Machine learning analysis of humoral and cellular responses to SARS-CoV-2 infection in young adults.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces B and T cell responses, contributing to virus neutralization. In a cohort of 2,911 young adults, we identified 65 individuals who had an asymptomatic or mildly symptomatic SARS-CoV-2 infection and characterized their humoral and T cell responses to the Spike (S), Nucleocapsid (N) and Membrane (M) proteins. We found that previous infection induced CD4 T cells that vigorously responded to pools of peptides derived from the S and N proteins. By using statistical and machine learning models, we observed that the T cell response highly correlated with a compound titer of antibodies against the Receptor Binding Domain (RBD), S and N. However, while serum antibodies decayed over time, the cellular phenotype of these individuals remained stable over four months. Our computational analysis demonstrates that in young adults, asymptomatic and paucisymptomatic SARS-CoV-2 infections can induce robust and long-lasting CD4 T cell responses that exhibit slower decays than antibody titers. These observations imply that next-generation COVID-19 vaccines should be designed to induce stronger cellular responses to sustain the generation of potent neutralizing antibodies.

Learning how to perform ultrasound-guided interventions with and without augmented reality visualization: a randomized study.

OBJECTIVES: Augmented reality (AR), which entails overlay of in situ images onto the anatomy, may be a promising technique for assisting image-guided interventions. The purpose of this study was to investigate and compare the learning experience and performance of untrained operators in puncture of soft tissue lesions, when using AR ultrasound (AR US) compared with standard US (sUS). METHODS: Forty-four medical students (28 women, 16 men) who had completed a basic US course, but had no experience with AR US, were asked to perform US-guided biopsies with both sUS and AR US, with a randomized selection of the initial modality. The experimental setup aimed to simulate biopsies of superficial soft tissue lesions, such as for example breast masses in clinical practice, by use of a turkey breast containing olives. Time to puncture(s) and success (yes/no) of the biopsies was documented. All participants completed questionnaires about their coordinative skills and their experience during the training. RESULTS: Despite having no experience with the AR technique, time to puncture did not differ significantly between AR US and sUS (median [range]: 17.0 s [6-60] and 14.5 s [5-41], p = 0.16), nor were there any gender-related differences (p = 0.22 and p = 0.50). AR US was considered by 79.5% of the operators to be the more enjoyable means of learning and performing US-guided biopsies. Further, a more favorable learning curve was achieved using AR US. CONCLUSIONS: Students considered AR US to be the preferable and more enjoyable modality for learning how to obtain soft tissue biopsies; however, they did not perform the biopsies faster than when using sUS. KEY POINTS: • Performance of standard and augmented reality US-guided biopsies was comparable • A more favorable learning curve was achieved using augmented reality US. • Augmented reality US was the preferred technique and was considered more enjoyable.

Results of Arthroscopic Revision Rotator Cuff Repair for Failed Open or Arthroscopic Repair: A Prospective Multicenter Study on 100 Cases.

BACKGROUND: Retears after rotator cuff repair (RCR) have been associated with poor clinical results. Meaningful data regarding the role of arthroscopic revision RCR are sparse thus far. PURPOSE/HYPOTHESIS: To investigate results after arthroscopic revision RCR. We hypothesized that (1) arthroscopic revision RCR would lead to improved outcomes, (2) the clinical results would be dependent on tendon integrity and (3) tear pattern, tendon involvement, and repair technique would influence clinical and structural results. STUDY DESIGN: Case series; Level of evidence 4. METHODS: During a 40-month period, 100 patients who underwent arthroscopic revision RCR were prospectively enrolled in this multicenter study. Outcomes were evaluated preoperatively, at 6 months (6M), and at 24 months (24M) using the Constant score (CS), the Oxford Shoulder Score (OSS), and the Subjective Shoulder Value (SSV). Tendon integrity at 2 years was analyzed using magnetic resonance imaging. A total of 13 patients (13%) were lost to follow-up, and 14 patients (14%) had a symptomatic retear before the 24M follow-up. RESULTS: All clinical scores improved significantly during the study period (CS: preoperative, 44 ± 16; 6M, 58 ± 22; 24M, 69 ± 19 points; OSS: preoperative, 27 ± 8; 6M, 36 ± 11; 24M, 40 ± 9 points; SSV: preoperative, 43% ± 18%; 6M, 66% ± 24%; 24M, 75% ± 22%) (P < .01). At 2 years, a retear rate of 51.8% (43/83) and a surgical revision rate of 12.6% (11/87) were observed. Mean full-thickness tear size decreased from 5.00 ± 1.61 cm2 to 3.25 ± 1.92 cm2 (P = .041). Although the Sugaya score improved from 4.5 ± 0.9 to 3.7 ± 1.4 (P = .043), tendon integrity did not correlate with better outcome scores. Previous open RCR, involvement of the subscapularis, chondral lesions of Outerbridge grade ≥2, and medial cuff failure were correlated with poorer SSV scores at 2 years (P≤ .047). Patients with traumatic retears had better CS and OSS scores at 2 years (P≤ .039). CONCLUSION: Although arthroscopic revision RCR improved shoulder function, retears were frequent but usually smaller. Patients with retears, however, did not necessarily have poorer shoulder function. Patient satisfaction at 2 years was lower when primary open RCR was performed, when a subscapularis tear or osteoarthritis was present, and when the rotator cuff retear was located at the musculotendinous junction. Patients with traumatic retears showed better functional improvement after revision.

