that in clinical practice, there is broad application of these procedures. A minority report was written arguing that the reviewer was unable to reach a conclusion about the use of the Activator Instrument other than it is used as a clinical and research tool. Of the 16 studies that dealt either explicitly or implicitly with safety, 4 were Class 1 evidence; 3 were Class 2 evidence and 9 were Class 3 evidence. Overall the committee reached consensus that the evidence supports that the Activator instrument is safe and has no more relative risk than do manual HVLA procedures. A minority report was written arguing that there is no evidence either to support or refute the view that MAD is safe. Of the 5 studies that dealt with educational requirements, all were Class 3 evidence. Overall the committee reached consensus that there was no evidence in the literature with respect to educational requirements to form any conclusions. A minority report was written offering opinion that there is evidence with respect to educational requirements.