Development and External Validation of a Model to Predict Overall Survival in Patients With Resected Gallbladder Cancer.

OBJECTIVE: The aim of this study was to develop and validate a clinical prediction model to predict overall survival in patients with nonmetastatic, resected gallbladder cancer (GBC). BACKGROUND: Although several tools are available, no optimal method has been identified to assess survival in patients with resected GBC. METHODS: Data from a Dutch, nation-wide cohort of patients with resected GBC was used to develop a prediction model for overall survival. The model was internally validated and a cohort of Australian GBC patients who underwent resection was used for external validation. The performance of the American Joint Committee on Cancer (AJCC) staging system and the present model were compared. RESULTS: In total, 446 patients were included; 380 patients in the development cohort and 66 patients in the validation cohort. In the development cohort median survival was 22 months (median follow-up 75 months). Age, T/N classification, resection margin, differentiation grade, and vascular invasion were independent predictors of survival. The externally validated C-index was 0.75 (95%CI: 0.69-0.80), implying good discriminatory capacity. The discriminative ability of the present model after internal validation was superior to the ability of the AJCC staging system (Harrell C-index 0.71, [95%CI: 0.69-0.72) vs. 0.59 (95% CI: 0.57-0.60)]. CONCLUSION: The proposed model for the prediction of overall survival in patients with resected GBC demonstrates good discriminatory capacity, reasonable calibration and outperforms the authoritative AJCC staging system. This model can be a useful tool for physicians and patients to obtain information about survival after resection and is available from https:// gallbladderresearch.shinyapps.io/Predict_GBC_survival/.

Arthroscopic partial meniscectomy vs non-surgical or sham treatment in patients with MRI-confirmed degenerative meniscus tears: a systematic review and meta-analysis with individual participant data from 605 randomised patients.

OBJECTIVE: To identify subgroups of patients with magnetic resonance imaging (MRI)-confirmed degenerative meniscus tears who may benefit from arthroscopic partial meniscectomy (APM) in comparison with non-surgical or sham treatment. METHODS: Individual participant data (IPD) from four RCTs were pooled (605 patients, mean age: 55 (SD: 7.5), 52.4% female) as to investigate the effectiveness of APM in patients with MRI-confirmed degenerative meniscus tears compared to non-surgical or sham treatment. Primary outcomes were knee pain, overall knee function, and health-related quality of life, at 24 months follow-up (0-100). The IPD were analysed in a one- and two-stage meta-analyses. Identification of potential subgroups was performed by testing interaction effects of predefined patient characteristics (e.g., age, gender, mechanical symptoms) and APM for each outcome. Additionally, generalized linear mixed-model trees were used for subgroup detection. RESULTS: The APM group showed a small improvement over the non-surgical or sham group on knee pain at 24 months follow-up (2.5 points (95% CI: 0.8-4.2) and 2.2 points (95% CI: 0.9-3.6), one- and two-stage analysis, respectively). Overall knee function and health-related quality of life did not differ between the two groups. Across all outcomes, no relevant subgroup of patients who benefitted from APM was detected. The generalized linear mixed-model trees did also not identify a subgroup. CONCLUSIONS: No relevant subgroup of patients was identified that benefitted from APM compared to non-surgical or sham treatment. Since we were not able to identify any subgroup that benefitted from APM, we recommend a restrained policy regarding meniscectomy in patients with degenerative meniscus tears.

Septoplasty versus non-surgical management for nasal obstruction in adults with a deviated septum: economic evaluation alongside a randomized controlled trial.

