Search

The end of each chromosome consists of a DNA region termed the telomeres. The telomeres serve as a protective shield against degradation of the coding DNA sequence, as the DNA strand inevitably ‒ with each cell division ‒ is shortened. Inherited genetic variants cause telomere biology disorders when located in genes (e.g. DKC1, RTEL1, TERC, TERT) playing a role in the function and maintenance of the telomeres. Subsequently patients with telomere biology disorders associated with both too short or too long telomeres have been recognized. Patients with telomere biology disorders associated with short telomeres are at increased risk of dyskeratosis congenita (nail dystrophy, oral leukoplakia, and hyper- or hypo-pigmentation of the skin), pulmonary fibrosis, hematologic disease (ranging from cytopenia to leukemia) and in rare cases very severe multiorgan manifestations and early death. Patients with telomere biology disorders associated with too long telomeres have in recent years been found to confer an increased risk of melanoma and chronic lymphocytic leukemia. Despite this, many patients have an apparently isolated manifestation rendering telomere biology disorders most likely underdiagnosed. The complexity of telomere biology disorders and many causative genes makes it difficult to design a surveillance program which will ensure identification of early onset disease manifestation without overtreatment.

Background The etiology of central nervous system (CNS) tumors in children is largely unknown and population-based studies of genetic predisposition are lacking. Methods In this prospective, population-based study, we performed germline whole-genome sequencing in 128 children with CNS tumors, supplemented by a systematic pedigree analysis covering 3543 close relatives. Results Thirteen children (10%) harbored pathogenic variants in known cancer genes. These children were more likely to have medulloblastoma (OR 5.9, CI 1.6–21.2) and develop metasynchronous CNS tumors (P = 0.01). Similar carrier frequencies were seen among children with low-grade glioma (12.8%) and high-grade tumors (12.2%). Next, considering the high mortality of childhood CNS tumors throughout most of human evolution, we explored known pediatric-onset cancer genes, showing that they are more evolutionarily constrained than genes associated with risk of adult-onset malignancies (P = 5e−4) and all other genes (P = 5e−17). Based on this observation, we expanded our analysis to 2986 genes exhibiting high evolutionary constraint in 141,456 humans. This analysis identified eight directly causative loss-of-functions variants, and showed a dose-response association between degree of constraint and likelihood of pathogenicity—raising the question of the role of other highly constrained gene alterations detected. Conclusions Approximately 10% of pediatric CNS tumors can be attributed to rare variants in known cancer genes. Genes associated with high risk of childhood cancer show evolutionary evidence of constraint.

Background: Studies suggest that Wilms tumours (WT) are caused by underlying genetic (5%-10%) and epigenetic (2%-29%) mechanisms, yet studies covering both aspects are sparse.Methods: We performed prospective whole-genome sequencing of germline DNA in Danish children diagnosed with WT from 2016 to 2021, and linked genotypes to deep phenotypes.Results: Of 24 patients (58% female), 3 (13%, all female) harboured pathogenic germline variants in WT risk genes (FBXW7, WT1 and REST). Only one patient had a family history of WT (3 cases), segregating with the REST variant. Epigenetic testing revealed one (4%) additional patient (female) with uniparental disomy of chromosome 11 and Beckwith-Wiedemann syndrome (BWS). We observed a tendency of higher methylation of the BWS-related imprinting centre 1 in patients with WT than in healthy controls. Three patients (13%, all female) with bilateral tumours and/or features of BWS had higher birth weights (4780 g vs 3575 g; p=0.002). We observed more patients with macrosomia (>4250 g, n=5, all female) than expected (OR 9.98 (95% CI 2.56 to 34.66)). Genes involved in early kidney development were enriched in our constrained gene analysis, including both known (WT1, FBXW7) and candidate (CTNND1, FRMD4A) WT predisposition genes. WT predisposing variants, BWS and/or macrosomia (n=8, all female) were more common in female patients than male patients (p=0.01).Conclusion: We find that most females (57%) and 33% of all patients with WT had either a genetic or another indicator of WT predisposition. This emphasises the need for scrutiny when diagnosing patients with WT, as early detection of underlying predisposition may impact treatment, follow-up and genetic counselling. Background: Studies suggest that Wilms tumours (WT) are caused by underlying genetic (5%-10%) and epigenetic (2%-29%) mechanisms, yet studies covering both aspects are sparse.Methods: We performed prospective whole-genome sequencing of germline DNA in Danish children diagnosed with WT from 2016 to 2021, and linked genotypes to deep phenotypes.Results: Of 24 patients (58% female), 3 (13%, all female) harboured pathogenic germline variants in WT risk genes (FBXW7, WT1 and REST). Only one patient had a family history of WT (3 cases), segregating with the REST variant. Epigenetic testing revealed one (4%) additional patient (female) with uniparental disomy of chromosome 11 and Beckwith-Wiedemann syndrome (BWS). We observed a tendency of higher methylation of the BWS-related imprinting centre 1 in patients with WT than in healthy controls. Three patients (13%, all female) with bilateral tumours and/or features of BWS had higher birth weights (4780 g vs 3575 g; p=0.002). We observed more patients with macrosomia (>4250 g, n=5, all female) than expected (OR 9.98 (95% CI 2.56 to 34.66)). Genes involved in early kidney development were enriched in our constrained gene analysis, including both known (WT1, FBXW7) and candidate (CTNND1, FRMD4A) WT predisposition genes. WT predisposing variants, BWS and/or macrosomia (n=8, all female) were more common in female patients than male patients (p=0.01).Conclusion: We find that most females (57%) and 33% of all patients with WT had either a genetic or another indicator of WT predisposition. This emphasises the need for scrutiny when diagnosing patients with WT, as early detection of underlying predisposition may impact treatment, follow-up and genetic counselling.

