Patch and matrix striatonigral neurons differentially regulate locomotion.

The striatonigral neurons are known to promote locomotion1,2. These neurons reside in both the patch (also known as striosome) and matrix compartments of the dorsal striatum3-5. However, the specific contribution of patch and matrix striatonigral neurons to locomotion remain largely unexplored. Using molecular identifier Kringle-Containing Protein Marking the Eye and the Nose (Kremen1) and Calbidin (Calb1)6, we showed in mouse models that patch and matrix striatonigral neurons exert opposite influence on locomotion. While a reduction in neuronal activity in matrix striatonigral neurons precedes the cessation of locomotion, fiber photometry recording during self-paced movement revealed an unexpected increase of patch striatonigral neuron activity, indicating an inhibitory function. Indeed, optogenetic activation of patch striatonigral neurons suppressed locomotion, contrasting with the locomotion-promoting effect of matrix striatonigral neurons. Consistently, patch striatonigral neuron activation markedly inhibited dopamine release, whereas matrix striatonigral neuron activation initially promoted dopamine release. Moreover, the genetic deletion of inhibitory GABA-B receptor Gabbr1 in Aldehyde dehydrogenase 1A1-positive (ALDH1A1+) nigrostriatal dopaminergic neurons (DANs) completely abolished the locomotion-suppressing effect caused by activating patch striatonigral neurons. Together, our findings unravel a compartment-specific mechanism governing locomotion in the dorsal striatum, where patch striatonigral neurons suppress locomotion by inhibiting the activity of ALDH1A1+ nigrostriatal DANs.

Patch and matrix striatonigral neurons differentially regulate locomotion.

Striatonigral neurons, known to promote locomotion, reside in both the patch and matrix compartments of the dorsal striatum. However, their compartment-specific contributions to locomotion remain largely unexplored. Using molecular identifier Kremen1 and Calb1 , we showed in mouse models that patch and matrix striatonigral neurons exert opposite influences on locomotion. Matrix striatonigral neurons reduced their activity before the cessation of self-paced locomotion, while patch striatonigral neuronal activity increased, suggesting an inhibitory function. Indeed, optogenetic activation of patch striatonigral neurons suppressed ongoing locomotion with reduced striatal dopamine release, contrasting with the locomotion-promoting effect of matrix striatonigral neurons, which showed an initial increase in dopamine release. Furthermore, genetic deletion of the GABA-B receptor in Aldehyde dehydrogenase 1A1-positive (ALDH1A1 + ) nigrostriatal dopaminergic neurons completely abolished the locomotion-suppressing effect of patch striatonigral neurons. Our findings unravel a compartment-specific mechanism governing locomotion in the dorsal striatum, where patch striatonigral neurons suppress locomotion by inhibiting ALDH1A1 + nigrostriatal dopaminergic neurons.

Incidence of Osteoarthritis Diagnosis Within 5 Years of Surgery Was Greater Following Partial Meniscectomy Than Meniscus Repair and/or Anterior Cruciate Ligament Reconstruction.

Purpose: To compare knee osteoarthritis (OA) incidence within 5 years of surgery between 5 common sports medicine procedures: isolated anterior cruciate ligament (ACL) reconstruction, isolated meniscus repair (MR), isolated arthroscopic partial meniscectomy (APM), ACL reconstruction with MR (ACL + MR), and ACL reconstruction with APM (ACL + APM). Methods: The PearlDiver Mariner M157Ortho database was searched. Five cohorts were identified using Current Procedural Terminology (CPT) codes and included those 16 to 60 years old who underwent isolated ACL reconstruction, isolated MR, ACL + MR, isolated APM, or ACL + APM repair. Groups were matched by age, sex, and presence of diagnosis codes for obesity. The incidence of knee OA diagnosis within 5 years of the index procedure was determined for each group, and odds ratios (ORs) were calculated and compared against isolated ACL reconstruction. Results: Each group consisted of 7,672 patients (3,450 females, 4,222 males). A significantly greater proportion of the APM group was diagnosed with knee OA within 5 years of surgery compared to isolated ACL reconstruction (APM = 1,032/7,672 [13.5%] vs ACL = 745/7,672 [9.7%]; P ≤ .001; OR, 1.45; 95% confidence interval [CI], 1.31-1.60). Similarly, a greater proportion of the MR group was diagnosed with OA compared to isolated ACL reconstruction (MR = 826/7,672 [10.7%]; P = .030; OR, 1.12; 95% CI, 1.01-1.25). No differences in OA incidence were noted between the ACL + APM group when compared to isolated ACL reconstruction (P = .81). Patients undergoing ACL + MR demonstrated the lowest OA incidence with reduced odds when compared to isolated ACL reconstruction (ACL + MR = 575/7,672 [7.5%]; P < .001; OR, 0.75; 95% CI, 0.67-0.84). Conclusions: In this analysis using CPT codes, APM was associated with the highest knee OA incidence, and ACL + MR was associated with the lowest OA incidence within 5 years of surgery. Level of Evidence: Level III, retrospective cohort study.

