Regenerative Variability of Human Juvenile Chondrocyte Sheets From Different Cell Donors in an Athymic Rat Knee Chondral Defect Model.

PURPOSE: This study aimed to establish a combined histological assessment system of neo-cartilage outcomes and to evaluate variations in an established rat defect model treated with human juvenile cartilage-derived chondrocyte (JCC) sheets fabricated from various donors. METHODS: JCCs were isolated from the polydactylous digits of eight patients. Passage 2 (P2) JCC sheets from all donors were transplanted into nude rat chondral defects for 4 weeks (27 nude rats in total). Defect-only group served as control. Histological samples were stained for safranin O, collagen 1 (COL1), and collagen 2 (COL2). (1) All samples were scored, and correlation coefficients for each score were calculated. (2) Donors were divided into "more effective" and "less effective" groups based on these scores. Then, differences between each group in each category of modified O'Driscoll scoring were evaluated. RESULTS: (1) Modified O'Driscoll scores were negatively correlated with %COL1 area, and positively correlated with %COL2 area and COL2/1 ratio. (2) Four of 8 donors exhibited significantly higher modified O'Driscoll scores and %COL2 areas. JCC donors were divided into two groups by average score values. Significant differences between the two groups were observed in modified O'Driscoll categories of "Nature of predominant tissue," "Reconstruction of subchondral bone," and "Safranin O staining." CONCLUSION: The combined histological evaluation method is useful for detailed in vivo efficacy assessments of cartilage defect regeneration models. Variations in histological scores among juvenile cartilage-derived chondrocyte donors were correlated to the quality of regenerated cartilage hyaline structure and subchondral bone remodeling observed in the nude rat defect model.

B cell depletion with anti-CD20 promotes neuroprotection in a BAFF-dependent manner in mice and humans.

Anti-CD20 therapy to deplete B cells is highly efficacious in preventing new white matter lesions in patients with relapsing-remitting multiple sclerosis (RRMS), but its protective capacity against gray matter injury and axonal damage is unclear. In a passive experimental autoimmune encephalomyelitis (EAE) model whereby TH17 cells promote brain leptomeningeal immune cell aggregates, we found that anti-CD20 treatment effectively spared myelin content and prevented myeloid cell activation, oxidative damage, and mitochondrial stress in the subpial gray matter. Anti-CD20 treatment increased B cell survival factor (BAFF) in the serum, cerebrospinal fluid, and leptomeninges of mice with EAE. Although anti-CD20 prevented gray matter demyelination, axonal loss, and neuronal atrophy, co-treatment with anti-BAFF abrogated these benefits. Consistent with the murine studies, we observed that elevated BAFF concentrations after anti-CD20 treatment in patients with RRMS were associated with better clinical outcomes. Moreover, BAFF promoted survival of human neurons in vitro. Together, our data demonstrate that BAFF exerts beneficial functions in MS and EAE in the context of anti-CD20 treatment.

Under the influence: environmental factors as modulators of neuroinflammation through the IL-10/IL-10R axis.

The IL-10/IL-10 receptor (IL-10R) axis plays an important role in attenuating neuroinflammation in animal models of Multiple Sclerosis (MS) and increased IL-10 has been associated with a positive response to MS disease modifying therapy. Because environmental factors play an important role in MS susceptibility and disease course, identification of environmental factors that impact the IL-10/IL-10R axis has therapeutic potential. In this review, we provide historical and updated perspectives of how IL-10R signaling impacts neuroinflammation, discuss environmental factors and intestinal microbes with known impacts on the IL-10/IL-10R axis, and provide a hypothetical model for how B cells, via their production of IL-10, may be important in conveying environmental "information" to the inflamed central nervous system.

A New Source of Mutilating Hand Injuries: The Side-by-Side Utility Terrain Vehicle.