Background Next-generation sequencing (NGS) based population screening holds great promise for disease prevention and earlier diagnosis, but the costs associated with screening millions of humans remain prohibitive. New methods for population genetic testing that lower the costs of NGS without compromising diagnostic power are needed. Methods We developed double batched sequencing where DNA samples are batch-sequenced twice — directly pinpointing individuals with rare variants. We sequenced batches of at-birth blood spot DNA using a commercial 113-gene panel in an explorative (n = 100) and a validation (n = 100) cohort of children who went on to develop pediatric cancers. All results were benchmarked against individual whole genome sequencing data. Results We demonstrated fully replicable detection of cancer-causing germline variants, with positive and negative predictive values of 100% (95% CI, 0.91–1.00 and 95% CI, 0.98–1.00, respectively). Pathogenic and clinically actionable variants were detected in RB1, TP53, BRCA2, APC, and 19 other genes. Analyses of larger batches indicated that our approach is highly scalable, yielding more than 95% cost reduction or less than 3 cents per gene screened for rare disease-causing mutations. We also show that double batched sequencing could cost-effectively prevent childhood cancer deaths through broad genomic testing. Conclusions Our ultracheap genetic diagnostic method, which uses existing sequencing hardware and standard newborn blood spots, should readily open up opportunities for population-wide risk stratification using genetic screening across many fields of clinical genetics and genomics.

BACKGROUND: Guidelines from the European Hereditary Tumor Group as well as The Danish National Guidelines for Peutz-Jeghers Syndrome (PJS) state that both prenatal diagnosis and preimplantation genetic testing for monogenic disorders (PGT-M) should be offered to patients with PJS. However, only a few cases resulting in viable pregnancies have been published.OBJECTIVE: We present two cases of PJS patients going through PGT-M for PJS. We highlight the awareness of this possibility and discuss the technical and ethical challenges of performing PGT-M for PJS.METHODS AND RESULTS: Case 1: A 36-year-old male with PJS and his partner were referred for genetic counseling. The patient carried a pathogenic de novo variant in STK11. After a terminated pregnancy of a fetus carrying the same pathogenic variant, microsatellite polymorphic marker analysis was established, and the patient was offered PGT-M. The female partner of the patient gave birth to a healthy boy after five years of fertility treatment. Case 2: A 35-year-old female with PJS and her partner were referred for genetic counseling. She carried an inherited pathogenic STK11 variant. The couple was offered PGT-M. Genetic testing of the embryos was performed using microsatellite polymorphic markers. After two rounds of oocyte extraction a blastocyst predicted not to be affected by PJS was identified. The blastocyst was transferred; however, this did not result in a viable pregnancy.CONCLUSIONS: PGT-M can be offered to patients with PJS. The process may be long and filled with ethical dilemmas requiring patients to be motivated and persistent.