BACKGROUND: For years, the benefits of septoplasty have been questioned. Due to the scarce and inconclusive literature, several National Health Service (NHS) Clinical Commissioning Groups in England decided to add septal surgery to their list of restricted procedures with low clinical value. Recently, evidence was obtained that septoplasty is actually more effective than non-surgical management for nasal obstruction in adults with a deviated septum. However, the relation between costs and effects of septoplasty remains unknown. METHODS: We conducted an economic evaluation alongside an open, multicenter, pragmatic randomized controlled trial in two tertiary and 16 secondary referral hospitals in the Netherlands. Adults with nasal obstruction and a deviated septum were randomized to (1) septoplasty with or without concurrent turbinate surgery or (2) non-surgical management consisting of (a combination of) medical treatment and watchful waiting. Analyses were performed on an intention-to-treat basis. Single imputation nested in the bootstrap percentile method (using 5000 bootstrap replications) was performed to assess the effect of missing data. After 12 and 24 months, we assessed the incremental costs per quality-adjusted life year (QALY) gained from a healthcare and a societal perspective. RESULTS: A total of 203 adults were randomly assigned to septoplasty (N = 102) or non-surgical management (N = 101). After 12 months, the mean cost difference between septoplasty and non-surgical management using a healthcare or societal perspective was €1181 (95%CI €1038 to €1323) or €2192 per patient (95%CI €1714 to €2670), respectively. The mean QALY difference was 0.03 per patient (95%CI - 0.01 to 0.07). Incremental costs per QALY gained from a healthcare or societal perspective were €41,763 or €77,525, respectively. After 24 months, the mean cost difference between the two groups using a healthcare or societal perspective decreased to €936 (95%CI €719 to €1153) or €1671 per patient (95%CI €952 to €2390), respectively. The mean QALY difference increased to 0.05 per patient (95%CI - 0.03 to 0.14). Incremental costs per QALY gained from a healthcare or societal perspective became €17,374 or €31,024, respectively. Analyses of imputed data did not alter our findings. CONCLUSIONS: Depending on the selected perspective, cost-effectiveness threshold, and time horizon, septoplasty has the potential to be cost-effective. Despite considerable uncertainty, septoplasty seems to be cost-effective from a healthcare perspective, after 24 months against a threshold of €20,000 per QALY. From a societal perspective, septoplasty is not yet cost-effective after 24 months, but it comes closer to the cost-effectiveness threshold as time passes by. TRIAL REGISTRATION: Nederlands Trial Register, NTR3868 (https://www.trialregister.nl/trial/3698). Prospectively registered on February 21, 2013.

The protective effect of anterior cruciate ligament reconstruction on articular cartilage: a systematic review of animal studies.

OBJECTIVE: It is unclear if anterior cruciate ligament (ACL) reconstruction can prevent the onset of degenerative changes in the knee. Previous studies were inconclusive on this subject. The aim of this study was to systematically review all studies on the effect of ACL reconstruction on articular cartilage in animals. DESIGN: Pubmed and Embase were searched to identify all original articles concerning the effect of ACL reconstruction on articular cartilage compared with both its positive (ACL transection) and negative (sham and/or non-operated) control in animals. Subsequently a Risk of bias and meta analysis was conducted based on five outcomes (gross macroscopic assessment, medical imaging, histological histochemical grading, histomophometrics and biomechanical characterization) related to articular cartilage. RESULTS: From the 19 included studies, 29 independent comparisons could be identified which underwent ACL reconstruction with an average timing of data collection of 23 weeks (range 1-104 weeks). Due to limited data availability meta-analysis could only be conducted for gross macroscopic damage. ACL reconstruction caused significant gross macroscopic damage compared with intact controls (SMD 2.0 [0.88; 3.13]). These findings were supported by individual studies reporting on histomorphometrics, histology and imaging. No significant gross macroscopic damage was found when ACL reconstruction was compared with ACL transection (SMD -0.64 [-1.85; 0.57]). CONCLUSION: This systematic review with an average follow up of included studies of 23 weeks (range 1-104 weeks) demonstrates that, in animals, ACL reconstruction does not protect articular cartilage from degenerative changes. The consistency of the direction of effect, provides some reassurance that the direction of effect in humans might be the same.

The risk of revision after total hip arthroplasty in young patients depends on surgical approach, femoral head size and bearing type; an analysis of 19,682 operations in the Dutch arthroplasty register.