BACKGROUND: Rates of mutilating hand injuries are increasing from accidents caused by all-terrain vehicles (ATVs) and the recently popularized side-by-side utility terrain vehicles (UTVs). Increasing surgeon familiarity with upper extremity (UE) injury patterns, severity, and outcomes following ATV and UTV accidents may improve patient care and advocacy. METHODS: Retrospective comparisons of UE injury patterns, severity, hospital and intensive care unit (ICU) admission lengths, and number of operations were made between ATVs and UTVs. Findings were analyzed with Fisher exact tests, multivariate analysis of variance, analyses of variance with post hoc analyses, and multiple linear regressions. RESULTS: A total of 154 cases were identified for inclusion (ATV, n = 87; UTV, n = 67). Patient ages ranged from 4 to 89 years. The UTV group contained significantly more hand and finger injuries, and more of the fractures were open ( P = 0.005, P < 0.001, and P < 0.001, respectively). Riders of UTVs had nearly three times as many mutilating hand injuries and a nearly ninefold increase in amputations compared with ATV riders ( P < 0.001 and P < 0.001, respectively). On average, the UTV group spent 2.5 additional days in the hospital, 0.91 additional days in an ICU, and had 1.3 additional operations ( P = 0.001, P = 0.007, and P < 0.001, respectively). Vehicle type was the only variable significantly correlated with days in the hospital, ICU, and number of UE operations ( P = 0.002, P = 0.008, and P < 0.001, respectively). CONCLUSIONS: Hand surgeons are in a unique position to serve as forerunners for increasing public awareness of off-road vehicle risks and promoting rider safety. Collaborating with manufacturers and emergency care providers and directing teaching initiatives may improve patient outcomes. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.

Safety and efficacy of human juvenile chondrocyte-derived cell sheets for osteochondral defect treatment.

Knee cartilage does not regenerate spontaneously after injury, and a gold standard regenerative treatment algorithm has not been established. This study demonstrates preclinical safety and efficacy of scaffold-free, human juvenile cartilage-derived-chondrocyte (JCC) sheets produced from routine surgical discards using thermo-responsive cultureware. JCCs exhibit stable and high growth potential in vitro over passage 10, supporting possibilities for scale-up to mass production for commercialization. JCC sheets contain highly viable, densely packed cells, show no anchorage-independent cell growth, express mesenchymal surface markers, and lack MHC II expression. In nude rat focal osteochondral defect models, stable neocartilage formation was observed at 4 weeks by JCC sheet transplantation without abnormal tissue growth over 24 weeks in contrast to the nontreatment group showing no spontaneous cartilage repair. Regenerated cartilage was safranin-O positive, contained type II collagen, aggrecan, and human vimentin, and lacked type I collagen, indicating that the hyaline-like neocartilage formed originates from transplanted JCC sheets rather than host-derived cells. This study demonstrates the safety of JCC sheets and stable hyaline cartilage formation with engineered JCC sheets utilizing a sustainable tissue supply. Cost-benefit and scaling issues for sheet fabrication and use support feasibility of this JCC sheet strategy in clinical cartilage repair.

Fantastic IgA plasma cells and where to find them.

IgA is produced in large quantities at mucosal surfaces by IgA+ plasma cells (PC), protecting the host from pathogens, and restricting commensal access to the subepithelium. It is becoming increasingly appreciated that IgA+ PC are not constrained to mucosal barrier sites. Rather, IgA+ PC may leave these sites where they provide both host defense and immunoregulatory function. In this review, we will outline how IgA+ PC are generated within the mucosae and how they subsequently migrate to their "classical" effector site, the gut lamina propria. From there we provide examples of IgA+ PC displacement from the gut to other parts of the body, referencing examples during homeostasis and inflammation. Lastly, we will speculate on mechanisms of IgA+ PC displacement to other tissues. Our aim is to provide a new perspective on how IgA+ PC are truly fantastic beasts of the immune system and identify new places to find them.

A totally OSM gift to astrocytes relieves inflammation.

Dectin-1 is known for promoting anti-fungal responses through the signaling molecule Card9. In this issue of Immunity, Deerhake et al. now report that during autoimmune neuroinflammation, Dectin-1 can promote a neuroprotective feed-forward pathway through Card9-independent upregulation of Oncostatin M.

A Comparison of Open Carpal Tunnel Release Outcomes Between Procedure Room and Operating Room Settings.