Additional file 1. Containing supplementary Methods and Results, including additional figures and tables; Fig. S1-S13 and Table S1-S3.

Anne Marie Jelsig,1 Anna Byrjalsen,1 Majbritt Busk Madsen,2 Tine Plato Kuhlmann,3 Thomas van Overeem Hansen,1 Karin AW Wadt,1,4 John Gásdal Karstensen4,5 1Department of Clinical Genetics, University Hospital of Copenhagen, Copenhagen, Denmark; 2Center for Genomic Medicine, University Hospital of Copenhagen, Copenhagen, Denmark; 3Department of Pathology, University Hospital of Copenhagen, Herlev Hospital, Herlev, Denmark; 4Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark; 5Danish Polyposis Registry, Gastro Unit, Copenhagen University Hospital – Amager and Hvidovre, Copenhagen, DenmarkCorrespondence: Anne Marie JelsigDepartment of Clinical Genetics, University Hospital of Copenhagen, Rigshospitalet, Blegdamsvej 9, Copenhagen, 2100, DenmarkTel +45 20 36 18 85Email anne.marie.jelsig@regionh.dkAbstract: Hereditary polyposis syndromes are characterized by a large number and/or histopathologically specific polyps in the gastrointestinal tract and a high risk of both colorectal cancer and extracolonic cancer at an early age. While the genes responsible for some of the syndromes, eg, APC in familial adenomatous polyposis and STK11 in Peutz-Jeghers syndrome, have been known for decades, novel genetic causes have recently been detected that have shed light on the broader clinical spectrum of syndromes. Genetic diagnoses are important because they can facilitate a personalized surveillance program. Furthermore, at-risk members of the patient’s family can be tested and enrolled in surveillance as needed. In some cases, prenatal diagnostics should be offered. In this paper, we describe the development in germline genetics of the hereditary polyposis syndromes over the last 10– 12 years, their clinical characteristics, as well as how to implement genetic analyses in the diagnostic pipeline.Keywords: polyposis, hereditary, familial adenomatous polyposis, cancer, management

Hereditary polyposis syndromes are characterized by a large number and/or histopathologically specific polyps in the gastrointestinal tract and a high risk of both colorectal cancer and extracolonic cancer at an early age. While the genes responsible for some of the syndromes, eg, APC in familial adenomatous polyposis and STK11 in Peutz-Jeghers syndrome, have been known for decades, novel genetic causes have recently been detected that have shed light on the broader clinical spectrum of syndromes. Genetic diagnoses are important because they can facilitate a personalized surveillance program. Furthermore, at-risk members of the patient’s family can be tested and enrolled in surveillance as needed. In some cases, prenatal diagnostics should be offered. In this paper, we describe the development in germline genetics of the hereditary polyposis syndromes over the last 10–12 years, their clinical characteristics, as well as how to implement genetic analyses in the diagnostic pipeline.

Source Data Verification (SDV) has been reported to account for up to 25% of the budget in Clinical Trials (CT) and cost-benefit of SDV has been questioned. Guidelines for Risk-Based Monitoring (RBM) were published in 2013 by agencies and in 2016, ICH-GCP-E6-(R2) added a requirement for risk-based approaches. This report will perform a comparison of the impact of RBM versus Classic Monitoring (CM) on data quality (defined as accuracy of data reporting from source data to final trial data) and expected impact on costs of CTs.Data on residual errors from four, large, comparable randomised CTs were examined by post-trial SDV. Observed discrepancies were analysed in the categories of "overall" data, "major efficacy" and "major safety". In each category, the residual error rate was calculated as the number of discrepancies divided by the number of data-fields verified.1,716,087 data points were verified using CM and 323,174 using RBM. The overall error rate was 0.40% for RBM and 0.37% for CM (p0.01). For major efficacy, defined by risk assessment, the error rate was 0.15% and 0.28% (p0.0001); in major safety, defined by risk assessment, the error rate was 0.49% and 0.67% (p=0.15), both in favour of the RBM approach.These empirical data, directly comparing RBM with CM, suggest that RBM improves data quality regarding data-points of major importance to trial outcomes; efficacy and major safety. Overall, the RBM approach showed a correlation to reduced amount of data collection errors with major relevance for interpretation of study results and subject safety as well as reducing on-site monitoring and data cleaning resources.