The Schulthess local Shoulder Arthroplasty Registry (SAR): cohort profile.

PURPOSE: Clinical registries are essential for evaluation of surgical outcomes. The Schulthess Shoulder Arthroplasty Registry (SAR) was established in 2006 to evaluate safety, function, quality-of-life and patient satisfaction in patients undergoing shoulder arthroplasty. PARTICIPANTS: Adult patients undergoing anatomic or reverse shoulder joint replacement at the Schulthess Klinik, a high-volume, leading orthopaedic surgery centre in Zürich, Switzerland. FINDINGS TO DATE: Between March 2006 and December 2019, the registry covered 98% of eligible operations. Overall, 2332 patients were enrolled with a total of 2796 operations and 11 147 person-years of follow-up. Mean age at baseline was 71 (range: 20-95), 65% were women. Most common indication was rotator cuff tears with osteoarthritis (42%) and the mean preoperative Constant Score was 31 (±15). The most frequent arthroplasty type was reverse, increasing from 61% in 2006-2010 to 86% in 2015-2019. Functional recovery peaked at 12-month postoperatively and did not show a clinically relevant deterioration during the first ten follow-up years. Since its establishment, the registry was used to address multiple pertinent clinical and methodological questions. Primary focus was on comparing different implant configurations (eg, glenosphere diameter) and surgical techniques (eg, latissimus dorsi transfer) to maximise functional recovery. Additionally, the cohort contributed to the determination of the clinical relevance and validity of radiological monitoring of cortical bone resorption and scapular notching. Finally, SAR data helped to demonstrate that returning to sports was among key patient expectations after reverse shoulder arthroplasty. FUTURE PLANS: As first patients are approaching the 15 years follow-up landmark, the registry will continue providing essential data on long-term functional outcomes, implant stability, revision rates and aetiologies as well as patient satisfaction and quality-of-life. In addition to research and quality-control, the cohort data will be brought back to the patients by bolstering real-time clinical decision support.

Plating and cortical bone grafting of clavicular nonunions: clinical outcome and its relation to clavicular length restoration.

BACKGROUND: The goal of this study was to evaluate whether plating and cortical bone grafting of shortened clavicular nonunions would restore clavicular length and enable bone healing. The association between the clavicular length difference (CLD) between sides and long-term functional outcome was also explored. METHODS: For this retrospective 2-center study, patients who underwent plate fixation with cortical bone grafting of a clavicular nonunion were assessed after ≥2 years. The CLD and bone union were assessed using radiography and navigation ultrasound. The functional outcome was determined by the Constant score, Simple Shoulder Test score, and Subjective Shoulder Value, as well as local pain (0-10 numeric rating scale). RESULTS: Between 2 and 13 years after surgery, 25 patients (mean age, 53 years; 13 female patients) were examined. The median CLD was 0 mm (range, -17 to 13 mm) on ultrasound measurements and 2 mm (range, -32 to 9 mm) on radiographs. At follow-up, the median Constant score, Simple Shoulder Test score, Subjective Shoulder Value, and pain level were 82 points (range, 38-95 points), 12 points (range, 3-12 points), 95% (range, 60%-100%), and 0 (range, 0-8), respectively. There was no correlation between the CLD and all functional outcome scores. Bone union was achieved in all patients. After plate removal, 4 refractures occurred, 3 of which required revision. CONCLUSIONS: Plate fixation with cortical bone grafting of clavicular nonunions is associated with restoration of clavicular length and a high rate of bone union. There is, however, a considerable risk of refracture following plate removal. There was no association between the CLD and clinical outcome.