BACKGROUND: Total hip arthroplasty (THA) is used increasingly in younger patients. There is little knowledge about the effect of THA characteristics on risk of revision, especially in young patients. Therefore, we studied the influence of both patient-related and surgical factors on the risk of revision using data from the Dutch Arthroplasty Registry (LROI). METHODS: All patients younger than 55 years with a primary THA implanted in the Netherlands between 2007 and 2017 were selected (n = 19,682). The covariates age, sex, primary diagnosis, ASA-classification, surgical approach, fixation method, bearing type, head size and year of surgery were entered into Cox proportional hazards models to calculate hazard ratios for the risk of revision. RESULTS: The overall 5-year survival of primary THA was 95.3% (95% CI, 94.9-95.6). Use of the anterior approach resulted in a lower risk of revision than the use of the posterolateral approach (HR: 0.66, 95% CI: 0.47-0.92). THAs with a head diameter ≥ 38 mm had a higher risk of revision (HR: 1.90, 95% CI: 1.33-2.72) than THAs with 32 mm heads. Use of MoM bearings resulted in an increased risk when compared to C-PE (HR: 1.76, 95% CI: 1.27-2.43). CONCLUSION: The risk of revision in patients younger than 55 years depends on surgical approach, head size and bearing type. The anterior approach resulted in a decreased risk of revision, whereas use of ≥38 mm heads and MoM bearings resulted in an increased risk of revision for any reason.

Near-infrared fluorescence imaging for sentinel lymph node identification in colon cancer: a prospective single-center study and systematic review with meta-analysis.

BACKGROUND: Near-infrared (NIR) fluorescence imaging has the potential to overcome the current drawbacks of sentinel lymph node mapping (SLNM) in colon cancer. Our aim was to provide an overview of current SLNM performance and of factors influencing successful sentinel lymph node (SLN) identification using NIR fluorescence imaging in colon cancer. METHODS: A systematic review and meta-analysis was conducted to identify currently used methods and results. Additionally, we performed a single-center study using indocyanine green (ICG) as SLNM dye in colon cancer patients scheduled for a laparoscopic colectomy. SLNs were analyzed with conventional hematoxylin-and-eosin staining and additionally with serial sectioning and immunohistochemistry (extended histopathological assessment). A true-positive procedure was defined as a tumor-positive SLN either by conventional hematoxylin-and-eosin staining or by extended histopathological assessment, independently of regional lymph node status. SLN procedures were determined to be true negatives if SLNs and regional lymph nodes revealed no metastases after conventional and advanced histopathology. SLN procedures yielding tumor-negative SLNs in combination with tumor-positive regional lymph nodes were classified as false negatives. Sensitivity, negative predictive value and detection rate were calculated. RESULTS: This systematic review and meta-analysis included 8 studies describing 227 SLN procedures. A pooled sensitivity of 0.63 (95% CI 0.51-0.74), negative predictive value 0.81 (95% CI 0.73-0.86) and detection rate of 0.94 (95% CI 0.85-0.97) were found. Upstaging as a result of extended histopathological assessment was 0.15 (95% CI 0.07-0.25). In our single-center study, we included 30 patients. Five false-negative SLNs were identified, resulting in a sensitivity of 44% and negative predictive value of 80%, with a detection rate of 89.7%. Eight patients had lymph node metastases, in three cases detected after extended pathological assessment, resulting in an upstaging of 13% (3 of 23 patients with negative nodes by conventional hematoxylin and eosin staining). CONCLUSIONS: Several anatomical and technical difficulties make SLNM with NIR fluorescence imaging in colon cancer particularly challenging when compared to other types of cancer. As a consequence, reports of SLNM accuracy vary widely. Future studies should try to standardize the SLNM procedure and focus on early-stage colon tumors, validation of tracer composition, injection mode and improvement of real-time optical guidance.