To investigate acute changes in biochemical markers of bone and cartilage turnover in response to moderate intensity exercise with and without joint impact in healthy human subjects. A randomized, cross-over, exploratory, clinical study was conducted. Twenty healthy subjects with no history of joint trauma completed 30 min interventions of standardized moderate intensity cycling and running as well as a resting intervention 1 week apart. Blood samples were taken immediately before, four times after exercise and again the next day. Urine was sampled, before, after and the next day. On the day of rest, samples were taken at timepoints similar to the days of exercise. Markers of type I (CTX-I), II (C2M, CTX-II) and VI (C6M) collagen degradation, cartilage oligomeric matrix protein (COMP) and procollagen C-2 (PRO-C2) was measured. Trial registration number: NCT04542655, 02 September 2020, retrospectively registered. CTX-I was different from cycling (4.2%, 95%CI: 0.4–8.0%, p = 0.03) and resting (6.8%, 95%CI: 2.9–10.7%, p = 0.001) after running and the mean change in COMP was different from cycling (10.3%, 95%CI: 1.1–19.5%, p = 0.03), but not from resting (8.6%, 95%CI: − 0.7–17.8%, p = 0.07) after running. Overall, changes in other biomarkers were not different between interventions. In this exploratory study, running, but not cycling, at a moderate intensity and duration induced acute changes in biomarkers of bone and cartilage extra-cellular matrix turnover.

This review finds that, in children and adults with epilepsy, there are several treatment options. Multiple antiseizure medications are available and in case of drug-resistant epilepsy, a non-pharmacological approach is recommended, including epilepsy surgery, vagus nerve stimulation, or ketogenic diet treatment. The aim of the treatment is to avoid further seizures, but also to avoid negative cognitive, psychological, and social consequences of epilepsy.

This review finds that, in children and adults with epilepsy, there are several treatment options. Multiple antiseizure medications are available and in case of drug-resistant epilepsy, a non-pharmacological approach is recommended, including epilepsy surgery, vagus nerve stimulation, or ketogenic diet treatment. The aim of the treatment is to avoid further seizures, but also to avoid negative cognitive, psychological, and social consequences of epilepsy.

This review finds that, in children and adults with epilepsy, there are several treatment options. Multiple antiseizure medications are available and in case of drug-resistant epilepsy, a non-pharmacological approach is recommended, including epilepsy surgery, vagus nerve stimulation, or ketogenic diet treatment. The aim of the treatment is to avoid further seizures, but also to avoid negative cognitive, psychological, and social consequences of epilepsy.

This review finds that, in children and adults with epilepsy, there are several treatment options. Multiple antiseizure medications are available and in case of drug-resistant epilepsy, a non-pharmacological approach is recommended, including epilepsy surgery, vagus nerve stimulation, or ketogenic diet treatment. The aim of the treatment is to avoid further seizures, but also to avoid negative cognitive, psychological, and social consequences of epilepsy.

This review finds that, in children and adults with epilepsy, there are several treatment options. Multiple antiseizure medications are available and in case of drug-resistant epilepsy, a non-pharmacological approach is recommended, including epilepsy surgery, vagus nerve stimulation, or ketogenic diet treatment. The aim of the treatment is to avoid further seizures, but also to avoid negative cognitive, psychological, and social consequences of epilepsy.

De nære relationer mellem USA og Europa har i årtier været et centralt element i international politik. Men hvor kommer det transatlantiske forholds holdbarhed og modstandskraft fra? Dette spørgsmål optager mange forskere og aktualiseres nu af de igangværende forskydninger i verdenspolitikken. Bogessayet diskuterer derfor, hvordan de to bøger Special Relationships in World Politics (Haugevik, 2018) og Enduring Alliance (Sayle, 2019) fremmer vores viden om de bånd, der knytter staterne i det nordatlantiske område. Haugevik undersøger bilaterale amerikansk-britiske og britisk-norske ’specielle forhold’, mens Sayle ser nærmere på det multilaterale samarbejde i NATO. De tilbyder begge interessante teoretiske argumenter om samspillet mellem diplomatisk praksis og nationale politiske dynamikker samt imponerende empiriske analyser, som underbygger deres pointer. De to bøger rejser samtidig også nye vigtige spørgsmål, herunder om de indbyggede spændinger i liberale normer og værdier samt om betydningen af tillid for det transatlantiske forholds holdbarhed.

