Evinacumab for Pediatric Patients With Homozygous Familial Hypercholesterolemia.

BACKGROUND: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by severely elevated low-density lipoprotein cholesterol (LDL-C) levels due to profoundly defective LDL receptor (LDLR) function. Given that severely elevated LDL-C starts in utero, atherosclerosis often presents during childhood or adolescence, creating a largely unmet need for aggressive LDLR-independent lipid-lowering therapies in young patients with HoFH. Here we present the first evaluation of the efficacy and safety of evinacumab, a novel LDLR-independent lipid-lowering therapy, in pediatric patients with HoFH from parts A and B of a 3-part study. METHODS: The phase 3, part B, open-label study treated 14 patients 5 to 11 years of age with genetically proven HoFH (true homozygotes and compound heterozygotes) with LDL-C >130 mg/dL, despite optimized lipid-lowering therapy (including LDLR-independent apheresis and lomitapide), with intravenous evinacumab 15 mg/kg every 4 weeks. RESULTS: Evinacumab treatment rapidly and durably (through week 24) decreased LDL-C with profound reduction in the first week, with a mean (SE) LDL-C reduction of -48.3% (10.4%) from baseline to week 24. ApoB (mean [SE], -41.3% [9.0%]), non-high-density lipoprotein cholesterol (-48.9% [9.8%]), and total cholesterol (-49.1% [8.1%]) were similarly decreased. Treatment-emergent adverse events were reported in 10 (71.4%) patients; however, only 2 (14.3%) reported events that were considered to be treatment-related (nausea and abdominal pain). One serious treatment-emergent adverse event of tonsillitis occurred (n=1), but this was not considered treatment-related. CONCLUSIONS: Evinacumab constitutes a new treatment for pediatric patients with HoFH and inadequately controlled LDL-C despite optimized lipid-lowering therapy, lowering LDL-C levels by nearly half in these extremely high-risk and difficult-to-treat individuals. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04233918.

Increased incidence of traumatic spinal injury in patients aged 65 years and older in the Netherlands.

PURPOSE: The global population is ageing rapidly. As a result, an increasing number of older patients with traumatic spine injuries are seen in hospitals worldwide. However, it is unknown how the incidence of traumatic spinal injury has developed over the past decade. Therefore, this study aimed to determine the incidence and characteristics of traumatic spinal injury in patients aged under and above 65 years. METHODS: During three time periods: 2009-2010, 2014-2015 and 2019-2020, all adult patients with traumatic spinal injury in the Netherlands were identified from the Dutch National Trauma Registry. Patient-related characteristics and 1-year mortality were collected from a subgroup of patients treated at a level-1 trauma centre, and patients aged ≥ 65 years were compared to patients aged < 65 years. RESULTS: In the Dutch National Trauma Registry 25,737 patients with traumatic spinal injury were identified. The incidence of spine injury in patients > 65 years was 49.5/100,000/yr in 2009-2010, 68.8 in 2014-2015 and 65.9 in 2019-2020. The percentage of patients ≥ 65 years increased from 37% in 2009-2010, to 43% in 2014-2015, and to 47% in 2019-2020. In the subgroup of 1054 patients treated in a level-1 trauma centre, a similar increasing incidence was seen in patients aged ≥ 65 years. In these patients low energy falls were the most common trauma mechanism and the cervical spine was the most commonly injured region. Moreover, patients ≥ 65 years had significantly higher 1-year mortality compared with patients aged < 65 years, 22.7% versus 9.2%. CONCLUSION: The incidence of traumatic spinal injury in older patients in the Netherlands has increased over the last 12 years. Almost half of the patients with traumatic spinal injury are currently aged ≥ 65 years. The increasing incidence and the high 1-year mortality highlight the need to modify existing treatment protocols for these patients.