YouTube Is a Poor-Quality Source for Patient Information Regarding Patellar Dislocations.

Purpose: To evaluate the content and quality of YouTube videos concerning patellar dislocations. Methods: "Patellar dislocation" and "kneecap dislocation" were searched on the YouTube library. The Uniform Resource Locator of the first 25 suggested videos was extracted, for a total of 50 videos. The following variables were collected for each video: number of views, duration in minutes, video source/uploader, content type, days since upload, view ratio (views/day), and number of likes. Video source/uploader was categorized as academic, physician, nonphysician, medical source, patient, commercial, and other. The Journal of the American Medical Association (JAMA), Global Quality Scale (GQS), Patellar Dislocation Specific Score (PDSS), and DISCERN scores were used to assess each video. A series of linear regression models were used to explore relationships between each of these scores and the aforementioned variables. Results: The median video length was 4.11 minutes (interquartile range 2.07-6.03, range 0.31-53.56), and the total number of views for all 50 videos was 3,697,587 views. The mean overall JAMA benchmark score ± standard deviation was 2.56 ± 0.64, GQS: 3.54 ± 1.05, total PDSS: 5.76 ± 3.42. Physicians were the most common video source/uploader (42%). Academic sources had the greatest mean JAMA benchmark score (3.20), whereas nonphysician and physician sources had the greatest mean GQS scores (4.09 and 3.95, respectively). Videos uploaded by physicians had the greatest PDSS scores (7.5). Conclusions: The overall transparency, reliability, and content quality of YouTube videos on patellar dislocation measured by the JAMA benchmark score and PDSS, respectively, are poor. Additionally, the overall educational and video quality, as assessed by the GQS, was intermediate. Clinical Relevance: It is important to understand the quality of information patients receive on YouTube so providers can guide patients to greater-quality sources.

Human synovial fluid interleukin-6, but not type II collagen breakdown, positively correlated with pain after anterior cruciate ligament injury and reconstruction.

Anterior cruciate ligament (ACL) injury initiates a biochemical cascade thought to contribute to the onset and progression of posttraumatic osteoarthritis (PTOA). Interleukin-1ß (IL-1ß), IL-6, and C-telopeptide fragments of type II collagen (CTX-II) are implicated in joint inflammation and cartilage degradation following ACL injury; however, their association with pain is still being explored. The purpose of this study was to evaluate the associations between synovial fluid concentrations of IL-1ß, IL-6, and CTX-II with pain following ACL injury and reconstruction. We hypothesized that greater IL-1ß, IL-6, and CTX-II would correlate with greater Pain Visual Analogue Scale (VAS) scores. This was a secondary analysis of 23 patients (mean age = 18.4 years, BMI = 27.4, 13 females/10 males) with acute ACL tears who participated in a pilot randomized trial. Synovial fluid and VAS scores were collected on the day of initial presentation, at ACL reconstruction, and 1 and 4 weeks after surgery. Synovial fluid concentrations of IL-1ß, IL-6, and CTX-II were assessed using enzyme-linked immunoabsorbent assays, and repeated measures correlations were used to assess the relationships between pain and synovial IL-1ß, IL-6, or CTX-II after ACL injury and reconstruction. Pain was positively correlated with synovial fluid IL-6 concentrations (r = 0.52, p < 0.001); however, pain was inversely correlated with CTX-II (r = -0.39, p = 0.002). IL-1ß had no significant correlation with pain. Statement of clinical relevance: PTOA has been described as a "silent killer" and these results suggest that early PTOA may have pro-inflammatory pathways that are not primarily associated with pain but still lead to progressive cartilage loss.