Re-intervention and revision rates following primary reverse total shoulder arthroplasty - review of a local shoulder arthroplasty registry.

PURPOSE: Our primary aim was to describe the re-intervention and revision rates after primary reverse shoulder arthroplasty (RSA) documented in a local shoulder arthroplasty registry. We also identify the main indication for revision and re-intervention, which may be relevant for patient outcome post-RSA. METHODS: Since July 2006, RSAs are consecutively documented in our clinic registry and prospectively controlled with follow-ups. Any intervention after primary RSA requiring a return to the operating room for any shoulder-related indication was termed a re-intervention. Revisions were defined as surgeries involving any exchange, removal, or addition of at least one component. The study endpoints were survival rates at two, five and ten years follow-up for both definitions. RESULTS: Until July 2017, 63 from a total of 1480 primary RSAs required at least one re-intervention and 33 patients had a revision. Open reduction and internal fixation for fractures around the implant (n = 14) were the predominating indications for re-intervention. The re-intervention rate for instability was 0.5%. For re-interventions, survival rates were 97.7, 95.4 and 90.8% at two, five and ten years, respectively, and the respective rates for revisions were 98.7, 97.5 and 95.3%. CONCLUSION: The revision rate after primary RSA for our patient registry is low. A relevant number of additional interventions were noted that did not require any component revision but may impair the final outcome post-RSA. By only reporting revision rates, the number of post-RSA re-interventions is clearly underestimated. We recommend the documentation of all events leading to any re-intervention in arthroplasty registries.

Limited reliability of grading scapular notching according to Nerot-Sirveaux on anteroposterior radiographs.

INTRODUCTION: Incidences of scapular notching (SN) in reverse shoulder arthroplasty (RSA) range between 0% and 96%, and controversy remain as to its relevance for patient outcome. We assessed the reliability of scapular notching (SN) grading based on the Sirveaux classification system using anteroposterior radiographs. MATERIALS AND METHODS: 206 RSA procedures with 5-year postoperative anteroposterior shoulder radiographs were classified independently by seven assessors according to Sirveaux (session 1). After a review meeting, three assessors re-classified the radiographs along with quality criteria (session 2). SN grading by the majority of assessors was taken as the reference. Classification interobserver reliability was analyzed using Kappa statistics. RESULTS: The incidence of SN was estimated at 53% and 37% at the first and second sessions, respectively. Interobserver reliability Kappa coefficients resulting from the first and second sessions were 0.27 and 0.43, respectively. Case selection based on radiographic quality criteria did not improve SN grading reliability in the second session. CONCLUSION: Agreement between individual surgeons was low when grading SN in RSA according to Sirveaux using anteroposterior radiographs. Consensus among several assessors may increase reliability in research settings.

Latissimus dorsi muscle transfer reduces external rotation deficit at the cost of internal rotation in reverse shoulder arthroplasty patients: a cohort study.

HYPOTHESIS: We hypothesized that treatment of rotator cuff arthropathy (RCA) with reverse shoulder arthroplasty (RSA) and an additional latissimus dorsi transfer (LDT) in patients with an active external rotation deficit (ERD) would restore external rotation (ER) with concomitant deterioration in internal rotation. METHODS: In our cohort study, 26 RCA patients with an active ERD (ie, positive lag sign and maximum active ER of 0°) underwent RSA between September 2007 and February 2015; LDT was completed in 13 of these patients. In addition, 88 control patients without ERD who underwent only RSA were identified. Clinical outcomes of strength, range of motion, Constant-Murley score, and Shoulder Pain and Disability Index score, as well as complications, were documented 6, 12, 24, and 60 months postoperatively. We made comparative analyses using statistical mixed models. RESULTS: The LDT procedure extended the surgical time by 26 minutes (P = .003). LDT patients had up to 22° better postoperative active ER than control patients (P < .001), although this was accompanied by an internal rotation deficit (77% vs 46% of control patients could not reach the lumbosacral region, P = .010). We calculated a 23% risk of local procedure-related complications for RSA patients with an active ERD and LDT. CONCLUSION: Patients with RCA and an active ERD seem to benefit from an LDT, although this is accompanied by the potential loss of internal rotation. This additional procedure is associated with an extended surgical time as well as a possible increase in the risk of a complication occurring.