Genotype-phenotype correlation in a large cohort of pediatric patients with heterozygous and homozygous familial hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C) levels and premature cardiovascular disease (CVD). Both the heterozygous form and the very severe homozygous form can be diagnosed by genetic testing and by clinical criteria. Genetic testing can discern FH in a form caused by complete absence of the LDL-receptors, the negative variant and a form leading to reduced activity of the LDL receptors, the defective variant. The aim of this study is to provide more insight in the genotype-phenotype correlation in children and adolescents diagnosed with heterozygous FH (HeFH) and with homozygous FH (HoFH), specifically in relation to the clinical and therapeutic consequences of the negative and defective variant of FH. METHODS AND RESULTS: Data of 5904 children with a tentative diagnosis of FH referred to our center for genetic testing were collected. A lipid-profile was present in 3494 children, who became the study cohort. In this large cohort of children, which includes 2714 HeFH and 41 HoFH patients, it is shown that receptor negative variants are associated with significant higher LDL-C levels in HeFH patients than receptor defective variants (6.0 versus 4.9 mmol/L; p  < 0.001). A negative/negative variant is associated with a significant higher LDL-C level jn HoFH patients than a negative/defective variant, which in itself has a higher LDL-C level than a defective/defective variant. Significantly more premature CVD is present in close relatives of children with HeFH with negative variants compared to close relatives of HeFH children with defective variants (75% vs 59%; p  < 0.001). CONCLUSIONS: Performing genetic testing and identifying the type of underlying genetic variant is of added value in order to distinguish between pediatric patients with higher risks of premature CVD and to identify those that will benefit most from new types of lipid-lowering therapies. Since in children the phenotype of FH is less affected by environmental factors, the study substantiates the genotype-phenotype correlation in this large pediatric population.

OARSI year in review 2023: Rehabilitation and outcomes.

OBJECTIVE: We systematically reviewed the literature to identify comparative studies of core treatments (exercise, education, or weight management), adjunct treatments (e.g. electrotherapeutical modalities, bracing), or multimodal treatments (core plus other treatments), for treating osteoarthritis (OA) complaints, published between 1 March 2022 and 1 March 2023. DESIGN: We searched three electronic databases for peer-reviewed comparative studies evaluating core treatments, adjunct treatments, or multimodal treatments for OA affecting any joint, in comparison to other OA treatments. Two authors independently screened records. Methodological quality was assessed using the Physiotherapy Evidence Database (PEDro) scale. A narrative synthesis focusing on pain and function outcomes was performed in studies with a mean sample size of at least 46 participants per treatment arm. RESULTS: 33 publications (28 studies), 82% with PEDro ratings of good or excellent, were eligible for narrative synthesis: 23 studies evaluated knee OA; one knee OA or chronic low back pain; two knee or hip OA; one hip OA only; and one thumb OA. No studies identified a dose, duration or type of exercise that resulted in better pain or function outcomes. Core treatments generally showed modest benefits compared to no or minimal intervention controls. CONCLUSIONS: Rehabilitation research continues to be focused on the knee. Most studies are not adequately powered to assess pain efficacy. Further work is needed to better account for contextual effects, identify treatment responder characteristics, understand treatment mechanisms, and implement guideline care.

Smaller intercondylar notch size and smaller ACL volume increase posterior cruciate ligament rupture risk.

PURPOSE: Little is known about risk factors for sustaining a posterior cruciate ligament (PCL) rupture. Identifying risk factors is the first step in preventing a PCL rupture from occurring. The morphology of the knee in patients who ruptured their PCL may differ from that of control patients. The hypothesis was that the intercondylar notch dimensions, 3-D volumes of the intercondylar notch and, the 3-D volumes of both the ACL and the PCL were correlated to the presence of a PCL rupture. METHODS: The magnetic resonance imaging (MRI) scans of 30 patients with a proven PCL rupture were compared to 30 matched control patients with proven intact ACL and PCL. Control patients were selected from patients with knee trauma during sports but without cruciate ligament injury. Patients have been matched for age, height, weight, BMI, and sex. The volumes of the intercondylar notch and both the ACL and PCL were measured on 3D reconstructions. Second, the bicondylar width, the notch width, and the notch width index were measured of all subjects. The relationship between our measurements and the presence of a PCL rupture was analysed. RESULTS: The results show a significant difference in the volumes of the intercondylar notch and the ACL between patients with a ruptured PCL and control patients. Patients with a PCL rupture have smaller intercondylar notch volumes and smaller ACL volumes. There were no significant differences in the bicondylar width, notch width, and notch width index. In the control patients, a significant correlation between the volume of the PCL and the volume of the ACL was found (0.673, p < 0.001). CONCLUSION: Patients with a PCL rupture have smaller intercondylar volumes and smaller ACL volumes when compared to control patients. Second, patients with smaller ACL volumes have smaller PCL volumes. This study shows, for the first time, that there are significant size and volume differences in the shape of the knee between patients with a PCL rupture and control patients. LEVEL OF EVIDENCE: IV.