Background Osteoarthritis (OA) is a disease with multiple endotypes. A hallmark of OA is loss of cartilage; however, it is evident that the rate of cartilage loss differs among patients, which may partly be attributed to differential capacity for cartilage repair. We hypothesize that a low cartilage repair endotype exists and that such endotypes are more likely to progress radiographically. The aim of this study is to examine the associations of level of cartilage formation with OA severity and radiographic OA progression. We used the blood-based marker PRO-C2, reflecting type II collagen formation, to assess levels of cartilage formation. Materials and methods The type II collagen propeptide PRO-C2 was measured in the serum/plasma of knee OA subjects from New York University (NYU, n = 106) and a subcohort of the phase III oral salmon calcitonin (sCT) trial SMC021-2301 (SMC, n = 147). Risk of radiographic medial joint space narrowing (JSN) over 24 months was compared between quartiles (very low, low, moderate, and high) of PRO-C2. Associations were adjusted for age, gender, BMI, race, baseline pain levels, and baseline joint space width. Results In both the NYU and SMC cohorts, subjects with low PRO-C2 levels had greater JSN compared with subjects with high PRO-C2. Mean difference in JSN between subjects with very low and high levels of PRO-C2 was 0.65 mm (p = 0.002), corresponding to a 3.4 (1.4–8.6)-fold higher risk of progression. There was no significant effect of sCT treatment, compared with placebo, on JSN over 2 years before stratification based on baseline PRO-C2. However, there were proportionately fewer progressors in the sCT arm of the very low/low PRO-C2 group compared with the moderate/high group (Chi squared = 6.5, p = 0.011). Conclusion Serum/plasma level of type II collagen formation, PRO-C2, may be an objective indicator of a low cartilage repair endotype, displaying radiographic progression and superior response to a proanabolic drug. Level of evidence Level III post hoc exploratory analysis of one longitudinal cohort and a sub-study from one phase III clinical trial.

Next-generation sequencing (NGS) based population screening holds great promise for disease prevention and earlier diagnosis, but associated sequencing costs remain prohibitive. We developed double batched sequencing (DoBSeq) and tested it on neonatal blood spot DNA in an explorative (n = 100) and a validation (n = 100) cohort selected from a nation-wide childhood cancer whole genome sequencing (WGS) study. Each cohort was enriched for loss-of-function/pathogenic variants in cancer predisposition syndrome genes. Using a commercial 113-gene panel benchmarked against individual WGS data, we demonstrated replicable detection of deleterious and pathogenic variants, with positive and negative predictive values of 100% (95%CI 0.91-1.00 & 95%CI 0.98-1.00, respectively). Pathogenic variants were detected in RB1, TP53, BRCA2, APC, and 19 other genes. Analyses of larger batches (n = 24, 48, 72 & 96) indicate that DoBSeq is highly scalable and thus a promising, cost-effective method for realizing the potential of population-scale NGS-based screening.