Evaluating the bromodomain protein BRD1 as a therapeutic target in rheumatoid arthritis.

Targeting epigenetic reader proteins by small molecule inhibitors represents a new therapeutic concept in autoimmune diseases such as rheumatoid arthritis (RA). Although inhibitors targeting bromodomain protein 1 (BRD1) are in development, the function of BRD1 has hardly been studied. We investigated the therapeutic potential of BRD1 inhibition in joint-resident cells in RA, synovial fibroblasts (SF) and macrophages. The proliferation of SF was decreased upon BRD1 silencing, accompanied by the downregulation of genes involved in cell cycle regulation. Silencing of BRD1 in SF decreased the basal expression of MMP1 but increased TNF-α- and LPS-induced levels of MMP3, IL6 and IL8. In monocyte-derived macrophages (MDM), silencing of BRD1 decreased the LPS-induced expression of TNF-α, but did not significantly affect basal and the TNF-α- and LPS-induced expression of IL6 and IL8. Our data point to a cell type- and a stimulus-specific function of BRD1. Inhibiting BRD1 could have potential beneficial effects in RA via decreasing the proliferation of SF. Anti-inflammatory effects were limited and only observed in MDM.

Analysis of early changes in DNA methylation in synovial fibroblasts of RA patients before diagnosis.

DNA methylation is an important epigenetic modification that is known to be altered in rheumatoid arthritis synovial fibroblasts (RASF). Here, we compared the status of promoter DNA methylation of SF from patients with very early RA with SF from patients with resolving arthritis, fully established RA and from non-arthritic patients. DNA was hybridized to Infinium Human methylation 450k and 850k arrays and differential methylated genes and pathways were identified. We could identify a significant number of CpG sites that differed between the SF of different disease stages, showing that epigenetic changes in SF occur early in RA development. Principal component analysis confirmed that the different groups of SF were separated according to their DNA methylation state. Furthermore, pathway analysis showed that important functional pathways were altered in both very early and late RASF. By focusing our analysis on CpG sites in CpG islands within promoters, we identified genes that have significant hypermethylated promoters in very early RASF. Our data show that changes in DNA methylation differ in RASF compared to other forms of arthritis and occur at a very early, clinically yet unspecific stage of disease. The identified differential methylated genes might become valuable prognostic biomarkers for RA development.

TLR3 Ligand Poly(I:C) Exerts Distinct Actions in Synovial Fibroblasts When Delivered by Extracellular Vesicles.

Extracellular vesicles (EV) can modulate the responses of cells to toll-like receptor (TLR) ligation; conversely, TLR ligands such as double-stranded RNA (dsRNA) can enhance the release of EV and influence of the composition and functions of EV cargos. Inflamed synovial joints in rheumatoid arthritis (RA) are rich in EV and extracellular RNA; besides, RNA released from necrotic synovial fluid cells can activate the TLR3 signaling in synovial fibroblasts (SFs) from patients with RA. Since EV occur prominently in synovial joints in RA and may contribute to the pathogenesis, we questioned whether EV can interact with dsRNA, a TLR3 ligand, and modify its actions in arthritis. We have used as model the effects on RA SFs, of EV released from monocyte U937 cells and peripheral blood mononuclear cells upon stimulation with Poly(I:C), a synthetic analog of dsRNA. We show that EV released from unstimulated cells and Poly(I:C)-stimulated U937 cells [Poly(I:C) EV] differ in size but bind similar amounts of Annexin V and express comparable levels of MAC-1, the receptor for dsRNA, on the vesicular membranes. Specifically, Poly(I:C) EV contain or associate with Poly(I:C) and at least partially protect Poly(I:C) from RNAse III degradation. Poly(I:C) EV shuttle Poly(I:C) to SFs and reproduce the proinflammatory and antiviral gene responses of SFs to direct stimulation with Poly(I:C). Poly(I:C) EV, however, halt the death receptor-induced apoptosis in SFs, thereby inverting the proapoptotic nature of Poly(I:C). These prosurvival effects sharply contrast with the high toxicity of cationic liposome-delivered Poly(I:C) and may reflect the route of Poly(I:C) delivery via EV or the fine-tuning of Poly(I:C) actions by molecular cargo in EV. The demonstration that EV may safeguard extracellular dsRNA and allow dsRNA to exert antiapoptotic effects on SFs highlights the potential of EV to amplify the pathogenicity of dsRNA in arthritis beyond inflammation (by concurrently enhancing the expansion of the invasive synovial stroma).

