Torticollis with Atlantoaxial Rotatory Subluxation in Children: A Clinical Review.

A small proportion of children with a sudden onset torticollis ("wry neck") presents with an atlantoaxial rotatory subluxation, usually after mild trauma or recent head or neck infection. Torticollis is a clinical diagnosis and imaging is usually not indicated, though often performed in clinical practice. Atlantoaxial rotatory subluxation on imaging is often a physiological phenomenon in torticollis, and concomitant neurological symptoms are therefore rare. Treatment is primarily conservative, with analgesics, a rigid neck collar, and if needed benzodiazepines to counteract muscle spasms and anxiety. In case of treatment failure or chronic subluxation, cervical repositioning and fixation under general anesthesia may be considered. Surgical treatment is only indicated in a small percentage of patients with chronic refractory subluxation, concomitant cervical fractures, or congenital anomalies. Early diagnosis and treatment are important, since this is associated with a more successful conservative outcome than a prolonged approach.

Incorporating strontium enriched amorphous calcium phosphate granules in collagen/collagen-magnesium-hydroxyapatite osteochondral scaffolds improves subchondral bone repair.

Osteochondral defect repair with a collagen/collagen-magnesium-hydroxyapatite (Col/Col-Mg-HAp) scaffold has demonstrated good clinical results. However, subchondral bone repair remained suboptimal, potentially leading to damage to the regenerated overlying neocartilage. This study aimed to improve the bone repair potential of this scaffold by incorporating newly developed strontium (Sr) ion enriched amorphous calcium phosphate (Sr-ACP) granules (100-150 µm). Sr concentration of Sr-ACP was determined with ICP-MS at 2.49 ± 0.04 wt%. Then 30 wt% ACP or Sr-ACP granules were integrated into the scaffold prototypes. The ACP or Sr-ACP granules were well embedded and distributed in the collagen matrix demonstrated by micro-CT and scanning electron microscopy/energy dispersive x-ray spectrometry. Good cytocompatibility of ACP/Sr-ACP granules and ACP/Sr-ACP enriched scaffolds was confirmed with in vitro cytotoxicity assays. An overall promising early tissue response and good biocompatibility of ACP and Sr-ACP enriched scaffolds were demonstrated in a subcutaneous mouse model. In a goat osteochondral defect model, significantly more bone was observed at 6 months with the treatment of Sr-ACP enriched scaffolds compared to scaffold-only, in particular in the weight-bearing femoral condyle subchondral bone defect. Overall, the incorporation of osteogenic Sr-ACP granules in Col/Col-Mg-HAp scaffolds showed to be a feasible and promising strategy to improve subchondral bone repair.

Modulating design parameters to drive cell invasion into hydrogels for osteochondral tissue formation.

Background: The use of acellular hydrogels to repair osteochondral defects requires cells to first invade the biomaterial and then to deposit extracellular matrix for tissue regeneration. Due to the diverse physicochemical properties of engineered hydrogels, the specific properties that allow or even improve the behaviour of cells are not yet clear. The aim of this study was to investigate the influence of various physicochemical properties of hydrogels on cell migration and related tissue formation using in vitro, ex vivo and in vivo models. Methods: Three hydrogel platforms were used in the study: Gelatine methacryloyl (GelMA) (5% wt), norbornene hyaluronic acid (norHA) (2% wt) and tyramine functionalised hyaluronic acid (THA) (2.5% wt). GelMA was modified to vary the degree of functionalisation (DoF 50% and 80%), norHA was used with varied degradability via a matrix metalloproteinase (MMP) degradable crosslinker and THA was used with the addition of collagen fibrils. The migration of human mesenchymal stromal cells (hMSC) in hydrogels was studied in vitro using a 3D spheroid migration assay over 48h. In addition, chondrocyte migration within and around hydrogels was investigated in an ex vivo bovine cartilage ring model (three weeks). Finally, tissue repair within osteochondral defects was studied in a semi-orthotopic in vivo mouse model (six weeks). Results: A lower DoF of GelMA did not affect cell migration in vitro (p â€‹= â€‹0.390) and led to a higher migration score ex vivo (p â€‹< â€‹0.001). The introduction of a MMP degradable crosslinker in norHA hydrogels did not improve cell infiltration in vitro or in vivo. The addition of collagen to THA resulted in greater hMSC migration in vitro (p â€‹= â€‹0.031) and ex vivo (p â€‹< â€‹0.001). Hydrogels that exhibited more cell migration in vitro or ex vivo also showed more tissue formation in the osteochondral defects in vivo, except for the norHA group. Whereas norHA with a degradable crosslinker did not improve cell migration in vitro or ex vivo, it did significantly increase tissue formation in vivo compared to the non-degradable crosslinker (p â€‹< â€‹0.001). Conclusion: The modification of hydrogels by adapting DoF, use of a degradable crosslinker or including fibrillar collagen can control and improve cell migration and tissue formation for osteochondral defect repair. This study also emphasizes the importance of performing both in vitro and in vivo testing of biomaterials, as, depending on the material, the results might be affected by the model used.The translational potential of this article: This article highlights the potential of using acellular hydrogels to repair osteochondral defects, which are common injuries in orthopaedics. The study provides a deeper understanding of how to modify the properties of hydrogels to control cell migration and tissue formation for osteochondral defect repair. The results of this article also highlight that the choice of the used laboratory model can affect the outcome. Testing hydrogels in different models is thus advised for successful translation of laboratory results to the clinical application.