Injury Rates Remained Elevated in the Second National Football League Season After the Onset of the COVID-19 Pandemic.

Purpose: The purpose of this study was to compare the injury incidence of the 2018-2019 and 2020 National Football League (NFL) seasons with the 2021 season. Methods: Publicly released NFL weekly injury reports were queried to identify players listed as "out" or placed on injured reserve (IR) for at least 1 game in the 2018-2021 seasons. Injuries were then categorized into upper extremity, lower extremity, spine/core, and head. Incidence per 1,000 athlete exposures were calculated for each season, and proportions of injuries by position were calculated separately for the 2018-2019, 2020, and 2021 cohorts. Incidence rate ratios (IRR) were used to compare injury rates. Results: Overall injury incidence in the 2021 NFL season increased compared to the pre-COVID-19 seasons (2018-2019) in all anatomical zones except for the upper extremity (28.70 vs 23.09 per 1,000 exposures, IRR 1.24 [95% CI: 1.14-1.36]; P < .001). The injury rate remained elevated and further increased in 2021 compared to the 2020 season for all anatomical zones other than the spine/core [28.70 vs 21.64 per 1,000 exposures, IRR 1.33 (1.19-1.47); P < .001]. No significant difference existed during the early season (weeks 1-4); however, injury rates after week 4 increased in 2021 compared to both the 2018-2019 and 2020 seasons. Conclusions: The injury incidence in the 2021 season remained elevated and increased further compared to both the 2018-2019 and 2020 seasons. Traumatic injuries resulting in missed games increased despite return to a more traditional season since the beginning of the COVID-19 pandemic. The injury rates significantly increased in mid-season to late season. Level of Evidence: Level III, cross-sectional study.

The Quality of Online Information for the Treatment of Knee Osteoarthritis: A Google Study.

Introduction Affecting more than 30 million adults annually, osteoarthritis (OA) is the most common joint disorder in the United States. A variety of management options for knee OA exists, including physical therapy, weight loss, intra-articular corticosteroid injections, and total joint arthroplasty. With many treatments available, patients often utilize the internet to educate themselves about their condition and management options. The purpose of this study was to evaluate the quality, transparency, and readability of online information for the treatment of knee OA. Methods The search terms "knee," "arthritis," and "treatment" were entered into an incognito mode Google browser. Websites were classified by type (commercial, academic, nonacademic medical practice, government/patient advocacy, and other) and graded on content quality, transparency, and readability using the following scores, respectively: modified DISCERN, Journal of American Medical Association (JAMA) Benchmark, and Flesch-Kincaid (FK) grade level. Results Of the 95 websites evaluated, commercial (mean, 38.2) and academic (37.3) sites had the highest total DISCERN scores, which were significantly greater than nonacademic medical practice (31.8) and government/patient advocacy sites (33.4) (p≤0.035). Nonacademic medical practice sites had the lowest mean total DISCERN (31.8) and JAMA (1.47) scores and the highest FK grade level readability (9.5). There was a significant positive correlation between mean total DISCERN and JAMA scores (r=0.46, p<0.001). Conclusion The mean overall quality of websites regarding the treatment of OA was good as evidenced by greater modified DISCERN scores. However, website quality ranged from poor to excellent, indicating that some websites are still missing key information patients may find useful when assessing treatment options online.

A Plague of Their Own: Injury Incidence Remains Elevated in the 2021 Major League Baseball Season Compared to Pre-COVID-19 Seasons.