Return to sports after reverse shoulder arthroplasty-the Swiss perspective.

PURPOSE: This patient survey evaluated the return to previous sports activities in Swiss patients up to five years after reverse shoulder arthroplasty (RSA). METHODS: We screened our local shoulder arthroplasty registry for patients registered with a unilateral RSA due to rotator cuff deficiency between May 2010 and May 2015. Revision cases and patients already known as unwilling or unable to complete a German language questionnaire were excluded. Eligible patients received a paper questionnaire asking about their past and current sports activities, return time point and level of activity. RESULTS: Of 305 patients, 89% responded at a mean post-operative follow-up of 2.9 years (SD 1.1). The respondents had a mean age of 77.1 years (SD 7.8) and included 62% females. The overall rate of patients returning to a previous sports activity was 77%. Sixty-one percent (166/271) participated in regular sports activities before the onset of their shoulder disorders. After RSA, 47% (127/271) participated in at least one sport type with the most frequent activities including hiking (66), swimming (53), cycling (45) and callisthenics (43). Most patients carried out their main sports activity after surgery with a moderate level of intensity (83%) and between one to three times per week (69%). Forty-two percent of the respondents indicated that returning to sports was among their key demands after RSA. CONCLUSIONS: Returning to previous sports activities is an important expectation of RSA patients, and the majority do. Patient expectations of post-operative sports activity need to be addressed when planning RSA.

Glenosphere size in reverse shoulder arthroplasty: is larger better for external rotation and abduction strength?

BACKGROUND: The role of glenosphere size in reverse shoulder arthroplasty (RSA) may be important in prosthetic stability, joint kinematics, rotator cuff tension and excursion, scapular impingement, humeral lateralization, deltoid wrap, and the occurrence of "notching." This study compared short- and midterm clinical and radiographic outcomes for 2 different glenosphere sizes of a single RSA type with respect to implant positioning, glenoid size, and morphology. METHODS: This retrospective analysis included 68 RSA procedures that were prospectively documented in a local register during a 5-year postoperative period. Two glenosphere diameter sizes of 36 mm (n = 33) and 44 mm (n = 35) were used. Standard radiographs were made preoperatively (ie, baseline) and at 6, 12, 24, and 60 months after surgery. Range of motion, strength, the Constant-Murley score, and the Shoulder Pain and Disability Index were also assessed at all follow-up visits. The effect of glenosphere size on measured outcomes was adjusted for baseline values, patient gender, and humeral head diameter. RESULTS: No significant differences were found in the functional scores between treatment groups at all follow-up assessments. At the 12-month follow-up, patients with a 44-mm glenosphere had greater external rotation in adduction (mean difference, 12°; P = .001) and abduction strength (mean difference, 1.4 kg; P = .026) compared with those with the smaller implant. These differences remained at 60 months. Scapular notching was observed in 38% of all patients, without any relevant difference between the groups. CONCLUSION: An increase in glenosphere diameter leads to a clinically moderate but significant increase in external rotation in adduction and abduction strength at midterm follow-up.

The epigenetic architecture at gene promoters determines cell type-specific LPS tolerance.

Synovial fibroblasts (SF) drive inflammation and joint destruction in chronic arthritis. Here we show that SF possess a distinct type of LPS tolerance compared to macrophages and other types of fibroblasts. In SF and dermal fibroblasts, genes that were non-tolerizable after repeated LPS stimulation included pro-inflammatory cytokines, chemokines and matrix metalloproteinases, whereas anti-viral genes were tolerizable. In macrophages, all measured genes were tolerizable, whereas in gingival and foreskin fibroblasts these genes were non-tolerizable. Repeated stimulation of SF with LPS resulted in loss of activating histone marks only in promoters of tolerizable genes. The epigenetic landscape at promoters of tolerizable genes was similar in unstimulated SF and monocytes, whereas the basal configuration of histone marks profoundly differed in genes that were non-tolerizable in SF only. Our data suggest that the epigenetic configuration at gene promoters regulates cell-specific LPS-induced responses and primes SF to sustain their inflammatory response in chronic arthritis.