The smartphone as a tool to screen for scoliosis, applicable by everyone.

PURPOSE (MAIN PURPOSES AND RESEARCH QUESTION): The purpose of this study is to assess the accuracy and precision of the smartphone with application and casing (Scolioscreen) compared to the Scoliometer. METHODS: The Axial Trunk Rotation (ATR) was measured in adolescent scoliosis patients visiting the outpatient clinic while performing the Adam Forward Bending Test. The Scolioscreen measurements were performed by the orthopedic surgeon and a parent. They were compared to the measurement with the Scoliometer by the orthopedic surgeon, the gold standard. The accuracy was determined with the Pearson's correlation coefficient, and precision was determined by assessing the intra- and inter-variability with the intra-class correlation coefficient (ICC). RESULTS: Fifty patients with adolescent idiopathic scoliosis (44 girls) were included with a mean age of 14.1 years and a mean Cobb angle of 38.5°. The accuracy of both the parents and orthopedic surgeon was excellent with a Pearson correlation coefficient of 0.92 and 0.97, respectively. All the ICC's, both intra- and inter-observer, were over 0.92 demonstrating excellent precision. CONCLUSION: This study confirms the accuracy and precision of the Scolioscreen when measuring the ATR on patients with AIS. Therefore, the Scoliometer can be replaced by the more easily available Scolioscreen which can be used by both physician and parents.

Recovery and the use of postoperative physical therapy after total hip or knee replacement.

BACKGROUND: Total hip or knee arthroplasties (THA/TKA) show favorable long-term effects, yet the recovery process may take weeks to months. Physical therapy (PT) following discharge from hospital is an effective intervention to enhance this recovery process. To investigate the relation between recovery and postoperative PT usage, including the presence of comorbidities, 6 months after THA/TKA. METHODS: Multicenter, observational study in primary THA/TKA patients who completed preoperative and 6 months postoperative assessments. The assessments included questions on PT use (yes/no and duration; long term use defined as ≥ 12 weeks), comorbidities (musculoskeletal, non-musculoskeletal, sensory comorbidities and frequency of comorbidities). Recovery was assessed with the HOOS/KOOS on all 5 subdomains. Logistic regression with long term PT as outcome was performed adjusted for confounding including an interaction term (comorbidity*HOOS/KOOS-subdomain). RESULTS: In total, 1289 THA and 1333 TKA patients were included, of whom 95% received postoperative PT, 56% and 67% received postoperative PT ≥ 12 weeks respectively. In both THA and TKA group, less improvement on all HOOS/KOOS domain scores was associated with ≥ 12 weeks of postoperative PT (range Odds Ratios 0.97-0.99). In the THA group the impact of recovery was smaller in patient with comorbidities as non- musculoskeletal comorbidities modified all associations between recovery and postoperative PT duration (Odds Ratios range 1.01-1.05). Musculoskeletal comorbidities modified the associations between Function-in-Daily-Living-and Sport-and-recreation recovery and postoperative PT. Sensory comorbidities only had an effect on Sport-and-recreation recovery and postoperative PT. Also the frequency of comorbidities modified the relation between Function-in-Daily-Living, pain and symptoms recovery and postoperative PT. In the TKA group comorbidity did not modify the associations. CONCLUSION: Worse recovery was associated with longer duration of postoperative PT suggesting that PT provision is in line with patients' needs. The impact of physical recovery on the use of long-term postoperative PT was smaller in THA patients with comorbidities. TRIAL REGISTRATION: Registered in the Dutch Trial Registry on March 13, 2012. TRIAL ID NTR3348; registration number: P12.047. https://www.trialregister.nl/trial/3197 .

No added value for Computer-Assisted surgery to improve femoral component positioning and Patient Reported Outcomes in Hip Resurfacing Arthroplasty; a multi-center randomized controlled trial.