Background: Significant increases in injuries were observed in the 2020 Major League Baseball (MLB) season; these were attributed to an increased acute to chronic workload due to the interrupted preseason and compressed season during the coronavirus disease of 2019 (COVID-19) pandemic. In 2021, the MLB resumed its regular schedule. Hypothesis/Purpose: The purpose of this study was to determine the injury incidence and epidemiology of the 2021 MLB season compared to the injury incidence in the 2020 season and pre-COVID-19 seasons. The hypothesis was that, with the return to normal preseason training, injury incidence in 2021 would return to pre-COVID-19 rates. Additionally, it was hypothesized that injury list (IL) placements at midseason 2021 would be decreased relative to 2020 due to the uninterrupted preseason yet increased at full season 2021 due to increased overall workload from 2020. Study Design: Descriptive epidemiology study. Methods: The MLB transactions database was searched for players placed on the IL between 2018 and 2021. Injuries were categorized by body part and player position. Incidence per 1000 athlete-exposures was calculated for the pre-COVID-19 (2018-2019), 2020, and 2021 seasons. The z test for proportions was used to determine significant differences between injury incidences. Results: The injury incidence rate by midseason 2021 (9.32) compared to 2020 (8.66) was not significantly different (p=0.234). At full season 2021, injury incidence rate (8.69) was significantly higher than pre-COVID-19 seasons (5.13, p<0.001), but not 2020 (p=0.952). When comparing full season 2021 to 2020, increased foot/ankle (0.50 vs 0.14, respectively, p<0.001) and miscellaneous (1.92 vs 0.68, respectively, p<0.001) injuries were observed. Conclusion: The overall injury incidence in 2021 was significantly higher than pre-COVID-19 seasons, and no significant difference was observed between both mid- and full season 2021 and 2020, refuting the hypotheses. This signifies that injury incidence remained elevated in the 2021 season despite resumption of preseason training and a regular season. Level of Evidence: 3.

An Investigation of Google Searches for Knee Osteoarthritis and Stem Cell Therapy: What are Patients Searching Online?

Background: Stem cell therapies have emerged as a potential treatment for osteoarthritis (OA), but their role remains controversial. Their growing popularity may lead patients to search for information online, but search queries and sources are unknown. Purpose: We sought to (1) identify the most frequently asked questions on Google related to knee OA and stem cell therapy, (2) assess the types of websites accessed through these searches, and (3) evaluate the transparency of these websites. Methods: The search terms "knee," "osteoarthritis," and "stem cell" were entered into Google. Frequently asked questions suggested by Google, and their corresponding websites were extracted. Questions and websites were classified by type. Journal of the American Medical Association (JAMA) benchmark criteria were used as a measure of website transparency (range: 0-4). Analysis of variance tests were performed to compare JAMA benchmark criteria between website types. Results: Of the 145 questions and website extracted, the most common question subtype pertained to non-stem cell treatments (41.4%) for knee OA; the most common website types were medical publishers (24.8%) and nonacademic medical practices (22.8%). JAMA scores were highest for medical publishers (mean: 3.81) and lowest for nonacademic medical practices (mean: 1.55). Nonacademic medical practices had significantly worse JAMA scores compared with commercial, academic, and medical publishers. Conclusion: The most frequent questions pertained to non-stem cell treatments, although questions related to stem cell efficacy were most common among the 10 most frequent questions. Google searches on knee OA and stem cell therapies often directed the user to websites lacking transparency and verifiable information. Further research is warranted.

Blood Flow Restriction Therapy: An Evidence-Based Approach to Postoperative Rehabilitation.

➢: Blood flow restriction therapy (BFRT) involves the application of a pneumatic tourniquet cuff to the proximal portion of the arm or leg. This restricts arterial blood flow while occluding venous return, which creates a hypoxic environment that induces many physiologic adaptations. ➢: BFRT is especially useful in postoperative rehabilitation because it produces muscular hypertrophy and strength gains without the need for heavy-load exercises that are contraindicated after surgery. ➢: Low-load resistance training with BFRT may be preferable to low-load or high-load training alone because it leads to comparable increases in strength and hypertrophy, without inducing muscular edema or increasing pain.