Epigenetically-driven anatomical diversity of synovial fibroblasts guides joint-specific fibroblast functions.

A number of human diseases, such as arthritis and atherosclerosis, include characteristic pathology in specific anatomical locations. Here we show transcriptomic differences in synovial fibroblasts from different joint locations and that HOX gene signatures reflect the joint-specific origins of mouse and human synovial fibroblasts and synovial tissues. Alongside DNA methylation and histone modifications, bromodomain and extra-terminal reader proteins regulate joint-specific HOX gene expression. Anatomical transcriptional diversity translates into joint-specific synovial fibroblast phenotypes with distinct adhesive, proliferative, chemotactic and matrix-degrading characteristics and differential responsiveness to TNF, creating a unique microenvironment in each joint. These findings indicate that local stroma might control positional disease patterns not only in arthritis but in any disease with a prominent stromal component.

Radiological and functional 24-month outcomes of resurfacing versus stemmed anatomic total shoulder arthroplasty.

PURPOSE: This study compared clinical and radiographic outcomes of patients undergoing resurfacing total shoulder arthroplasty (TSA) with those treated with a stemmed TSA. METHODS: Patients with primary osteoarthritis who underwent humeral resurfacing (RES) or stemmed (STA) TSA were identified in our shoulder arthroplasty register for retrospective analysis. Standard radiographs and clinical/patient-rated assessments were made up to 24 months post-surgery. Implant revisions were assessed. Patients were frequency-matched in a 1:1 (RES:STA) ratio based on gender and age, and compared with regard to operation time and shoulder function (Constant, SPADI and Quick DASH scores). Mixed models with statistical adjustments were applied. RESULTS: From 2006 to 2014, 44 RES and 137 STA operations were performed in 157 patients; one and two revisions were recorded in the RES and STA group, respectively. The final matched cohort included a total of 69 patients and 37 operations per treatment group. Resurfacing TSA was 17 min shorter (95%CI: 5-28) compared to the stemmed procedure (p = 0.005). RES and STA patients showed significant functional improvement six months post-implantation, yet all measured scores did not differ between the groups at 2 years (p ≥ 0.131). The status of static centering of the humeral head, acromiohumeral distance, and a lack of signs of implant loosening were also similar between treatments. CONCLUSION: Similar 24-month post-operative radiological and functional outcome is achieved by RES and STA patients, even with a shorter RES surgery time. Larger cohorts and longer follow-up are required to better assess implant survival.

Expression and Regulation of PIWIL-Proteins and PIWI-Interacting RNAs in Rheumatoid Arthritis.

OBJECTIVE: The PIWIL (P-element induced wimpy testis like protein) subfamily of argonaute proteins is essential for Piwi-interacting RNA (piRNA) biogenesis and their function to silence transposons during germ-line development. Here we explored their presence and regulation in rheumatoid arthritis (RA). METHODS: The expression of PIWIL genes in RA and osteoarthritis (OA) synovial tissues and synovial fibroblasts (SF) was analysed by Real-time PCR, immunofluorescence and Western blot. The expression of piRNAs was quantified by next generation small RNA sequencing (NGS). The regulation of PIWI/piRNAs, proliferation and methylation of LINE-1 after silencing of PIWIL genes were studied. RESULTS: PIWIL2 and 4 mRNA were similarly expressed in synovial tissues and SF from RA and OA patients. However, on the protein level only PIWIL4 was strongly expressed in SF. Using NGS up to 300 piRNAs were identified in all SF without significant differences in expression levels between RA and OASF. Of interest, the analysis of the co-expression of the detected piRNAs revealed a less tightly regulated pattern of piRNA-823, -4153 and -16659 expression in RASF. In RASF and OASF, stimulation with TNFα+IL1ß/TLR-ligands further significantly increased the expression levels of PIWIL2 and 4 mRNA and piRNA-16659 was significantly (4-fold) induced upon Poly(I:C) stimulation. Silencing of PIWIL2/4 neither affect LINE-1 methylation/expression nor proliferation of RASF. CONCLUSION: We detected a new class of small regulatory RNAs (piRNAs) and their specific binding partners (PIWIL2/4) in synovial fibroblasts. The differential regulation of co-expression of piRNAs in RASF and the induction of piRNA/Piwi-proteins by innate immune stimulators suggest a role in inflammatory processes.