BACKGROUND: Computer Assisted Surgery (CAS) has proven to improve the accuracy in several orthopedic procedures. Therefore we used this technique to evaluate femoral component positioning in Hip Resurfacing Arthroplasty (HRA). The aim of this study was to evaluate imageless CAS compared to manually implanted femoral components and subsequently evaluates Patient Related Outcome Measures (PROMs). We hypothesized that the use of CAS optimizes the position of the femoral component and improves PROMs. METHODS: This is a multicenter, single-blinded, randomized, controlled trial of two groups. In the CAS group guiding of the femoral component was done with imageless navigation. In the Conventional (control) group the femoral component was placed manually according to the preplanned position. The primary outcome measure consists of a maximum of 3 degrees difference between the postoperative Stem Shaft Angle (SSA) and preplanned SSA. Secondary outcome measures consist of the Hip disability and Osteoarthritis Outcome Scale (HOOS), the Harris Hip Score (HHS) and Visual Analogue Scale (VAS) pain score. RESULTS: A total of 122 patients were randomized, 61 in the CAS group and 61 in the conventional group. There was no significant differences in accuracy of femoral implant position. The mean difference between the postoperative- and preplanned SSA was - 2.26 and - 1.75 degrees (more varus) respectively in the CAS and Conventional group. After surgery both groups show significant improvement in all PROMs compared to the baseline measurements, with no significant differences between the groups. CONCLUSION: Our cohort indicates no benefit for the use of CAS in accuracy of placement of the femoral component in HRA compared to manual implantation. There are no clinical differences in PROMs after 1 year follow up. This study showed no added value and no justification for the use of CAS in femoral component positioning in HRA. TRIAL REGISTRATION: This trial is registered at ClinicalTrails.gov ( https://clinicaltrials.gov/ ) on the 25th of October 2006: NCT00391937. LEVEL OF INCIDENCE: Level IIb, multicenter randomized controlled trial.

PROMs in paediatric knee ligament injury: use the Pedi-IKDC and avoid using adult PROMs.

PURPOSE: The aim of this systematic review was to present an evidence-based overview of psychometric properties of patient-reported outcome measures (PROMs) for children with knee ligament injury. METHODS: A systematic search of literature was performed in PubMed, EMBASE and Cochrane databases. The inclusion criteria were diagnostic studies evaluating psychometric properties (validity, reliability, responsiveness) and comprehensibility of PROMs as well as studies including children (age < 18 years) with knee ligament injury. The systematic review was performed following the PRISMA statement. RESULTS: Ten studies were included. Eight studies evaluated psychometric properties of PROMs, and two studies analysed comprehensibility of PROMs. The Pedi-IKDC has been evaluated in four studies and has acceptable psychometric properties. The KOOS-Child is evaluated in one study and has acceptable psychometric properties. The use of adult PROMs in children causes problems in comprehensibility. CONCLUSION: The Pedi-IKDC is an adequate PROM for children with knee ligament injuries. It is valid, reliable and responsive. The KOOS-Child might be an alternative PROM for the Pedi-IKDC, but has only been evaluated in one study. The clinical relevance of the present systematic review is that adult versions of PROMs are not recommended in children and adolescents. LEVEL OF EVIDENCE: III.

The OARSI core set of performance-based measures for knee osteoarthritis is reliable but not valid and responsive.

PURPOSE: The Osteoarthritis Research Society International has identified a core set of performance-based tests of physical function for use in people with knee osteoarthritis (OA). The core set consists of the 30-second chair stand test (30-s CST), 4 × 10 m fast-paced walk test (40 m FPWT) and a stair climb test. The aim of this study was to evaluate the reliability, validity and responsiveness of these performance-based measures to assess the ability to measure physical function in knee OA patients. METHODS: A prospective cohort study of 85 knee OA patients indicated for total knee arthroplasty (TKA) was performed. Construct validity and responsiveness were assessed by testing of predefined hypotheses. A subgroup (n = 30) underwent test-retest measurements for reliability analysis. The Oxford Knee Score, Knee injury and Osteoarthritis Outcome Score-Physical Function Short Form, pain during activity score and knee extensor strength were used as comparator instruments. Measurements were obtained at baseline and 12 months after TKA. RESULTS: Appropriate test-retest reliability was found for all three tests. Intraclass correlation coefficient (ICC) for the 30-s CST was 0.90 (95% CI 0.68; 0.96), 40 m FPWT 0.93 (0.85; 0.96) and for the 10-step stair climb test (10-step SCT) 0.94 (0.89; 0.97). Adequate construct validity could not be confirmed for the three tests. For the 30-s CST, 42% of the predefined hypotheses were confirmed; for the 40 m FPWT, 27% and for the 10-step SCT 36% were confirmed. The 40 m FPWT was found to be responsive with 75% of predefined hypothesis confirmed, whereas the responsiveness for the other tests could not be confirmed. For the 30 s CST and 10-step SCT, only 50% of hypotheses were confirmed. CONCLUSIONS: The three performance-based tests had good reliability, but poor construct validity and responsiveness in the assessment of function for the domains sit-to-stand movement, walking short distances and stair negotiation. The findings of the present study do not justify their use for clinical practice. LEVEL OF EVIDENCE: Level 1. Diagnostic study.