Arthroscopic meniscectomy for degenerative meniscal tears reduces knee pain but is not cost-effective in a routine health care setting: a multi-center longitudinal observational study using data from the osteoarthritis initiative.

OBJECTIVES: It is disputed whether arthroscopic meniscectomy is an (cost-) effective treatment for degenerative meniscus tears in day-to-day clinical practice. The objective of this study was to assess the cost-effectiveness of arthroscopic meniscectomy in subjects with knee osteoarthritis, in routine clinical practice, while taking into account the increased risk for future knee replacement surgery. We compared cost-effectiveness of arthroscopic meniscectomy compared to no surgery. DESIGN: We used a state transition (Markov) simulation model to evaluate the cost-effectiveness of arthroscopic meniscectomy compared to no surgery in subjects with knee osteoarthritis (age range 45-79 years). Data used in the preparation of the current study were obtained from the Osteoarthritis Initiative (AOI) database. We applied a 9 years' time horizon (which is equal to the current OAI study follow up period), and evaluated cost-effectiveness from a societal perspective. The main outcome measure was the incremental cost-effectiveness ratio (Euros per quality adjusted life-year (QALY) gained). RESULTS: Arthroscopic meniscectomy was associated with 8.09 (SD ± 0.07) QALYs at a cost of € 21,345 (SD ± 841), whereas the no surgery was associated with 8.05 (SD ± 0.07) QALYs at a cost of € 16,284 (SD ± 855). For arthroscopic meniscectomy, the incremental cost per QALY gained was € 150,754. CONCLUSIONS: In day-to-day clinical practice, arthroscopic meniscectomy in subjects with knee osteoarthritis is associated with € 150,754 per QALY gained, which exceeds the generally accepted willingness to pay (WTP) (range € 20,000-€ 80,000).

Increased risk for knee replacement surgery after arthroscopic surgery for degenerative meniscal tears: a multi-center longitudinal observational study using data from the osteoarthritis initiative.

OBJECTIVE: The primary objective was to assess whether patients with knee osteoarthritis and whom undergo arthroscopic meniscectomy have an increased risk for future knee replacement surgery. DESIGN: Data used were obtained from the Osteoarthritis Initiative (OAI) study. SETTING: Participants were enrolled, in four clinical centers, between February 2004 and May 2006 and were followed up on an annual basis up to and including 108-months from enrollment. PARTICIPANTS: 4674 participants (58.4% female), aged 45-79, of all ethnic groups, who had, and those who were at high risk for developing, symptomatic knee osteoarthritis were included, of which 3337 (71.4%) were included in the final follow up visit. MAIN OUTCOME MEASURES: Hazard ratio of knee replacement surgery for participants who underwent arthroscopic meniscectomy during follow up compared to propensity score matched participants who did not undergo arthroscopic meniscectomy during follow up. RESULTS: 335 participants underwent arthroscopic meniscectomy during follow up, of which 63 (18.8%) underwent knee replacement surgery in the same knee. Of the 335 propensity score matched participants 38 (11.1%) underwent knee replacement surgery during follow up. Results from the Cox-proportional hazards model demonstrated that the hazard ratio of knee replacement surgery was 3.03 (95% CI (1.67-5.26)) for participants who underwent arthroscopic meniscectomy relative to the propensity score matched participants who did not undergo arthroscopic meniscectomy. CONCLUSIONS: In patients with knee osteoarthritis arthroscopic knee surgery with meniscectomy is associated with a three fold increase in the risk for future knee replacement surgery.

Relaxation of the MCL after an Open-Wedge High Tibial Osteotomy results in decreasing contact pressures of the knee over time.