Shared Decision Making in Health Care Visits for CKD: Patients' Decisional Role Preferences and Experiences.

RATIONALE & OBJECTIVE: Research on shared decision making (SDM) in chronic kidney disease (CKD) has focused almost exclusively on the modality of kidney replacement treatment. We explored what other CKD decisions are recognized by patients, what their preferences and experiences are regarding these decisions, and how decisions are made during their interactions with medical care professionals. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: Patients with CKD receiving (outpatient) care in 1 of 2 Dutch hospitals. EXPOSURE: Patients' preferred decisional roles for treatment decisions were measured using the Control Preferences Scale survey administered after a health care visit with medical professionals. OUTCOME: Number of decisions for which patients experienced a decisional role that did or did not match their preferred role. Observed levels of SDM and motivational interviewing in audio recordings of health care visits, measured using the 4-step SDM instrument (4SDM) and Motivational Interviewing Treatment Integrity coding tools. ANALYTICAL APPROACH: The results were characterized using descriptive statistics, including differences in scores between the patients' experienced and preferred decisional roles. RESULTS: According to the survey (n=122) patients with CKD frequently reported decisions regarding planning (112 of 122), medication changes (82 of 122), or lifestyle changes (59 of 122). Of the 357 reported decisions in total, patients preferred that clinicians mostly (125 of 357) or fully (101 of 357) make the decisions. For 116 decisions, they preferred a shared decisional role. For 151 of 357 decisions, the patients' preferences did not match their experiences. Decisions were experienced as "less shared/patient-directed" (76 of 357) or "more shared/patient-directed" (75 of 357) than preferred. Observed SDM in 118 coded decisions was low (median4; range, 0 - 22). Motivational interviewing techniques were rarely used. LIMITATIONS: Potential recall and selection bias, and limited generalizability. CONCLUSIONS: We identified multiple discrepancies between preferred, experienced, and observed SDM in health care visits for CKD. Although patients varied in their preferred decisional role, a considerable number of patients expressed a preference for shared decision making for many decisions. However, SDM behavior during the health care visits was observed infrequently. PLAIN-LANGUAGE SUMMARY: Shared decision making (SDM) may be a valuable approach for common chronic kidney disease (CKD) decisions, but our knowledge is limited. We collected patient surveys after health care visits for CKD. Patients most frequently experienced decisions regarding planning, medication, and lifestyle. Three decisional roles were preferred by comparable numbers of patients: let the clinician alone decide, let the clinician decide for the most part, or "equally share" the decision. Patients' experiences of who made the decision did not always match their preferences. In audio recordings of the health care visits, we observed low levels of SDM behavior. These findings suggest that the preference for "sharing decisions" is often unmet for a large number of patients.

Quality of Life in Patients With Definite Chronic Pancreatitis: A Nationwide Longitudinal Cohort Study.