Development of a prediction model for future risk of radiographic hip osteoarthritis.

OBJECTIVE: To develop and validate a prognostic model for incident radiologic hip osteoarthritis (HOA) and determine the value of previously identified predictive factors. DESIGN: We first validated previously reported predictive factors for HOA by performing univariate and multivariate analyses for all predictors in three large prospective cohorts (total sample size of 4548 with 653 incident cases). The prognostic model was developed in 2327 individuals followed for 10 years from the Rotterdam Study-I (RS-I) cohort. External validation of the model was tested on discrimination in two other cohorts: RS-II (n = 1435) and the Cohort Hip and Cohort Knee (CHECK) study (n = 786). RESULTS: From the total number of 28 previously reported predictive factors, we were able to replicate 13 factors, while 15 factors were not significantly predictive in a meta-analysis of the three cohorts. The basic model including the demographic, questionnaire, and clinical examination variables (area under the receiver-operating characteristic curve (AUC) = 0.67) or genetic markers (AUC = 0.55) or urinary C-terminal cross-linked telopeptide of type II collagen (uCTX-II) levels (AUC = 0.67) alone were poor predictors of HOA in all cohorts. Imaging factors showed the highest predictive value for the development of HOA (AUC = 0.74). Addition of imaging variables to the basic model led to substantial improvement in the discriminative ability of the model (AUC = 0.78) compared with uCTX-II (AUC = 0.74) or genetic markers (AUC = 0.68). Applying external validation, similar results were observed in the RS-II and the CHECK cohort. CONCLUSIONS: The developed prediction model included demographic, a limited number of questionnaire, and imaging risk factors seems promising for prediction of HOA.

Is a high tibial osteotomy (HTO) superior to non-surgical treatment in patients with varus malaligned medial knee osteoarthritis (OA)? A propensity matched study using 2 randomized controlled trial (RCT) datasets.

OBJECTIVE: No randomized controlled trial (RCT) has compared the high tibial osteotomy (HTO) with non-surgical treatment in patients with medial knee osteoarthritis (OA) and varus malalignment. The aim was to compare the effectiveness of an unloader brace treatment or a usual care program to the HTO regarding pain severity and knee function. DESIGN: Surgical treatment (HTO) to two non-surgical options was compared by combining the data of two RCTs. One RCT (n = 117) compared an unloader brace to usual care treatment; the other RCT (n = 92) compared closing to opening wedge HTO. One-to-many propensity score matching was used to equalize patient characteristics. We compared clinical outcome at 1 year follow-up (VAS pain (0-10) and knee function (HSS, 0-100)) with mixed model analysis. RESULTS: Propensity score matching resulted in a comparison of 30 brace patient with 83 HTO patients, and of 28 usual care patients with 71 HTO patients. Pain at 1 year after HTO (VAS 3.8) was lower than after valgus bracing (VAS 5.0) with a mean difference of -1.1 (95% CI -2.2; -0.1). Function showed a nonsignificant mean difference of 2.1 [95% CI -3.1; 7.3]. Comparing HTO to usual care a difference was seen in pain (-1.7 [95% CI -2.8; -0.6]) and function (6.6 [95% CI 0.2; 13.1]), in favor of the HTO. CONCLUSIONS: Our data suggest that HTO was more effective in pain reduction compared to both non-surgical treatments. Function improved only when HTO was compared to usual care treatment. These small differences question the benefits of surgical treatment over the brace treatment.

Influence of delayed gadolinium enhanced MRI of cartilage (dGEMRIC) protocol on T2-mapping: is it possible to comprehensively assess knee cartilage composition in one post-contrast MR examination at 3 Tesla?