PURPOSE: Carpal tunnel release (CTR) surgical costs are minimized when performed in the procedure room (PR) setting, compared with the operating room. However, it remains unclear whether outcomes differ between surgical settings. Our purpose was to compare outcomes at 1 year or greater follow-up after open CTR between patients treated in PR versus operating room settings using the Boston Carpal Tunnel Questionnaire (BCTQ). METHODS: A change in clinical care protocols at our institution occurred in 2014. Before this, all CTRs were performed in the operating room; thereafter, these were transitioned to the PR. Adult patients who underwent isolated unilateral or bilateral open CTR in either surgical setting were considered for inclusion, in which procedures were conducted between January 2014 and October 2018 for the PR group and January 2009 and March 2014 for the operating room group. The Functional Status Scale (FSS) and the Symptom Severity Scale (SSS) components of the BCTQ were collected for all eligible patients at a minimum of 1 year after surgery. We used univariate and multivariable linear regression to determine whether postoperative BCTQ scores were equivalent between PR and operating room groups within a threshold of one-fourth of the lowest estimates of the minimal clinically important difference. RESULTS: No differences in demographics, comorbidities, or insurance type were observed between the 104 PR and 112 operating room patients. Survey response rate was 25% and 25% for the PR and operating room patients, respectively. At a mean follow-up of 3 ± 1 years, FSS and SSS scores were equivalent between PR and operating room groups on bivariate analysis. The multivariable equivalence test also demonstrated equivalent FSS and SSS scores between PR and operating room groups within a one-fourth minimal clinically important difference threshold while controlling for age, sex, presence of diabetes or thyroid disease, unilateral versus bilateral CTR, and surgeon. CONCLUSIONS: Clinical outcomes did not differ between PR and operating room settings after open CTR. Type of study/level of evidence: Therapeutic III.

Evaluating the Safety of the Hand Surgery Procedure Room: A Single-Center Cohort of 1,404 Surgical Encounters.

PURPOSE: Performing hand surgeries in the procedure room (PR) setting instead of the operating room effectively reduces surgical costs. Understanding the safety or complication rates associated with the PR is important in determining the value of its use. Our purpose was to describe the incidence of medical and surgical complications among patients undergoing minor hand surgeries in the PR. METHODS: We retrospectively reviewed all adult patients who underwent an operation in the PR setting between December 2013 and May 2019 at a single tertiary academic medical center by 1 of 5 fellowship-trained orthopedic hand surgeons. Baseline patient characteristics were described. Complication rates were obtained via chart review. RESULTS: For 1,404 PR surgical encounters, 1,796 procedures were performed. Mean patient age was 59 ± 15 years, 809 were female (57.6%), and average follow-up was 104 days. The most common surgeries were carpal tunnel release (39.9%), trigger finger release (35.9%), and finger mass or cyst excision (9.6%). Most surgeries were performed using a nonpneumatic wrist tourniquet (58%), whereas 42% used no tourniquet. No patient experienced a major medical complication. No procedure was aborted owing to intolerance. No patient required admission. No intraoperative surgical or medical complications occurred. Observed complications included delayed capillary refill requiring phentolamine administration after a trigger thumb release performed using epinephrine without a tourniquet (n = 1; 0.1%), complex regional pain syndrome (n = 3; 0.2%), infection requiring surgical debridement (n = 2; 0.2%), and recurrent symptoms requiring reoperation (n = 8; 0.7%). CONCLUSIONS: In this cohort of patients in whom surgery was performed in a PR, there were no major intraoperative surgical or medical complications. There was a low rate of postoperative infection, development of complex regional pain syndrome, and a low need for revision surgery. These observations do not support the concern for safety as a barrier to performing minor hand surgery in the PR setting. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Plasma Cells: From Cytokine Production to Regulation in Experimental Autoimmune Encephalomyelitis.