INTRODUCTION: Chronic pancreatitis (CP) has a negative impact on quality of life (QoL). Because CP is a chronic condition, multiple assessments of QoL are required to obtain a thorough understanding of its impact on patients. Such studies are currently lacking. This study aims to gain insight into the course and predictors of QoL in patients with CP using prospective longitudinal data from a large cohort of patients. METHODS: Post hoc analysis of consecutive patients with definite CP registered in a prospective database between 2011 and 2019 in the Netherlands. Patient and disease characteristics, nutritional status, pain severity, medication usage, pancreatic function, and pancreatic interventions were assessed from medical records and through standard follow-up questionnaires. The physical and mental component summary scales of the Short-Form 36 were used to assess physical and mental QoL at baseline and during follow-up. The course of both physical and mental QoL and their associated factors were longitudinally assessed by using generalized linear mixed models. RESULTS: Overall, 1,165 patients with definite CP were included for this analysis. During 10-year follow-up, generalized linear mixed model analyses revealed improvements in both physical (41.6-45.2, P < 0.001) and mental (45.9-46.6, P = 0.047) QoL. Younger age, current alcohol consumption, employment, no need for dietetic consultation, no steatorrhea, lower Izbicki pain score, and pain coping mechanism were positively associated with physical QoL ( P < 0.05). For mental QoL, a positive correlation was found between employment, nonalcoholic CP, no need for dietetic consultation, no steatorrhea, lower Izbicki pain score, pain coping mechanism, and surgical treatment. No association was observed between disease duration and longitudinal QoL per patient. DISCUSSION: This nationwide study provides insight into the dynamics of physical and mental QoL in patients with CP over time. Important and potentially influenceable factors to improve QoL are nutritional status, exocrine pancreatic function, employment status, and patients' coping strategy.

Long-term outcomes of pancreatoscopy-guided electrohydraulic lithotripsy for the treatment of obstructive pancreatic duct stones.

Background and study aims Pancreatoscopy-guided electrohydraulic lithotripsy (EHL) has proven to be an effective first-line therapy in symptomatic chronic pancreatitis (CP) patients with obstructing pancreatic duct (PD) stones 1 . However, long-term outcomes of endoscopic EHL remain unknown. The aim of the present study was to evaluate the long-term treatment effects of EHL as first-line therapy and to compare with those obtained in a historical cohort of patients who underwent extracorporeal shockwave lithotripsy (ESWL) as primary treatment. Patients and methods An observational retrospective single-center long-term follow-up study was performed including 19 consecutive patients who previously underwent endoscopic EHL compared to 18 patients who underwent ESWL followed by endoscopic retrograde pancreatography (ERP). The primary endpoint was long-term treatment success after EHL or ESWL defined as no recurrence of symptomatic intraductal stones confirmed on imaging. Secondary endpoints for the EHL-population included long-term clinical success (i. e., a similar or lower Izbicki Pain Score or reduction in opiate usage as compared to 6-month follow-up), quality of life (QoL), pancreatic function and hospital re-admission rate. Results In the EHL group, 37 % of the patients developed recurrent symptomatic PD stones versus 61 % in the ESWL group after a median follow-up of 35.0 and 76.5 months. Of the patients with recurrence, 71 % versus 100 % underwent a reintervention. Median time to recurrence was 12.0 versus 13.0 months. Clinical success sustained in 58 % of the EHL patients. QoL was not significantly different compared with 6-month follow-up and baseline. Conclusions Also at long-term follow-up, endoscopic EHL as first-line treatment is moderately effective for symptomatic CP patients with treatment success rates that seems at least equally effective as ESWL.

Predicting outcomes in chronic kidney disease: needs and preferences of patients and nephrologists.