OBJECTIVE: To evaluate the possibility of assessing knee cartilage with T2-mapping and delayed gadolinium enhanced magnetic resonance imaging (MRI) of cartilage (dGEMRIC) in one post-contrast MR examination at 3 Tesla (T). DESIGN: T2 mapping was performed in 10 healthy volunteers at baseline; directly after baseline; after 10 min of cycling; and after 90 min delay, and in 16 osteoarthritis patients before and after intravenous administration of a double dose gadolinium dimeglumine contrast agent, reflecting key dGEMRIC protocol elements. Differences in T2 relaxation times between each timepoint and baseline were calculated for 6 cartilage regions using paired t tests or Wilcoxon signed-rank tests and the smallest detectable change (SDC). RESULTS: After cycling, a significant change in T2 relaxation times was found in the lateral weight-bearing tibial plateau (+1.0 ms, P = 0.04). After 90 min delay, significant changes were found in the lateral weight-bearing femoral condyle (+1.2 ms, P = 0.03) and the lateral weight-bearing tibial plateau (+1.3 ms, P = 0.01). In these regions of interests (ROIs), absolute differences were small and lower than the corresponding SDCs. T2-mapping after contrast administration only showed statistically significantly lower T2 relaxation times in the medial posterior femoral condyle (-2.4 ms, P < 0.001) with a change exceeding the SDC. CONCLUSION: Because dGEMRIC protocol elements resulted in only small differences in T2 relaxation times that were not consistent and lower than the SDC in the majority of regions, our results suggest that T2-mapping and dGEMRIC can be performed reliably in a single imaging session to assess cartilage biochemical composition in knee osteoarthritis (OA) at 3 T.

Adverse events and survival after closing- and opening-wedge high tibial osteotomy: a comparative study of 412 patients.

PURPOSE: Varus medial knee osteoarthritis (OA) can be treated with a closing-wedge (CW) or opening-wedge (OW) high tibial osteotomy (HTO). Little is known about the adverse event (AE) rate of these techniques. The purpose of this study was to examine the AE rate and survival rate of a consecutive series of 412 patients undergoing CW- or OW-HTO. METHODS: Medical records were retrospectively screened, and all patients who underwent HTO from 1993 to 2012 at the Erasmus University Medical Centre were assessed with a self-administered questionnaire. Patients filled in the intermittent and constant osteoarthritis pain score, knee injury and osteoarthritis outcome score, and a general questionnaire focusing on AE. RESULTS: Medical records of 412 patients (354 CW- and 112 OW-HTOs) were screened. Of the 358 eligible patients, 291 (81 %) returned their questionnaire. A total of 80 AE (17 %) were found in 466 osteotomies. In the CW-group, 47 (13 %) serious adverse events (SAE) and 2 (0.6 %) AE were found. In the OW-group, 17 (15 %) SAE and 14 (13 %) AE were found. The most common AE was in 14 (4 %) patients of the CW-group sensory palsy of the common peroneal nerve. The most common AE in the OW-group was persistent pain at the iliac crest [11 (9.8 %) patients]. Hardware was removed in 48 % of the CW-osteotomies and 71 % of the OW-osteotomies (p < 0.05). The probability of survival was 75 % after 10 years in the CW-group versus 90 % in the OW-group (p < 0.05). In both groups, an equal number of patients were "in need for prosthesis" according to OARSI criteria. CONCLUSION: OW-HTO was associated with more AE than CW-HTO. OW-HTO resulted in better survival than CW-HTO. However, in both groups an equal number of patients were in need for prosthesis. LEVEL OF EVIDENCE: Retrospective comparative study, Level III.

Quantitative in vivo CT arthrography of the human osteoarthritic knee to estimate cartilage sulphated glycosaminoglycan content: correlation with ex-vivo reference standards.