B cells are a critical arm of the adaptive immune system. After encounter with antigen, B cells are activated and differentiate into plasmablasts (PBs) and plasma cells (PCs). Although their frequency is low, PB/PCs can be found in all lymphoid organs including peripheral lymph nodes and spleen. Upon immunization, depending on the location of where B cells encounter their antigen, PB/PCs subsequently home to and accumuate in the bone marrow and the intestine where they can survive as long-lived plasma cells for years, continually producing antibody. Recent evidence has shown that, in addition to producing antibodies, PB/PCs can also produce cytokines such as IL-17, IL-10, and IL-35. In addition, PB/PCs that produce IL-10 have been shown to play a regulatory role during experimental autoimmune encephalomyelitis, an animal model of neuroinflammation. The purpose of this review is to describe the phenotype and function of regulatory PB/PCs in the context of experimental autoimmune encephalomyelitis and in patients with multiple sclerosis.

Closed manipulation under anesthesia for pediatric post-traumatic elbow arthrofibrosis.

BACKGROUND: Post-traumatic elbow arthrofibrosis (PEA) and its associated limitations to elbow range of motion (ROM) are a recognized consequence of trauma to the pediatric elbow. Closed manipulation under anesthesia (CMUA) of the elbow can be performed in pediatric patients as a nonoperative attempt to improve dysfunctional ROM. Minimal outcome data to support CMUA exist. The study evaluates the efficacy of CMUA for PEA in pediatric patients. METHODS: Patients younger than 18 years who underwent CMUA (Current Procedural Terminology code 24300) for PEA between 2005 and 2015 at 3 institutions were included. A retrospective chart review was performed to collect demographic data and ROM premanipulation and at last follow-up. Paired 2-tailed t tests were used to compare pre- and postmanipulation elbow ROM. RESULTS: Thirteen patients with a mean age of 12.2 ± 2.6 years (range 6.7-15.6 years) met the inclusion criteria. Median time to CMUA from initial surgery was 4.2 months (interquartile range [IQR] 3.6-8.4, range 1.4-19.7 months). Median follow-up time was 6 months with an IQR of 3.3-10.0 months. At last follow-up, there was significant improvement in elbow flexion of 22° ± 17° (P < .001) and extension of 29° ± 21° (P < .001). The average premanipulation motion arc of 60° ± 24° significantly increased to 110° ± 22° at final assessment (P < .001). CONCLUSION: CMUA appears to be a valuable alternative and reliable procedure for improving PEA in pediatric patients who exhaust nonoperative interventions.

Syndactyly release: a comparison of skin graft versus graftless techniques in the same patient.

Syndactyly release may be done by skin graft or graftless techniques. We prospectively examined bilateral syndactyly releases in the same patient at one operation. The grafted side was randomized and the contralateral side was done graftless. Fourteen patients had surgery at a mean age of 27 months (range 7-166). The mean follow-up was 52 months (range 6-111). The mean tourniquet time was 97 minutes (range 66-135) for graft and 84 minutes (55-120) for graftless. The mean finger abduction was 57° (32°-80°) for graft and 54° (38°-80°) for graftless. The mean web creep score was 1.2 (0-3) for graft and 2.1 (0-3) for graftless. The mean scar score was 1.9 (1-3) bilaterally. The mean parents' visual analogue scale for graft cosmesis was 7.1 (5-9) and 6.2 (4.3-8) for graftless. The surgeon's visual analogue scale for graft was 7.9 (6.4-9.5) and 6.2 (4-8.7) for graftless. The therapist's visual analogue scale was 7.9 (6.5-10) and 6.4 (4.7-8) for graftless. Although there is a longer tourniquet time with grafting, there may be advantages in appearance and web creep. Level of evidence: II.

Recirculating Intestinal IgA-Producing Cells Regulate Neuroinflammation via IL-10.

Plasma cells (PC) are found in the CNS of multiple sclerosis (MS) patients, yet their source and role in MS remains unclear. We find that some PC in the CNS of mice with experimental autoimmune encephalomyelitis (EAE) originate in the gut and produce immunoglobulin A (IgA). Moreover, we show that IgA+ PC are dramatically reduced in the gut during EAE, and likewise, a reduction in IgA-bound fecal bacteria is seen in MS patients during disease relapse. Removal of plasmablast (PB) plus PC resulted in exacerbated EAE that was normalized by the introduction of gut-derived IgA+ PC. Furthermore, mice with an over-abundance of IgA+ PB and/or PC were specifically resistant to the effector stage of EAE, and expression of interleukin (IL)-10 by PB plus PC was necessary and sufficient to confer resistance. Our data show that IgA+ PB and/or PC mobilized from the gut play an unexpected role in suppressing neuroinflammation.