PURPOSE: The objective of this study was to investigate the effect of a medial open-wedge osteotomy (OWO) and the release of the superficial medial collateral ligament (MCL) on the tibiofemoral cartilage pressure, the MCL tension and the valgus laxity of the knee. METHODS: Seven fresh-frozen, human cadaveric knees were used. Medial and lateral mean contact pressure (CP), peak contact pressure (peakCP), and contact area (CA) were measured using a pressure-sensitive film (I-Scan; Tekscan, Boston, MA). The MCL tension was measured using a custom-made device. These measurements were continuously recorded for 5 min after an OWO of 10°. After the osteotomy, the valgus laxity was measured with a handheld Newtonmeter. For one knee, the measurements were continued for 24 h. At the end, a complete release of the superficial MCL was performed and the measurements were repeated at 10°. RESULTS: There was relaxation of the MCL after the osteotomy; the tension dropped in 5 min with 10.7% (mean difference 20.5 N (95% CI 16.1-24.9)), and in 24 h, the tension decreased by 24.2% (absolute difference 38.8 N) (one knee). After the osteotomy, the mean CP, peakCP and CA increased in the medial compartment (absolute difference 0.17 MPa (95% CI 0.14-0.20), 0.27 MPa (95% CI 0.24-0.30), 132.9mm2 (95% CI 67.7-198.2), respectively), and decreased in the lateral compartment (absolute difference 0.02 MPa (95% CI 0.03 -0.01), 0.08 MPa (95% CI 0.11 - 0.04), 47.0 mm2 (95% CI -105.8 to 11.8), respectively). Only after a release of the superficial MCL, the mean CP, peak CP and CA significantly decreased in the medial compartment (absolute difference 0.17, 0.27 MPa, 119.8 mm2, respectively), and increased in the lateral compartment (absolute difference 0.02, 0.11 MPa, 52.4 mm2, respectively). After the release of the superficial MCL, a mean increase of 7.9° [mean difference - 0.1° (95% CI -1.9 to 1.6)] of the valgus laxity was found. CONCLUSIONS: A release of the superficial MCL helps achieve the goal of reducing medial cartilage pressure in an OWO. There was considerable relaxation of the MCL after an OWO that resulted in a decrease of the mean CP in the medial and lateral compartments of the knee over time. However, cartilage pressure shifted from the medial to the lateral compartment only after release of the superficial MCL. The release of the superficial MCL caused a significant increase in the valgus laxity, which could influence stability after an OWO. LEVEL OF EVIDENCE: I.

Ageing is associated with reduction of mechanically-induced activation of Smad2/3P signaling in articular cartilage.

OBJECTIVE: Mechanical signals control key cellular processes in articular cartilage. Previously we have shown that mechanical compression is an important ALK5/Smad2/3P activator in cartilage explants. However, age-related changes in the cartilage are known to affect tissue mechanosensitivity and also ALK5/Smad2/3P signaling. We have investigated whether ageing of cartilage is associated with an altered response to mechanical compression. DESIGN: Articular cartilage explants of two different age groups (young-6-36 months old, aged-6 - 13 years old) were subjected to dynamic mechanical compression with 3 MPa (physiological) or 12 MPa (excessive) load. Subsequently, essential cartilage extracellular matrix (ECM) components and tissue growth factors gene expression was measured in young and aged cartilage by QPCR. Furthermore, the ability of young and aged cartilage, to activate the Smad2/3P signaling in response to compression was analyzed and compared. This was done by immunohistochemical (IH) Smad2P detection and Smad3-responsive gene expression analysis. RESULTS: Aged cartilage showed a highly reduced capacity for mechanically-mediated activation of Smad2/3P signaling when compared to young cartilage. Compression of aged cartilage, induced collagen type II (Col2a1) and fibronectin (Fn1) expression to a far lesser extent than in young cartilage. Additionally, in aged cartilage no mechanically mediated up-regulation of bone morphogenetic protein 2 (Bmp2) and connective tissue growth factor (Ctgf) was observed. CONCLUSIONS: We identified age-related changes in cellular responses to mechanical stimulation of articular cartilage. We propose that these changes might be associated with age-related alterations in cartilage functioning and can underlie mechanisms for development of age-related cartilage diseases like osteoarthritis (OA).