OBJECTIVE: Recently, computed tomography arthrography (CTa) was introduced as quantitative imaging biomarker to estimate cartilage sulphated glycosaminoglycan (sGAG) content in human cadaveric knees. Our aim was to assess the correlation between in vivo CTa in human osteoarthritis (OA) knees and ex vivo reference standards for sGAG and collagen content. DESIGN: In this prospective observational study 11 knee OA patients underwent CTa before total knee replacement (TKR). Cartilage X-ray attenuation was determined in six cartilage regions. Femoral and tibial cartilage specimens harvested during TKR were re-scanned using equilibrium partitioning of an ionic contrast agent with micro-CT (EPIC-µCT), which served as reference standard for sGAG. Next, cartilage sGAG and collagen content were determined using dimethylmethylene blue (DMMB) and hydroxyproline assays. The correlation between CTa X-ray attenuation, EPIC-µCT X-ray attenuation, sGAG content and collagen content was assessed. RESULTS: CTa X-ray attenuation correlated well with EPIC-µCT (r = 0.76, 95% credibility interval (95%CI) 0.64 to 0.85). CTa correlated moderately with the DMMB assay (sGAG content) (r = -0.66, 95%CI -0.87 to -0.49) and to lesser extent with the hydroxyproline assay (collagen content) (r = -0.56, 95%CI -0.70 to -0.36). CONCLUSIONS: Outcomes of in vivo CTa in human OA knees correlate well with sGAG content. Outcomes of CTa also slightly correlate with cartilage collagen content. Since outcomes of CTa are mainly sGAG dependent and despite the fact that further validation using hyaline cartilage of other joints with different biochemical composition should be conducted, CTa may be suitable as quantitative imaging biomarker to estimate cartilage sGAG content in future clinical OA research.

Association of urinary biomarker COLL2-1NO2 with incident clinical and radiographic knee OA in overweight and obese women.

OBJECTIVE: To investigate the association between urinary biomarker Coll2-1NO2 (uColl2-1NO2) and incident knee OA after 2.5 years follow-up in middle-aged overweight and obese women at high risk for knee osteoarthritis (OA). DESIGN: Data were used from PROOF, a randomized controlled trial with 2.5 years follow-up evaluating the preventive effects of a diet and exercise program and oral glucosamine sulphate (double blind and placebo controlled), on development of incident knee OA in women with body mass index ≥ 27 kg/m(2) without signs of knee OA at baseline. Baseline and 2.5 years uColl2-1NO2 concentrations were assessed with enzyme-linked immunosorbent assay (ELISA). Primary outcome measure was incidence of knee OA in one or both knees, defined as incidence of either Kellgren & Lawrence grade ≥2, joint space narrowing of ≥1.0 mm or knee OA according to the combined clinical and radiographic ACR-criteria. We used binary logistic regression for the association analyses. RESULTS: 254 women were available for analyses. At 2.5 years follow-up, incident knee OA was present in 72 of 254 women (28.3%). An inversed association was found between baseline uColl2-1NO2 and incident knee OA at 2.5 years (OR 0.74, 95% CI 0.55-0.99). The concentration at 2.5 years and the change in concentration over 2.5 years did not show significant associations with the outcome. CONCLUSIONS: In overweight and obese middle-aged women, not higher but lower baseline uColl2-1NO2 concentration was significantly associated with an increased risk for incident knee OA. This interesting but counterintuitive outcome makes further validation of this biomarker warranted.

How to define subregional osteoarthritis progression using semi-quantitative MRI osteoarthritis knee score (MOAKS).

OBJECTIVE: Recently, the MRI Osteoarthritis Knee Score (MOAKS), a new semi-quantitative magnetic resonance imaging (MRI) scoring tool, was introduced by a panel of experienced researchers in osteoarthritis (OA). The MOAKS is primarily applicable to quantify OA status, since the interpretation of change in the MOAKS features was not described. In order to enable longitudinal evaluation, we propose definitions for progression and improvement of the main MOAKS features. METHOD: Clear definitions for progression and improvement of the main MOAKS features are given in this brief report. 687 baseline and 30 months follow-up MRIs of the knees of 348 overweight and obese middle-aged women, free of OA at baseline, were scored using the MOAKS. Baseline prevalence and the change of MOAKS features after 30 months follow-up, based on our definitions for progression and improvement, are presented. RESULTS: The proposed definitions showed 3% to 23% progression and 0% to 11% improvement in the MOAKS features during the 30 months follow-up. Overall, progression rates were higher in the medial than in the lateral tibiofemoral (TF) joint. Progression of bone marrow lesions (BMLs) and cartilage defects was highest in the patellofemoral (PF) joint. Inter-rater reliability of the MOAKS scores was moderate to nearly perfect (PABAK 0.77-0.88), with high percentage of agreement overall (89-94%). CONCLUSION: This brief report presents definitions for progression and improvement of the main MOAKS features for the longitudinal evaluation of knee OA features on MRI. We advocate uniform usage of the proposed definitions across studies, but welcome suggestions for optimization.