A Prospective, Randomized Trial of Mobilization Protocols Following Ligament Reconstruction and Tendon Interposition.

BACKGROUND: The purpose of this study was to evaluate the hypothesis that an increased duration of immobilization following trapeziectomy with ligament reconstruction and tendon interposition (LRTI) leads to improved patient-reported outcomes compared with an early mobilization protocol. METHODS: At 2 institutions, we prospectively randomized 223 patients (238 thumbs) undergoing LRTI to receive 1 of 2 postoperative rehabilitation protocols. The immobilization protocol consisted of use of a postoperative forearm-based thumb-spica splint for 7 days followed by a forearm-based thumb-spica cast for 5 weeks and then by a custom forearm-based thermoplastic thumb-spica splint for an additional 6 weeks. An active range of motion (ROM) was started 6 weeks postoperatively. The early mobilization protocol consisted of the same postoperative splint for 7 days followed by use of a forearm-based thermoplastic thumb-spica splint for 3 weeks and then by a hand-based thumb-spica splint for 4 weeks. An active ROM was started 4 weeks postoperatively. The outcome measures included the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire; pinch and grip strength; 9-hole peg test (NHP); visual analog scale (VAS) for pain; VAS for patient satisfaction; and wrist and thumb ROM. These were measured preoperatively and at 6, 12, 26, 52, and 104 weeks postoperatively. Differences in continuous and categorical variables were assessed with use of Tukey multiple comparisons following 1-way analysis of variance and Fisher exact tests, respectively. RESULTS: A minimum follow-up of 1 year (mean, 1.7 years) was achieved for 71% (169) of the 238 randomized thumbs (157 of the 223 patients): 74 patients (80 thumbs) treated with the immobilization protocol and 83 patients (89 thumbs) treated with the early mobilization protocol. DASH scores, VAS pain scores, VAS patient satisfaction scores, and strength all improved similarly with no significant differences between groups at any time point. Wrist and thumb ROM and NHP outcomes were significantly worse for the immobilization group at 6 weeks postoperatively, with no differences observed between groups at 12 weeks and beyond. CONCLUSIONS: A conservative immobilization protocol does not improve functional outcomes, satisfaction, strength, or ROM following LRTI compared with an early mobilization protocol. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

The responsiveness of the PROMIS instruments and the qDASH in an upper extremity population.

BACKGROUND: This study evaluated the responsiveness of several PROMIS patient-reported outcome measures in patients with hand and upper extremity disorders and provided comparisons with the qDASH instrument. METHODS: The PROMIS Upper Extremity computer adaptive test (UE CAT) v1.2, the PROMIS Physical Function (PF) CAT v1.2, the PROMIS Pain Interference (PI) CAT v1.1 and the qDASH were administered to patients presenting to an orthopaedic hand clinic during the years 2014-2016, along with anchor questions. The responsiveness of these instruments was assessed using anchor based methods. Changes in functional outcomes were evaluated by paired-sample t-test, effect size, and standardized response mean. RESULTS: There were a total of 255 patients (131 females and 124 males) with an average age of 50.75 years (SD = 15.84) included in our study. Based on the change and no change scores, there were three instances (PI at 3 months, PI >3 months, and qDASH >3 months follow-ups) where scores differed between those experiencing clinically meaningful change versus no clinically meaningful change. Effect sizes for the responsiveness of all instruments were large and ranged from 0.80-1.48. All four instruments demonstrated high responsiveness, with a standardized response mean ranging from 1.05 to 1.63. CONCLUSION: The PROMIS UE CAT, PF CAT, PI CAT, and qDASH are responsive to patient-reported functional change in the hand and upper extremity patient population.

Replantation of the upper extremity: current concepts.