INTRODUCTION: Guidelines on chronic kidney disease (CKD) recommend that nephrologists use clinical prediction models (CPMs). However, the actual use of CPMs seems limited in clinical practice. We conducted a national survey study to evaluate: 1) to what extent CPMs are used in Dutch CKD practice, 2) patients' and nephrologists' needs and preferences regarding predictions in CKD, and 3) determinants that may affect the adoption of CPMs in clinical practice. METHODS: We conducted semi-structured interviews with CKD patients to inform the development of two online surveys; one for CKD patients and one for nephrologists. Survey participants were recruited through the Dutch Kidney Patient Association and the Dutch Federation of Nephrology. RESULTS: A total of 126 patients and 50 nephrologists responded to the surveys. Most patients (89%) reported they had discussed predictions with their nephrologists. They most frequently discussed predictions regarded CKD progression: when they were expected to need kidney replacement therapy (KRT) (n = 81), and how rapidly their kidney function was expected to decline (n = 68). Half of the nephrologists (52%) reported to use CPMs in clinical practice, in particular CPMs predicting the risk of cardiovascular disease. Almost all nephrologists (98%) reported discussing expected CKD trajectories with their patients; even those that did not use CPMs (42%). The majority of patients (61%) and nephrologists (84%) chose a CPM predicting when patients would need KRT in the future as the most important prediction. However, a small portion of patients indicated they did not want to be informed on predictions regarding CKD progression at all (10-15%). Nephrologists not using CPMs (42%) reported they did not know CPMs they could use or felt that they had insufficient knowledge regarding CPMs. According to the nephrologists, the most important determinants for the adoption of CPMs in clinical practice were: 1) understandability for patients, 2) integration as standard of care, 3) the clinical relevance. CONCLUSION: Even though the majority of patients in Dutch CKD practice reported discussing predictions with their nephrologists, CPMs are infrequently used for this purpose. Both patients and nephrologists considered a CPM predicting CKD progression most important to discuss. Increasing awareness about existing CPMs that predict CKD progression may result in increased adoption in clinical practice. When using CPMs regarding CKD progression, nephrologists should ask whether patients want to hear predictions beforehand, since individual patients' preferences vary.

Effectiveness of BMP-2 and PDGF-BB Adsorption onto a Collagen/Collagen-Magnesium-Hydroxyapatite Scaffold in Weight-Bearing and Non-Weight-Bearing Osteochondral Defect Bone Repair: In Vitro, Ex Vivo and In Vivo Evaluation.

Despite promising clinical results in osteochondral defect repair, a recently developed bi-layered collagen/collagen-magnesium-hydroxyapatite scaffold has demonstrated less optimal subchondral bone repair. This study aimed to improve the bone repair potential of this scaffold by adsorbing bone morphogenetic protein 2 (BMP-2) and/or platelet-derived growth factor-BB (PDGF-BB) onto said scaffold. The in vitro release kinetics of BMP-2/PDGF-BB demonstrated that PDGF-BB was burst released from the collagen-only layer, whereas BMP-2 was largely retained in both layers. Cell ingrowth was enhanced by BMP-2/PDFG-BB in a bovine osteochondral defect ex vivo model. In an in vivo semi-orthotopic athymic mouse model, adding BMP-2 or PDGF-BB increased tissue repair after four weeks. After eight weeks, most defects were filled with bone tissue. To further investigate the promising effect of BMP-2, a caprine bilateral stifle osteochondral defect model was used where defects were created in weight-bearing femoral condyle and non-weight-bearing trochlear groove locations. After six months, the adsorption of BMP-2 resulted in significantly less bone repair compared with scaffold-only in the femoral condyle defects and a trend to more bone repair in the trochlear groove. Overall, the adsorption of BMP-2 onto a Col/Col-Mg-HAp scaffold reduced bone formation in weight-bearing osteochondral defects, but not in non-weight-bearing osteochondral defects.

Recurrence characteristics after focal salvage HDR brachytherapy in prostate cancer.

BACKGROUND AND PURPOSE: Radiorecurrent prostate cancer is often confined to the prostate, predominantly near the index lesion. The purpose of this study was to look at recurrence characteristics in patients treated with focal salvage high dose-rate (HDR) brachytherapy. MATERIALS AND METHODS: Patients treated with MRI-guided HDR brachytherapy, with a single fraction of 19 Gy from July 2013 to October 2021 as focal salvage treatment, were prospectively included in the current study. Imaging data were collected regarding the occurrence of local, regional and distant recurrences, including location of local recurrences (LR) in relation to the HDR radiotherapy field. RESULTS: One hundred seventy-five patients were included after focal salvage HDR brachytherapy (median follow-up 36 months (IQR 23-50)). Three-years biochemical recurrence-free survival, LR-free survival, in-field LR-free survival, out-of-field LR-free survival, any-recurrence-free survival and ADT-free survival were 43% (95%CI 34%-52%), 51% (41%-61%), 70% (61%-80%), 92% (88%-97%), 42% (32%-52%) and 86% (80%-92%), respectively. Larger GTV-size and shorter PSA doubling time were associated with in-field LR in multivariable analysis. CONCLUSION: After focal salvage HDR brachytherapy with a dose of 1x19 Gy for local prostate cancer recurrence, subsequent recurrences are mostly local and in-field.