BackgroundThe underlying cause of central nervous system (CNS) tumors in children is largely unknown. In this nationwide, prospective population-based study we investigate rare germline variants across known and putative CPS genes and genes exhibiting evolutionary intolerance of inactivating alterations in children with CNS tumors.MethodsOne hundred and twenty-eight children with CNS tumors underwent whole-genome sequencing of germline DNA. Single nucleotide and structural variants in 315 cancer related genes and 2,986 highly evolutionarily constrained genes were assessed. A systematic pedigree analysis covering 3,543 close relatives was performed.ResultsThirteen patients harbored rare pathogenic variants in nine known CPS genes. The likelihood of carrying pathogenic variants in CPS genes was higher for patients with medulloblastoma than children with other tumors (OR 5.9, CI 1.6-21.2). Metasynchronous CNS tumors were observed exclusively in children harboring pathogenic CPS gene variants (n=2, p=0.01).In general, known pCPS genes were shown to be significantly more constrained than both genes associated with risk of adult-onset malignancies (p=5e−4) and all other genes (p=5e−17). Forty-seven patients carried 66 loss-of-functions variants in 60 constrained genes, including eight variants in six known pCPS genes. A deletion in the extremely constrained EHMT1 gene, formerly somatically linked with sonic hedgehog medulloblastoma, was found in a patient with this tumor.Conclusions∽10% of pediatric CNS tumors can be attributed to rare variants in known CPS genes. Analysis of evolutionarily constrained genes may increase our understanding of pediatric cancer susceptibility.3 key points∽10% of children with CNS tumors carry a pathogenic variant in a known cancer predisposition geneKnown pediatric-onset cancer predisposition genes show high evolutionary constraintLoss-of-function variants in evolutionarily constrained genes may explain additional riskImportance of this studyAlthough CNS tumors constitute the most common form of solid neoplasms in childhood, our understanding of their underlying causes remains sparse. Predisposition studies often suffer from selection bias, lack of family and clinical data or from being limited to SNVs in established cancer predisposition genes. We report the findings of a prospective, population-based investigation of genetic predisposition to pediatric CNS tumors. Our findings illustrate that 10% of children with CNS tumors harbor a damaging alteration in a known cancer gene, of which the majority (9/13) are loss-of-function alterations. Moreover, we illustrate how recently developed knowledge on evolutionarily loss-of-function intolerant genes may be used to investigate additional pediatric cancer risk and present EHMT1 as a putative novel predisposition gene for SHH medulloblastoma. Previously undescribed links between variants in known cancer predisposition genes and specific brain tumors are presented and the importance of assessing both SV and SNV is illustrated.

Anne Marie Jelsig,1 Anna Byrjalsen,1 Majbritt Busk Madsen,2 Tine Plato Kuhlmann,3 Thomas van Overeem Hansen,1 Karin AW Wadt,1,4 John Gásdal Karstensen4,5 1Department of Clinical Genetics, University Hospital of Copenhagen, Copenhagen, Denmark; 2Center for Genomic Medicine, University Hospital of Copenhagen, Copenhagen, Denmark; 3Department of Pathology, University Hospital of Copenhagen, Herlev Hospital, Herlev, Denmark; 4Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark; 5Danish Polyposis Registry, Gastro Unit, Copenhagen University Hospital – Amager and Hvidovre, Copenhagen, DenmarkCorrespondence: Anne Marie JelsigDepartment of Clinical Genetics, University Hospital of Copenhagen, Rigshospitalet, Blegdamsvej 9, Copenhagen, 2100, DenmarkTel +45 20 36 18 85Email anne.marie.jelsig@regionh.dkAbstract: Hereditary polyposis syndromes are characterized by a large number and/or histopathologically specific polyps in the gastrointestinal tract and a high risk of both colorectal cancer and extracolonic cancer at an early age. While the genes responsible for some of the syndromes, eg, APC in familial adenomatous polyposis and STK11 in Peutz-Jeghers syndrome, have been known for decades, novel genetic causes have recently been detected that have shed light on the broader clinical spectrum of syndromes. Genetic diagnoses are important because they can facilitate a personalized surveillance program. Furthermore, at-risk members of the patient’s family can be tested and enrolled in surveillance as needed. In some cases, prenatal diagnostics should be offered. In this paper, we describe the development in germline genetics of the hereditary polyposis syndromes over the last 10– 12 years, their clinical characteristics, as well as how to implement genetic analyses in the diagnostic pipeline.Keywords: polyposis, hereditary, familial adenomatous polyposis, cancer, management