Tissue adhesives for meniscus tear repair: an overview of current advances and prospects for future clinical solutions.

Menisci are crucial structures in the knee joint as they play important functions in load transfer, maintaining joint stability and in homeostasis of articular cartilage. Unfortunately, ones of the most frequently occurring knee injuries are meniscal tears. Particularly tears in the avascular zone of the meniscus usually do not heal spontaneously and lead to pain, swelling and locking of the knee joint. Eventually, after a (partial) meniscectomy, they will lead to osteoarthritis. Current treatment modalities to repair tears and by that restore the integrity of the native meniscus still carry their drawbacks and a new robust solution is desired. A strong tissue adhesive could provide such a solution and could potentially improve on sutures, which are the current gold standard. Moreover, a glue could serve as a carrier for biological compounds known to enhance tissue healing. Only few tissue adhesives, e.g., Dermabond(®) and fibrin glue, are already successfully used in clinical practice for other applications, but are not considered suitable for gluing meniscus tissue due to their sub-optimal mechanical properties or toxicity. There is a growing interest and research field focusing on the development of novel polymer-based tissue adhesives, but up to now, there is no material specially designed for the repair of meniscal tears. In this review, we discuss the current clinical gold standard treatment of meniscal tears and present an overview of new developments in this field. Moreover, we discuss the properties of different tissue adhesives for their potential use in meniscal tear repair. Finally, we formulate recommendations regarding the design criteria of material properties and adhesive strength for clinically applicable glues for meniscal tears.

Functional biomechanical performance of a novel anatomically shaped polycarbonate urethane total meniscus replacement.

PURPOSE: To evaluate the functional biomechanical performance of a novel anatomically shaped, polycarbonate urethane total meniscus implant. METHODS: Five human cadaveric knees were flexed between 0° and 90° under compressive loads mimicking a squat movement. Anteroposterior (AP) laxity tests were performed in 30° and 90° flexion. Meniscal kinematics and knee laxity were quantified using roentgen stereophotogrammetric analysis. Tibial cartilage contact mechanics were determined in 90° flexion. Measurements were repeated for the native medial meniscus, the implant, after total medial meniscectomy and allograft transplantation. RESULTS: The implant and allograft displayed increased posterior and medial displacements compared to the native meniscus, yet no differences were found between the implant and allograft. Meniscal condition did not affect rotational laxity. Compared to the native joint, AP laxity for the implant was increased in 30° flexion, but not in 90°. The implant reduced the mean contact pressure compared to meniscectomy but could not restore contact pressures to native meniscus levels. Compared to the native meniscus, the implant significantly increased the peak pressure, while the contact area was reduced. Contact mechanics of the implant and allograft were never statistically different. CONCLUSIONS: Biomechanical performance was similar for the implant and allograft. However, both meniscal replacements could not restore outcomes to native meniscus levels or sufficiently improve outcomes after meniscectomy. This was presumably caused by the mobility allowed by the suture-only horn fixation. The similarity of implant and allograft performance suggests that the novel implant has the biomechanical potential to serve as an alternative to meniscal allograft transplantation.

The protective effect of meniscus allograft transplantation on articular cartilage: a systematic review of animal studies.