Improved Understanding of the Inflammatory Response in Synovial Fluid and Serum after Traumatic Knee Injury, Excluding Fractures of the Knee: A Systematic Review.

BACKGROUND: Traumatic knee injury results in a 4- to 10-fold increased risk of post-traumatic osteoarthritis (PTOA). Currently, there are no successful interventions for preventing PTOA after knee injury. The aim of this study is to identify inflammatory proteins that are increased in serum and synovial fluid after acute knee injury, excluding intra-articular fractures. METHODS: A literature search was done according to the PRISMA guidelines. Articles reporting about inflammatory proteins after knee injury, except fractures, up to December 8, 2021 were collected. Inclusion criteria were as follows: patients younger than 45 years, no radiographic signs of knee osteoarthritis at baseline, and inflammatory protein measurement within 1 year after trauma. Risk of bias was assessed of the included studies. The level of evidence was determined by the Strength of Recommendation Taxonomy. RESULTS: Ten studies were included. All included studies used a healthy control group or the contralateral knee as healthy control. Strong evidence for interleukin 6 (IL-6) and limited evidence for CCL4 show elevated concentrations of these proteins in synovial fluid (SF) after acute knee injury; no upregulation in SF for IL-2, IL-10, CCL3, CCL5, CCL11, granulocyte colony-stimulating factor (G-CSF), and granulocyte-macrophage colony-stimulating factor (GM-CSF) was found. Limited evidence was found for no difference in serum concentration of IL-1ß, IL-6, IL-10, CCL2, and tumor necrosis factor alpha (TNF-α) after knee injury. CONCLUSION: Interleukin 6 and CCL4 are elevated in SF after acute knee injury. Included studies failed to demonstrate increased concentration of inflammatory proteins in SF samples taken 6 weeks after trauma. Future research should focus on SF inflammatory protein measurements taken less than 6 weeks after injury.

Cost-effectiveness of Early Surgery Versus Endoscopy-first Approach for Painful Chronic Pancreatitis in the ESCAPE Trial.

OBJECTIVE: Economic evaluation of early surgery compared to the endoscopy-first approach in CP. BACKGROUND: In patients with painful CP and a dilated main pancreatic duct, early surgery, as compared with an endoscopy-first approach, leads to more pain reduction with fewer interventions. However, it is unknown if early surgery is more cost-effective than the endoscopy-first approach. METHODS: The multicenter Dutch ESCAPE trial randomized patients with CP and a dilated main pancreatic duct between early surgery (surgery within 6 weeks) or the endoscopy-first approach in 30 centers (April 2011-September 2016). Healthcare utilization was prospectively recorded up to 18 months after randomization. Unit costs of resources were determined, and cost-effectiveness and cost-utility analyses were performed from societal and healthcare perspectives. Primary outcomes were the costs per unit decrease on the Izbicki pain score and per gained quality-adjusted life-year. RESULTS: In total, 88 patients were included in the analysis, with 44 patients randomized to each group. Total costs were lower in the early surgery group but did not reach statistical significance (mean difference €-4,815 (95% bias-corrected and accelerated confidence interval €-13,113 to €3411; P = 0.25). Early surgery had a probability percentage of 88.4% of being more cost-effective than the endoscopy-first approach at a willingness-to-pay threshold of €0 per day per unit decrease on the Izbicki pain score. The probability percentage per additional gained quality-adjusted life-year was 75.7% at a willingness-to-pay threshold of €50,000. CONCLUSION: In patients with painful CP and a dilated main pancreatic duct, early surgery was more cost-effective than the endoscopy-first approach.

A culture model to analyze the acute biomaterial-dependent reaction of human primary neutrophils in vitro.