Background: Menopause is associated with detrimental changes in turnover of bone and cartilage and a variety of symptoms with negative impact on the quality of life. Naturally occurring isoflavones from Radix Pueraria lobata, Kudzu root, may possess chondroprotective and symptom-relieving properties, but efficacy and safety of dosing and dose frequencies required for pharmacological action is unclear.Purpose: This clinical trial evaluates the efficacy on bone and cartilage turnover, menopausal symptoms, and safety of five dose regimens of Kudzu root extract administered either once, twice or three times daily in women with at least mild menopausal symptoms.Materials and Methods: Fifty postmenopausal women were randomized equally into five different dose regimen groups of Kudzu root extract in a four-week, parallel group, open-label, single-center, exploratory study design. Biomarkers CTX-I and CTX-II reflecting bone and cartilage degradation, respectively, were assessed in blood samples and 24-h urine samples. Change from baseline in the Menopause Rating Scale (MRS) and subscales was evaluated. Safety endpoints were frequency of adverse events, changes in hematology and safety chemistry data, vital signs and electrocardiogram.Results: Fifty women (Age 54.2 years, SD: 2.9) were randomized. After 4 weeks of treatment, biomarkers of bone resorption and cartilage degradation were statistically significantly reduced from baseline levels in the group receiving two capsules three times a day, serum/urine CTX-I (−18.4%, 95% CI: −8.1 to −27.5, p = 0.001/−34.2%, 95% CI: −21.6 to −44.7, p < 0.0001), urine CTX-II (−17.4% 95% CI: −2.5 to −30.0, p = 0.02). The observed effects were consistent across study groups but appeared to favour three times daily dosing. Four weeks of treatment led to statistically significant reductions in the MRS Total Score (p < 0.0001–0.03) in four out of five treatment groups. Kudzu root extract was well tolerated in all dose regimens, and no serious adverse events were reported.Conclusion: The results indicate that Kudzu extract may possess beneficial effects on bone and cartilage health and may be a promising natural alternative to existing treatments for menopausal symptoms. Kudzu root extract was well tolerated for short-term treatment of mild to severe menopausal symptoms in women in all tested doses and dose frequencies.

Osteoarthritis (OA) development programmes face challenges due to discordance between structural changes and symptoms. A novel cathepsin-K inhibitor, MIV-711, recently reported structural benefits, but did not demonstrate a significant difference from placebo in symptoms. Previous work suggests that pain from non-target joints may confound OA pain outcomes. We therefore conducted an exploratory analysis in participants with predominantly unilateral knee pain from the MIV-711-201 trial.Participants scoring below median contralateral knee NRS pain at baseline from the MIV-711-201 phase 2a clinical trial (n=119) were analysed by treatment group for differences in change from baseline in WOMAC pain, quantitative magnetic resonance imaging bone area and cartilage thickness with a repeated-measures mixed model adjusting for relevant co-variates.In the subgroup with unilateral knee pain, treatment with MIV-711 100 mg led to greater reduction in WOMAC pain compared to placebo (-5.0, 95% CI: -8.69 to -1.3, p=0.008), while 200 mg did not (-2.5, 95% CI: -6.5 to 1.6, p=0.23). MIV-711 treatment was associated with a reduced change in bone area compared to placebo (200 mg; -19.6 mm2 , 95% CI: -36.2 to -3.0, p=0.02, and 100 mg; -12.5 mm2 , 95% CI: -27.8 to 2.8, p=0.11,). No observed differences between treatment groups in cartilage thickness were found in this subgroup.In a subgroup with predominantly unilateral knee pain, significant reduction in OA pain by MIV-711 100 mg treatment was found, with concurrent beneficial structural effects, highlighting the importance of appropriate pain inclusion criteria in OA trials.

Even if liberal democracies generally disfavour subversion, some kinds of subversive efforts may be necessary.

Publisher's version (útgefin grein)., Bone area is one measure of bone size that is easily derived from dual-energy X-ray absorptiometry (DXA) scans. In a GWA study of DXA bone area of the hip and lumbar spine (N ≥ 28,954), we find thirteen independent association signals at twelve loci that replicate in samples of European and East Asian descent (N = 13,608 – 21,277). Eight DXA area loci associate with osteoarthritis, including rs143384 in GDF5 and a missense variant in COL11A1 (rs3753841). The strongest DXA area association is with rs11614913[T] in the microRNA MIR196A2 gene that associates with lumbar spine area (P = 2.3 × 10−42, β = −0.090) and confers risk of hip fracture (P = 1.0 × 10−8, OR = 1.11). We demonstrate that the risk allele is less efficient in repressing miR-196a-5p target genes. We also show that the DXA area measure contributes to the risk of hip fracture independent of bone density., We thank all the study subjects for their valuable participation, the staff from all studies and the participating physicians. A part of this research has been conducted using the UK Biobank Resource under Application Number 23359. arcOGEN (http://www.arcogen.org.uk/) was funded by a special purpose grant from Arthritis Research UK (grant 18030).