Lateral Patellar Dislocation: A Critical Review and Update of Evidence-Based Rehabilitation Practice Guidelines and Expected Outcomes.

¼: Nonoperative treatment of a lateral patellar dislocation produces favorable functional results, but as high as 35% of individuals experience recurrent dislocations. ¼: Medial patellofemoral ligament reconstruction is an effective treatment to prevent recurrent dislocations and yield excellent outcomes with a high rate of return to sport. ¼: Both nonoperative and postoperative rehabilitation should center on resolving pain and edema, restoring motion, and incorporating isolated and multijoint progressive strengthening exercises targeting the hip and knee. ¼: Prior to return to sports, both functional and isolated knee strength measurements should be used to determine leg symmetry strength and to utilize patient-reported outcome measures to assess the patient's perceived physical abilities and patellofemoral joint stability.

Deficiency in endocannabinoid synthase DAGLB contributes to early onset Parkinsonism and murine nigral dopaminergic neuron dysfunction.

Endocannabinoid (eCB), 2-arachidonoyl-glycerol (2-AG), the most abundant eCB in the brain, regulates diverse neural functions. Here we linked multiple homozygous loss-of-function mutations in 2-AG synthase diacylglycerol lipase ß (DAGLB) to an early onset autosomal recessive Parkinsonism. DAGLB is the main 2-AG synthase in human and mouse substantia nigra (SN) dopaminergic neurons (DANs). In mice, the SN 2-AG levels were markedly correlated with motor performance during locomotor skill acquisition. Genetic knockdown of Daglb in nigral DANs substantially reduced SN 2-AG levels and impaired locomotor skill learning, particularly the across-session learning. Conversely, pharmacological inhibition of 2-AG degradation increased nigral 2-AG levels, DAN activity and dopamine release and rescued the locomotor skill learning deficits. Together, we demonstrate that DAGLB-deficiency contributes to the pathogenesis of Parkinsonism, reveal the importance of DAGLB-mediated 2-AG biosynthesis in nigral DANs in regulating neuronal activity and dopamine release, and suggest potential benefits of 2-AG augmentation in alleviating Parkinsonism.

Preseason elimination impact on anterior cruciate ligament injury in the National Football League.

BACKGROUND: Anterior cruciate ligament (ACL) injuries represent detrimental injuries in the National Football League (NFL). A significant portion of these injuries often occur in preseason exhibitions. The Coronavirus disease 2019 pandemic presented a unique disruption to preseason NFL football with the cancelation of all preseason games. AIM: To compare the incidence of ACL tears through the first eight weeks of the NFL season in 2020 to the mean incidence over the previous 5 seasons (2015-2019) and determine if there was any change in incidence with the elimination of the preseason. METHODS: NFL players who suffered ACL tears during the preseason and first eight weeks of the NFL season from 2015-2020 were identified. The number of ACL injuries for the 2015-2019 seasons was compared to the 2020 season for four different timeframes. For each analysis, the cumulative number of ACL injuries to that time point was used to calculate the percent difference for descriptive analysis. Additionally, the number of teams with at least one player suffering an ACL tear were identified and compared using Chi-Squared testing. Finally, a cumulative relative risk was calculated for each week played. RESULTS: There were 14 ACL tears through the first four games of the 2020 season, a 118.8% (14 vs 6.4) increase in comparison to the 5-year average over the first 4 regular season weeks of 2015-2019. However, when accounting for injuries occurring during the preseason from 2015-2019, there were 18.6% (14 vs 17.2) fewer total ACL injuries through regular season week 4 with no significant difference in percentage of teams impacted when these preseason injuries were accounted for P = 0.394. Results were similar (19 vs 17.2) over 8 total games played (whether regular season or preseason), and over 8 regular season games (P = 0.196, P = 0.600). CONCLUSION: The elimination of the NFL preseason resulted in a higher rate of injuries during the first 4 games of the regular season. However, these increases are offset by the injuries typically sustained during the preseason. This suggests there may be front-loading of injuries over the course of an NFL season, such that players may be more prone to injury when the intensity of play suddenly increases, whether in the preseason or regular season.