AAA-ATPase p97 suppresses apoptotic and autophagy-associated cell death in rheumatoid arthritis synovial fibroblasts.

Valosin containing protein (p97) is a chaperone implicated in a large number of biological processes including endoplasmic reticulum (ER)-associated protein degradation and autophagy. Silencing of p97 in rheumatoid arthritis (RA) synovial fibroblasts (RASFs) increased the amount of polyubiquitinated proteins, whereas silencing of its interaction partner histone deacetylase 6 (HDAC6) had no effect. Furthermore, silencing of p97 in RASFs increased not only rates of apoptotic cell death induced by TRAIL but also induced an autophagy-associated cell death during ER stress that was accompanied by the formation of polyubiquitinated protein aggregates and large vacuoles. Finally, we demonstrated an anti-arthritic effect of siRNAs targeting p97 in collagen-induced arthritis in rats. Our data indicate that p97 may be a new potential target in the treatment of RA.

Conversion to hemiarthroplasty as a salvage procedure for failed reverse shoulder arthroplasty.

BACKGROUND: Optimal treatment of a failed reverse shoulder arthroplasty (RSA) is unclear. In the case of poor glenoid bone stock, retaining a RSA may be infeasible. We report our experience with conversions to hemiarthroplasty. METHODS: Within 7 years, 16 patients underwent conversion to hemiarthroplasty after failed RSA. All patients had insufficient bone stock for reimplantation of another RSA. Standard radiographs and Constant, Shoulder Pain and Disability Index, and the 11-item version of the Disabilities of the Arm, Shoulder and Hand scores were assessed preoperatively and up to a minimum of 24 months after surgery. Postoperative superior migration and complications were also documented. RESULTS: Glenoid loosening was the primary reason for RSA failure in 11 patients. Three required revision surgery because of infection. Postoperative functional outcome was generally poor at the latest follow-up, with mean Constant, Shoulder Pain and Disability Index, and 11-item version of the Disabilities of the Arm, Shoulder and Hand scores of 25, 37, and 63 points, respectively. Baseline pain also did not improve. Medialization progressed beyond the coracoid in 6 patients, and complete anterosuperior escape was reported in 3 patients. Three postoperative complications were recorded by the final follow-up, including 2 periprosthetic humeral fractures treated conservatively and 1 patient with painful humeral component medialization leading to resection arthroplasty. CONCLUSION: With excessive bone stock loss, hemiarthroplasty remains an option, despite the associated risks of uncertain pain relief and poor functional outcome. This technique offers a lower likelihood of undertaking further surgical interventions within the short-term to midterm postoperative period. Nevertheless, resection arthroplasty may still be considered another valuable solution.

Risk of insufficient internal rotation after bilateral reverse shoulder arthroplasty: clinical and patient-reported outcome in 57 patients.

BACKGROUND: Bilateral reverse shoulder arthroplasty (RSA) is controversial because of potential rotational deficits impairing daily living activities. We assessed achievement of insufficient internal rotation (IR) and associated factors in bilateral RSA patients. METHODS: Fifty-seven staged bilateral RSA patients with a minimum of 1 year of follow-up after the second intervention were identified from our local monocentric register. Shoulder range of motion (including IR using the Apley scratch test), strength, and Constant and Shoulder Pain and Disability Index scores were assessed preoperatively and 6, 12, and 24 months postoperatively. RESULTS: Before surgery, both shoulders were similar regarding imaging parameters, but first operated shoulders tended to have poorer function. One year after the first RSA, 21% of patients had insufficient IR (not reaching the lumbosacral junction) compared with 33% after the second intervention (P = .180). At 2 years, 5% of patients had insufficient IR on both sides. Patients with insufficient IR on the second side at baseline (relative risk [RR], 1.8 [1.0-3.2]) and patients with insufficient IR 1 year after the first RSA (RR, 3.0 [1.6-5.6]) were more likely to have insufficient IR 1 year after the second RSA. Constant and Shoulder Pain and Disability Index scores and abduction of the second side were significantly worse 1 year after the second RSA (P ≤ .047); at 2 years, there were no differences in functional outcome between shoulders. CONCLUSION: A minority of bilateral RSA patients did not achieve sufficient IR on at least 1 side. Staged surgery is justified, particularly when the outcome of the initial operation is satisfactory.