Replantation is the process of reattaching amputated parts. Relative indications for replantation in the upper extremity include amputation of the thumb or multiple digits as well as amputations proximal to zone II and pediatric finger amputations at any level. Preoperatively, the part should be sealed in a bag and placed on ice; maximum ischemia times are approximately 12 hours of warm and 24 hours of cold time for digits, with shorter times tolerated for amputations at more proximal levels. With multiple digit involvement, an assembly line approach is used in the operating room. Postoperatively, close attention must be paid to detect thrombosis because secondary ischemia times are shorter. Success rates vary; survival is predicted in part by the mechanism of injury, with sharp cut injuries having better outcomes. There is no consensus on appropriate postoperative anticoagulation, the number of vessels that must be anastomosed, or whether replantations should be centralized or performed in every hospital.

Results of Treatment of Delta Triphalangeal Thumbs by Excision of the Extra Phalanx.

BACKGROUND: We examined the long-term results of treatment of delta triphalangeal thumbs by excision of the delta ossicle alone with respect to range of motion (ROM), pain, and angulation at the interphalangeal (IP) joint. METHODS: We retrospectively reviewed charts to identify patients who had Woods type I delta triphalangeal thumbs and underwent treatment by excision of the extra ossicle. Patients with >2 years' follow-up were then brought in for examination and radiographs. RESULTS: We identified 21 thumbs in 14 patients. All patients with bilateral thumb involvement, except 1, had them treated at the same surgery. The average age at surgery was 22 months (range, 5 to 69 mo). Preoperatively, 2 patients had tip radial angulation, averaging 53 degrees. The other 19 thumbs were deviated tip ulnarly with an average preoperative angulation of 40 degrees (range, 20 to 85 degrees). All patients had pinning of the IP joint for an average of 4.5 weeks (range, 3 to 9 wk), and 14 thumbs had collateral ligament repair. We obtained follow-up data >2 years on 14 thumbs in 10 patients. The average follow-up was 6.7 years (range, 2 to 17 y). Average ROM at final follow-up was <-4-degree extension (range, -20 to 0 degrees) to 56-degree flexion (range, 30 to 82 degrees). Average clinical angulation was <1 degree (range, 0 to 10 degrees) and the average radiographic angulation was 7 degrees (range, 0 to 25 degrees). No degenerative changes were noted. There were no complaints of pain and 1 patient had persistent IP instability. No other surgeries had been performed on the affected thumbs and there were no other complications. CONCLUSIONS: Delta triphalangeal thumbs treated by excision of the extra ossicle can be expected to yield good long-lasting results with acceptable thumb IP ROM and no pain. Clinical appearance of the thumb with regard to angulation tends to be superior to radiographic findings. We prefer this method in treating Woods type I delta triphalangeal thumbs. LEVEL OF EVIDENCE: IV.

The importance of shoulder external rotation in activities of daily living: improving outcomes in traumatic brachial plexus palsy.

PURPOSE: To define the importance of shoulder external rotation in activities of daily living in normal individuals to better understand how restoration of shoulder external rotation in traumatic brachial plexus palsy could improve patient function. METHODS: Thirty-one normal individuals performed 12 common activities of daily living (ADLs) wearing a custom shoulder orthosis designed to selectively limit shoulder external rotation to 3 different settings, ranging from 0° (most restrictive) to 90° (least restrictive) of external rotation. Outcomes were measured with a visual analog scale of perceived difficulty in accomplishing the ADLs with each orthosis setting and the Disabilities of the Arm, Shoulder, and Hand questionnaire administered after each set of 12 ADLs was completed. RESULTS: Subjects perceived increasing difficulty during all ADLs tested and registered higher disability scores with increasing restriction of shoulder external rotation. The ADLs requiring motions predominantly above the waist exhibited more marked and earlier changes in visual analog scale scores with increasing shoulder external rotation restriction. CONCLUSIONS: Traditionally, surgeons have pursued restoration of shoulder abduction and forward elevation in secondary reconstruction of traumatic brachial plexus injuries. Recently, the concept of preferentially restoring shoulder external rotation has been proposed, without clear evidence in the literature of the role of shoulder external rotation in ADLs. CLINICAL RELEVANCE: Our results support the notion that restoring shoulder external rotation in the treatment of traumatic brachial plexus palsy patients might improve outcomes by decreasing patient disability and increasing the ability to perform ADLs.