Neutrophils play a pivotal role in orchestrating the immune system response to biomaterials, the onset and resolution of chronic inflammation, and macrophage polarization. However, the neutrophil response to biomaterials and the consequent impact on tissue engineering approaches is still scarcely understood. Here, we report an in vitro culture model that comprehensively describes the most important neutrophil functions in the light of tissue repair. We isolated human primary neutrophils from peripheral blood and exposed them to a panel of hard, soft, naturally- and synthetically-derived materials. The overall trend showed increased neutrophil survival on naturally derived constructs, together with higher oxidative burst, decreased myeloperoxidase and neutrophil elastase and decreased cytokine secretion compared to neutrophils on synthetic materials. The culture model is a step to better understand the immune modulation elicited by biomaterials. Further studies are needed to correlate the neutrophil response to tissue healing and to elucidate the mechanism triggering the cell response and their consequences in determining inflammation onset and resolution.

Development of an online patient decision aid for kidney failure treatment modality decisions.

BACKGROUND: Patient decision aids (PtDAs) support patients and clinicians in shared decision-making (SDM). Real-world outcome information may improve patients' risk perception, and help patients make decisions congruent with their expectations and values. Our aim was to develop an online PtDA to support kidney failure treatment modality decision-making, that: 1) provides patients with real-world outcome information, and 2) facilitates SDM in clinical practice. METHODS: The International Patient Decision Aids Standards (IPDAS) development process model was complemented with a user-centred and convergent mixed-methods approach. Rapid prototyping was used to develop the PtDA with a multidisciplinary steering group in an iterative process of co-creation. The results of an exploratory evidence review and a needs-assessment among patients, caregivers, and clinicians were used to develop the PtDA. Seven Dutch teaching hospitals and two national Dutch outcome registries provided real-world data on selected outcomes for all kidney failure treatment modalities. Alpha and beta testing were performed to assess the prototype and finalise development. An implementation strategy was developed to guide implementation of the PtDA in clinical practice. RESULTS: The 'Kidney Failure Decision Aid' consists of three components designed to help patients and clinicians engage in SDM: 1) a paper hand-out sheet, 2) an interactive website, and 3) a personal summary sheet. A 'patients-like-me' infographic was developed to visualise survival probabilities for each treatment modality on the website. Other treatment outcomes were incorporated as event rates (e.g. hospitalisation rates) or explained in text (e.g. the flexibility of each treatment modality). No major revisions were needed after alpha and beta testing. During beta testing, some patients ignored the survival probabilities because they considered these too confronting. Nonetheless, patients agreed that every patient has the right to choose whether they want to view this information. Patients and clinicians believed that the PtDA would help patients make informed decisions, and that it would support values- and preferences-based decision-making. Implementation of the PtDA has started in October 2020. CONCLUSIONS: The 'Kidney Failure Decision Aid' was designed to facilitate SDM in clinical practice and contains real-world outcome information on all kidney failure treatment modalities. It is currently being investigated for its effects on SDM in a clinical trial.

Intra-articular Administration of Triamcinolone Acetonide in a Murine Cartilage Defect Model Reduces Inflammation but Inhibits Endogenous Cartilage Repair.

BACKGROUND: Cartilage defects result in joint inflammation. The presence of proinflammatory factors has been described to negatively affect cartilage formation. PURPOSE: To evaluate the effect and timing of administration of triamcinolone acetonide (TAA), an anti-inflammatory drug, on cartilage repair using a mouse model. STUDY DESIGN: Controlled laboratory study. METHODS: A full-thickness cartilage defect was created in the trochlear groove of 10-week-old male DBA/1 mice (N = 80). Mice received an intra-articular injection of TAA or saline on day 1 or 7 after induction of the defect. Mice were euthanized on days 10 and 28 for histological evaluation of cartilage defect repair, synovial inflammation, and synovial membrane thickness. RESULTS: Mice injected with TAA had significantly less synovial inflammation at day 10 than saline-injected mice independent of the time of administration. At day 28, the levels of synovitis dropped toward healthy levels; nevertheless, the synovial membrane was thinner in TAA- than in saline-injected mice, reaching statistical significance in animals injected on day 1 (70.1 ± 31.9 µm vs 111.9 ± 30.9 µm, respectively; P = .01) but not in animals injected on day 7 (68.2 ± 21.86 µm vs 90.2 ± 21.29 µm, respectively; P = .26). A thinner synovial membrane was moderately associated with less filling of the defect after 10 and 28 days (r = 0.42, P = .02; r = 0.47, P = .01, respectively). Whereas 10 days after surgery there was no difference in the area of the defect filled and the cell density in the defect area between saline- and TAA-injected knees, filling of the defect at day 28 was lower in TAA- than in saline-injected knees for both injection time points (day 1 injection, P = .04; day 7 injection, P = .01). Moreover, there was less collagen type 2 staining in the filled defect area in TAA- than in saline-injected knees after 28 days, reaching statistical significance in day 1-injected knees (2.6% vs 18.5%, respectively; P = .01) but not in day 7-injected knees (7.4% vs 15.8%, respectively; P = .27). CONCLUSION: Intra-articular injection of TAA reduced synovial inflammation but negatively affected cartilage repair. This implies that inhibition of inflammation may inhibit cartilage repair or that TAA has a direct negative effect on cartilage formation. CLINICAL RELEVANCE: Our findings show that TAA can inhibit cartilage defect repair. Therefore, we suggest not using TAA to reduce inflammation in a cartilage repair setting.