Bone mineral density changes in the knee following anterior cruciate ligament rupture.

OBJECTIVE: The pathophysiology of anterior cruciate ligament (ACL) rupture leading to knee osteoarthritis (OA) remains largely unknown. It seems that bone loss occurs after ACL rupture. The purpose of our study was to determine bone mineral density (BMD) changes in the knee after ACL rupture during 2-year follow-up period and to compare BMD changes between the injured and healthy contralateral knee. DESIGN: Patients were included in an observational prospective follow-up study within 6 months after ACL trauma and evaluated for 2 years. Patients were treated operatively or non-operatively. At baseline and at the one- and 2-year follow-ups, BMD was measured in six regions of the tibia and femur for both knees (medial, central, lateral) using a Dual-energy X-ray Absorptiometry (DXA) scanner. RESULTS: One hundred forty-one patients were included, with the following characteristics: 66% were male, median age at baseline was 25.3 (inter-quartile range 11.3) years, and 63% were treated operatively. After 1 year, BMD was significantly lower in all regions of the injured knee of the operatively treated patients compared to baseline. After 2 years, BMD was significantly increased, but remained lower than the baseline levels. In all regions for all measurements, the mean BMD was significantly lower in the injured knee than in the healthy contralateral knee. CONCLUSIONS: During a 2-year follow-up period after ACL rupture, the BMD level in the injured knee was found to be lower than in the healthy contralateral knee. In operatively treated patients, the BMD decreased in the first year and increased in the second follow-up year.

Cam impingement: defining the presence of a cam deformity by the alpha angle: data from the CHECK cohort and Chingford cohort.

INTRODUCTION: Cam impingement is characterized by abnormal contact between the proximal femur and acetabulum caused by a non-spherical femoral head, known as a cam deformity. A cam deformity is usually quantified by the alpha angle; greater alpha angles substantially increase the risk for osteoarthritis (OA). However, there is no consensus on which alpha angle threshold to use to define the presence of a cam deformity. AIM: To determine alpha angle thresholds that define the presence of a cam deformity and a pathological cam deformity based on development of OA. METHODS: Data from both the prospective CHECK cohort of 1002 individuals (45-65 years) and the prospective population-based Chingford cohort of 1003 women (45-64 years) with respective follow-up times of 5 and 19 years were combined. The alpha angle was measured at baseline on anteroposterior radiographs, from which a threshold for the presence of a cam deformity was determined based on its distribution. Further, a pathological alpha angle threshold was determined based on the highest discriminative ability for development of end-stage OA at follow-up. RESULTS: A definite bimodal distribution of the alpha angle was found in both cohorts with a normal distribution up to 60°, indicating a clear distinction between normal and abnormal alpha angles. A pathological threshold of 78° resulted in the maximum area under the ROC curve. CONCLUSION: Epidemiological data of two large cohorts shows a bimodal distribution of the alpha angle. Alpha angle thresholds of 60° to define the presence of a cam deformity and 78° for a pathological cam deformity are proposed.

Current and emerging monoclonal antibodies for treating familial hypercholesterolemia in children.

INTRODUCTION: Heterozygous familial hypercholesterolemia (HeFH) is a common genetic disorder caused by pathogenic variants in the LDL-C metabolism. Lifelong exposure to elevated LDL-C levels leads to a high risk of premature cardiovascular disease. To reduce that risk, children with HeFH should be identified and treated with lipid-lowering therapy. The cornerstone consists of statins and ezetimibe, but not in all patients this lowers the LDL-C levels to treatment targets. For these patients, more intensive lipid-lowering therapy is needed. AREAS COVERED: In this review, we provide an overview of the monoclonal antibodies which are currently available or being tested for treating HeFH in childhood. EXPERT OPINION: Monoclonal antibodies that inhibit PCSK9 are first in line lipid-lowering treatment options if oral statin and ezetimibe therapy are insufficient, due to intolerance or very high baseline LDL-C levels. Both evolocumab and alirocumab have been shown to be safe and effective in children with HeFH. For children, evolocumab has been registered from the age of 10 years old and alirocumab from the age of 8 years old. The costs of these new agents are much higher than oral therapy, which makes it important to only use them in a selected patient population.