Despite widespread reporting on clinical results, the effect of meniscus allograft transplantation on the development of osteoarthritis is still unclear. The aim of this study was to systematically review all studies on the effect of meniscus allograft transplantation on articular cartilage in animals. Pubmed and Embase were searched for original articles concerning the effect of meniscus allograft transplantation on articular cartilage compared with both its positive (meniscectomy) and negative (either sham or non-operated) control in healthy animals. Outcome measures related to assessment of damage to articular cartilage were divided in five principal outcome categories. Standardized mean differences (SMD) were calculated and pooled to obtain an overall SMD and 95% confidence interval. 17 articles were identified, representing 14 original animal cohorts with an average timing of data collection of 24 weeks [range 4 weeks; 30 months]. Compared to a negative control, meniscus allograft transplantation caused gross macroscopic (1.45 [0.95; 1.95]), histological (3.43 [2.25; 4.61]) damage to articular cartilage, and osteoarthritic changes on radiographs (3.12 [1.42; 4.82]). Moreover, results on histomorphometrics and cartilage biomechanics are supportive of this detrimental effect on cartilage. On the other hand, meniscus allograft transplantation caused significantly less gross macroscopic (-1.19 [-1.84; -0.54]) and histological (-1.70 [-2.67; -0.74]) damage to articular cartilage when compared to meniscectomy. However, there was no difference in osteoarthritic changes on plain radiographs (0.04 [-0.48; 0.57]), and results on histomorphometrics and biomechanics did neither show a difference in effect between meniscus allograft transplantation and meniscectomy. In conclusion, although meniscus allograft transplantation does not protect articular cartilage from damage, it reduces the extent of it when compared with meniscectomy.

Combining bisphosphonates with allograft bone for implant fixation.

The aim of this review was to discuss the current state of research of combining bisphosphonates with allograft bone for implant fixation. The allograft bone can only be reached by the bisphosphonate once it has been revascularized. However, this can be circumvented by local administration of bisphosphonates. Several animal studies showed that local application of bisphosphonates might protect the graft from resorption. There seems to be an optimum concentration for local application, however, this optimum varies for all different bisphosphonates. It can be concluded that local administration of bisphosphonates might play an important role in improving stability after surgery in which a prosthesis is combined with allograft bone to restore bony defects, however caution should be taken when extrapolating results of animal research to the human clinical situation. More research is needed to study the effect of local bisphophonate use in humans and to study possible side effects.

Anakinra in cerebral haemorrhage to target secondary injury resulting from neuroinflammation (ACTION): Study protocol of a phase II randomised clinical trial.

BACKGROUND: Inflammation plays a vital role in the development of secondary brain injury after spontaneous intracerebral haemorrhage (ICH). Interleukin-1 beta is an early pro-inflammatory cytokine and a potential therapeutic target. AIM: To determine the effect of treatment with recombinant human interleukin-1 receptor antagonist anakinra on perihematomal oedema (PHO) formation in patients with spontaneous ICH compared to standard medical management, and investigate whether this effect is dose-dependent. METHODS: ACTION is a phase-II, prospective, randomised, three-armed (1:1:1) trial with open-label treatment and blinded end-point assessment (PROBE) at three hospitals in The Netherlands. We will include 75 patients with a supratentorial spontaneous ICH admitted within 8 h after symptom onset. Participants will receive anakinra in a high dose (loading dose 500 mg intravenously, followed by infusion with 2 mg/kg/h over 72 h; n = 25) or in a low dose (loading dose 100 mg subcutaneously, followed by 100 mg subcutaneous twice daily for 72 h; n = 25), plus standard care. The control group (n = 25) will receive standard medical management. OUTCOMES: Primary outcome is PHO, measured as oedema extension distance on MRI at day 7 ± 1. Secondary outcomes include the safety profile of anakinra, the effect of anakinra on serum inflammation markers, MRI measures of blood brain barrier integrity, and functional outcome at 90 ± 7 days. DISCUSSION: The ACTION trial will provide insight into whether targeting interleukin-1 beta in the early time window after ICH onset could ameliorate secondary brain injury. This may contribute to the development of new treatment options to improve clinical outcome after ICH.

Bone ingrowth potential of electron beam and selective laser melting produced trabecular-like implant surfaces with and without a biomimetic coating.