Modulation of Inflamed Synovium Improves Migration of Mesenchymal Stromal Cells in Vitro Through Anti-Inflammatory Macrophages.

OBJECTIVE: Inflammation is known to negatively affect cartilage repair. However, it is unclear how inflammation influences the migration of mesenchymal stromal cells (MSCs) from the underlying bone marrow into the defect. We therefore aimed to investigate how synovial inflammation influences MSC migration, and whether modulation of inflammation with triamcinolone acetonide (TAA) may influence migration. DESIGN: Inflamed human osteoarthritic synovium, M(IFNγ+TNFα) pro-inflammatory macrophages, M(IL4) repair macrophages, M(IL10) anti-inflammatory macrophages, or synovial fibroblasts were cultured with/without TAA. Conditioned medium (CM) was harvested after 24 hours, and the effect on MSC migration was studied using a Boyden chamber assay. Inflammation was evaluated with gene expression and flow cytometry analysis. RESULTS: Synovium CM increased MSC migration. Modulation of synovial inflammation with TAA further increased migration 1.5-fold (P < 0.01). TAA significantly decreased TNFA, IL1B, and IL6 gene expression in synovium explants and increased CD163, a gene associated with anti-inflammatory macrophages. TAA treatment decreased the percentage of CD14+/CD80+ and CD14+/CD86+ pro-inflammatory macrophages and increased the percentage of CD14+/CD163+ anti-inflammatory macrophages in synovium explants. Interestingly, MSC migration was specifically enhanced by medium conditioned by M(IL4) macrophages and by M(IL10) macrophages treated with TAA, and unaffected by CM from M(IFNγ+TNFα) macrophages and synovial fibroblasts. CONCLUSION: Macrophages secrete factors that stimulate the migration of MSCs. Modulation with TAA increased specifically the ability of anti-inflammatory macrophages to stimulate migration, indicating that they play an important role in secreting factors to attract MSCs. Modulating inflammation and thereby improving migration could be used in approaches based on endogenous repair of full-thickness cartilage defects.

Short- and long-term outcomes of selective use of Frey or extended lateral pancreaticojejunostomy in chronic pancreatitis.

BACKGROUND: Surgery is the most effective treatment in patients with painful chronic pancreatitis and a dilated pancreatic duct. Studies reporting the outcomes of selected surgical approach according to the pancreatic head size in these patients are lacking. METHOD: This was a retrospective, observational single-centre study of consecutive patients who underwent either a Frey procedure or extended lateral pancreaticojejunostomy (eLPJ) for pain due to chronic pancreatitis with a dilated main pancreatic duct (5 mm or more) between 2006 and 2017. A Frey procedure was used in patients with pancreatic head enlargement (40 mm or more) and eLPJ (full-length pancreaticojejunostomy, including transection of the gastroduodenal artery) in others. A biliodigestive bypass was added in the case of biliary obstruction. RESULTS: Overall, 140 of 220 patients met the eligibility criteria: 70 underwent a Frey procedure and 70 an eLPJ. Hepaticojejunostomy was added in 17.1 per cent of patients (Frey: 24.3 per cent; eLPJ: 10.0 per cent (P = 0.025)). Major morbidity occurred in 15.0 per cent of patients (Frey: 21.4 per cent; eLPJ: 8.6 per cent (P = 0.033)). After a median 7.8 years of follow-up, the mean (s.d.) decrease in Izbicki pain score was 33 (27) points (34 (28) points after a Frey procedure; 32 (26) points after an eLPJ). Pain relief was reported as 'very much' by 87.5 per cent of patients (Frey: 86.1 per cent; eLPJ: 88.9 per cent) and as 'partial' by 11.1 per cent (Frey: 13.8 per cent; eLPJ: 8.3 per cent). CONCLUSION: Selective-use of either a Frey procedure or eLPJ in patients with symptomatic chronic pancreatitis was-associated with low morbidity and long-term pain relief. Adding a-biliodigestive bypass did not increase morbidity.