Diverse midbrain dopaminergic neuron subtypes and implications for complex clinical symptoms of Parkinson's disease.

Parkinson's disease (PD), the most common degenerative movement disorder, is clinically manifested with various motor and non-motor symptoms. Degeneration of midbrain substantia nigra pas compacta (SNc) dopaminergic neurons (DANs) is generally attributed to the motor syndrome. The underlying neuronal mechanisms of non-motor syndrome are largely unexplored. Besides SNc, midbrain ventral tegmental area (VTA) DANs also produce and release dopamine and modulate movement, reward, motivation, and memory. Degeneration of VTA DANs also occurs in postmortem brains of PD patients, implying an involvement of VTA DANs in PD-associated non-motor symptoms. However, it remains to be established that there is a distinct segregation of different SNc and VTA DAN subtypes in regulating different motor and non-motor functions, and that different DAN subpopulations are differentially affected by normal ageing or PD. Traditionally, the distinction among different DAN subtypes was mainly based on the location of cell bodies and axon terminals. With the recent advance of single cell RNA sequencing technology, DANs can be readily classified based on unique gene expression profiles. A combination of specific anatomic and molecular markers shows great promise to facilitate the identification of DAN subpopulations corresponding to different behavior modules under normal and disease conditions. In this review, we first summarize the recent progress in characterizing genetically, anatomically, and functionally diverse midbrain DAN subtypes. Then, we provide perspectives on how the preclinical research on the connectivity and functionality of DAN subpopulations improves our current understanding of cell-type and circuit specific mechanisms of the disease, which could be critically informative for designing new mechanistic treatments.

Nerve Compression Syndromes of the Shoulder.

Nerve compression syndromes of the shoulder contribute to pain, paresthesia, and weakness of the upper extremity. This review examines the recent literature regarding thoracic outlet syndrome, suprascapular neuropathy, long thoracic nerve palsy, and quadrilateral space syndrome. Overlapping features are common among shoulder pathologies, and thus, key anatomical features, pathophysiology, clinical manifestations, diagnostic techniques, and treatments are highlighted for all aforementioned conditions.

Early application of an intermittent pneumatic compression device assists dilation of radiocephalic fistulas.

INTRODUCTION:: Radiocephalic fistulas are the preferred type of arteriovenous fistula due to their advantageous location. However, radiocephalic fistula maturation has historically been inferior to brachiocephalic fistulas. Research indicates that intermittent compression may aid in forearm vein dilation. Early use of a compression device may assist radiocephalic fistula maturation. OBJECTIVES:: This prospective, randomized, placebo controlled study evaluates device safety and the effect of intermittent compression on vein size of radiocephalic fistulas and brachiocephalic fistulas. METHODS:: This was an institutional review board-approved study. After fistula creation, a novel, intermittent pneumatic compression device (Fist Assist®) was worn 15 cm proximal to fistulas 6 h daily for 30 days. Those in the treatment group (n = 43) wore Fist Assist® (24 with brachiocephalic fistulas and 19 with radiocephalic fistulas). Clinical controls (n = 16) wore a sham device. Vein diameter was measured at 0 and 30 days by duplex measurement. Percentage increase was recorded and tested for significance. RESULTS:: After 30 days, the mean percentage increase in vein diameter in the radiocephalic fistula treatment group was significantly larger than brachiocephalic fistulas in the treatment group at all proximal locations from the anastomosis. Increases in percentage vein dilation for those in the radiocephalic fistula treatment group were significantly larger than those in the control group. All fistulas treated with Fist Assist® are still functional with no reported complications. CONCLUSION:: Early application of the Fist Assist® device may be more effective at helping radiocephalic fistula mature as compared to brachiocephalic fistulas. Successful radiocephalic fistula maturation may decrease vascular access costs, reduce complications, and preserve upper arm veins for future use in vascular access.