The bone ingrowth potential of trabecular-like implant surfaces produced by either selective laser melting (SLM) or electron beam melting (EBM), with or without a biomimetic calciumphosphate coating, was examined in goats. For histological analysis and histomorphometry of bone ingrowth depth and bone implant contact specimens were implanted in the femoral condyle of goats. For mechanical push out tests to analyse mechanical implant fixation specimens were implanted in the iliac crest. The follow up periods were 4 (7 goats) and 15 weeks (7 goats). Both the SLM and EBM produced trabecular-like structures showed a variable bone ingrowth after 4 weeks. After 15 weeks good bone ingrowth was found in both implant types. Irrespective to the follow up period, and the presence of a coating, no histological differences in tissue reaction around SLM and EBM produced specimens was found. Histological no coating was detected at 4 and 15 weeks follow up. At both follow up periods the mechanical push out strength at the bone implant interface was significantly lower for the coated SLM specimens compared to the uncoated SLM specimens. The expected better ingrowth characteristics and mechanical fixation strength induced by the coating were not found. The lower mechanical strength of the coated specimens produced by SLM is a remarkable result, which might be influenced by the gross morphology of the specimens or the coating characteristics, indicating that further research is necessary.

Sustained inflammation, coagulation activation and elevated endothelin-1 levels without macrovascular dysfunction at 3 months after COVID-19.

INTRODUCTION: Endothelial damage and thrombosis caused by COVID-19 may imperil cardiovascular health. More than a year since the WHO declared COVID-19 pandemic, information on its effects beyond the acute phase is lacking. We investigate endothelial dysfunction, coagulation and inflammation, 3 months post-COVID-19. MATERIALS AND METHODS: A cohort study was conducted including 203 patients with prior COVID-19. Macrovascular dysfunction was assessed by measuring the carotid artery diameter in response to hand immersion in ice-water. A historic cohort of 312 subjects served as controls. Propensity score matching corrected for baseline differences. Plasma concentrations of endothelin-1 were measured in patients post-COVID-19, during the acute phase, and in matched controls. Coagulation enzyme:inhibitor complexes and inflammatory cytokines were studied. RESULTS AND CONCLUSIONS: The prevalence of macrovascular dysfunction did not differ between the COVID-19 (18.6%) and the historic cohort (22.5%, RD -4%, 95%CI: -15-7, p = 0.49). Endothelin-1 levels were significantly higher in acute COVID-19 (1.67 ± 0.64 pg/mL) as compared to controls (1.24 ± 0.37, p < 0.001), and further elevated 3 months post-COVID-19 (2.74 ± 1.81, p < 0.001). Thrombin:antithrombin(AT) was high in 48.3%. Markers of contact activation were increased in 16-30%. FVIIa:AT (35%) and Von Willebrand Factor:antigen (80.8%) were elevated. Inflammatory cytokine levels were high in a majority: interleukin(IL)-18 (73.9%), IL-6 (47.7%), and IL-1ra (48.9%). At 3 months after acute COVID-19 there was no indication of macrovascular dysfunction; there was evidence, however, of sustained endothelial cell involvement, coagulation activity and inflammation. Our data highlight the importance of further studies on SARS-CoV-2 related vascular inflammation and thrombosis, as well as longer follow-up in recovered patients.

The effect of bone ingrowth depth on the tensile and shear strength of the implant-bone e-beam produced interface.

New technologies, such as selective electron beam melting, allow to create complex interface structures to enhance bone ingrowth in cementless implants. The efficacy of such structures can be tested in animal experiments. Although animal studies provide insight into the biological response of new structures, it remains unclear how ingrowth depth is related to interface strength. Theoretically, there could be a threshold of ingrowth, above which the interface strength does not further increase. To test the relationship between depth and strength we performed a finite element study on micro models with simulated uncoated and hydroxyapatite (HA) coated surfaces. We examined whether complete ingrowth is necessary to obtain a maximal interface strength. An increase in bone ingrowth depth did not always enhance the bone-implant interface strength. For the uncoated specimens a plateau was reached at 1,500 µm of ingrowth depth. For the specimens with a simulated HA coating, a bone ingrowth depth of 500 µm already yielded a substantial interface strength, and deeper ingrowth did not enhance the interface strength considerably. These findings may assist in optimizing interface morphology (its depth) and in judging the effect of bone ingrowth depth on interface strength.