Neuregulin-1 enhances cell-cycle activity, delays cardiac fibrosis, and improves cardiac performance in rat pups with right ventricular pressure load.

OBJECTIVES: Right ventricular (RV) failure is a leading cause of death in patients with congenital heart disease. RV failure is kept at bay during childhood. Limited proliferation of cardiomyocytes is present in the postnatal heart. We propose that cardiomyocyte proliferation improves RV adaptation to pressure load (PL). We studied adaptation in response to increased RV PL and the role of increased cardiomyocyte cell cycle activity (CCA) in rat pups growing into adulthood. METHODS: We induced RV PL at day of weaning in rats (3 weeks; 30-40 g) by pulmonary artery banding and followed rats into adulthood (300 g). We performed histological analyses and RNA sequencing analysis. To study the effects of increased cardiomyocyte cell cycle activity, we administered neuregulin-1 (NRG1), a growth factor involved in cardiac development. RESULTS: PL induced an increase in CCA, with subsequent decline of CCA (sham/PL at 4 weeks: 0.14%/0.83%; P = .04 and 8 weeks: 0.00%/0.00%; P = .484) and cardiac function (cardiac index: control/PL 4 weeks: 4.41/3.29; P = .468 and 8 weeks: 3.57/1.44; P = .024). RNA sequencing analysis revealed delayed maturation and increased CCA pathways. NRG1 stimulated CCA (PL vehicle/NRG1 at 2 weeks: 0.62%/2.28%; P = .003), improved cardiac function (cardiac index control vs vehicle/NRG1 at 2 weeks: 4.21 vs 3.07/4.17; P = .009/.705) and postponed fibrosis (control vs vehicle/NRG1 at 4 weeks: 1.66 vs 4.82%/2.97%; P = .009/.078) in RV PL rats during childhood. CONCLUSIONS: RV PL during growth induces a transient CCA increase. Further CCA stimulation improves cardiac function and delays fibrosis. This proof-of-concept study shows that stimulation of CCA can improve RV adaptation to PL in the postnatal developing heart and might provide a new approach to preserve RV function in patients with congenital heart disease.

Salvage Surgery for Patients With Local Recurrence or Persistent Disease After Treatment With Chemoradiotherapy for SCLC.

INTRODUCTION: The role of salvage surgery for patients with locoregional (LR) recurrence or persistent SCLC after radical chemoradiotherapy (CRT) for limited-stage disease is not well established. We evaluated our experience. METHODS: We conducted a retrospective study of consecutive patients who underwent salvage pulmonary resection for LR-recurrent or persistent SCLC between 2008 and 2020 at the Amsterdam University Medical Center. RESULTS: A total of 10 patients were identified. Median age at initial diagnosis of limited-stage SCLC was 58.5 years (48-71 y). All patients had radical-intent concurrent CRT. Of the 10 patients, 9 were diagnosed with LR-recurrent or persistent disease with a median of 18 months (3-78 y) after CRT. All patients underwent an anatomical radical resection and mediastinal lymph node dissection. No 90-day mortality was recorded. In addition, one patient developed a LR recurrence 7 months after resection. Distant progression was found in three patients at 6, 32, and 61 months after surgery, all of whom subsequently died of progressive SCLC. Median follow-up was 22.5 months (2-86 mos). Disease-free survival was 34 months; overall survival was not reached. CONCLUSIONS: For highly selected patients with LR-recurrent or persistent SCLC after CRT, salvage surgery is feasible and can result in clinically meaningful survival. Such patients should be presented to the multidisciplinary tumor board.