For several decades, the close relationship between the United States and Europe has been a key aspect of international politics. But what are the sources of the endurance and resilience of transatlantic ties? This question preoccupies researchers, and its salience is growing in light of current shifts in world politics. Accordingly, the book essay discusses how the two books Special Relationships in World Politics (Haugevik, 2018) and Enduring Alliance (Sayle, 2019) contribute to our knowledge about the international ties of the North Atlantic area. Haugevik examines bilateral American-British and British-Norwegian ‘special relationships’, while Sayles studies multilateral cooperation in NATO. They both offer interesting theoretical arguments about the interplay between diplomatic practice and national political dynamics. Moreover, they provide impressive empirical analyses to support their claims. At the same time, the two books raise new important questions, e.g. about the built-in tensions in liberal norms and values as well as about the significance of trust for enduring transatlantic ties.

ObjectiveThe FORWARD (FGF-18 Osteoarthritis Randomized Trial with Administration of Repeated Doses) trial assessed efficacy and safety of the potential disease-modifying osteoarthritis drug (DMOAD) sprifermin in patients with knee osteoarthritis. Here, we report 5-year efficacy and safety results.MethodsPatients were randomised to intra-articular sprifermin 100 µg or 30 µg every 6 months (q6mo) or 12 months, or placebo, for 18 months. The primary analysis was at year 2, with follow-up at years 3, 4 and 5. Additional post hoc exploratory analyses were conducted in patients with baseline minimum radiographic joint space width 1.5–3.5 mm and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain 40–90, a subgroup at risk (SAR) of progression.Results378 (69%) patients completed the 5-year follow-up. A significant dose-response in total femorotibial joint cartilage thickness with sprifermin (trend test, pConclusionIn the longest DMOAD trial reported to date, sprifermin maintained long-term structural modification of articular cartilage over 3.5 years post-treatment. Potential translation to clinical benefit was observed in the SAR.Trial registration numberNCT01919164

Increasing use of genomic sequencing enables standardized screening of all childhood cancer predisposition syndromes (CPS) in children with cancer. Gene panels currently used often include adult-onset CPS genes and genes without substantial evidence linking them to cancer predisposition. We have developed criteria to select genes relevant for childhood-onset CPS and assembled a gene panel for use in children with cancer. We applied our criteria to 381 candidate genes, which were selected through two in-house panels (n = 338), a literature search (n = 39), and by assessing two Genomics England’s PanelApp panels (n = 4). We developed evaluation criteria that determined a gene’s eligibility for inclusion on a childhood-onset CPS gene panel. These criteria assessed (1) relevance in childhood cancer by a minimum of five childhood cancer patients reported carrying a pathogenic variant in the gene and (2) evidence supporting a causal relation between variants in this gene and cancer development. 138 genes fulfilled the criteria. In this study we have developed criteria to compile a childhood cancer predisposition gene panel which might ultimately be used in a clinical setting, regardless of the specific type of childhood cancer. This panel will be evaluated in a prospective study. The panel is available on (pediatric-cancer-predisposition-genepanel.nl) and will be regularly updated. Supplementary Information The online version contains supplementary material available at 10.1007/s10689-021-00254-0.

BackgroundThere is a great unmet need for the development of effective treatments to treat the symptoms of OA. Nuclear-Factor Kappa-B (NF-κB) and Nrf2 play a key roles in OA pathogenesis and have been identified as potential targets. A fixed-dose combination of apocynin and paenol in a ratio of 2:7 (APPA) has been shown to inhibit activation of NF-κB and upregulate Nrf2. [1]ObjectivesWe report the results of a phase 2a study evaluating the efficacy and safety of APPA in patients with symptomatic knee OA.MethodsThe trial was a 28-day randomized, placebo-controlled, double-blind study comparing 800 mg of APPA twice daily with matched placebo capsules. Patients with radiographic knee OA KL-grade 2-3, and a WOMAC pain score ≥40 and ≤90/100 of target knee at screening and baseline were randomized 1:1 to APPA or placebo. Main exclusion criteria included recent intraarticular surgery or injection therapy, hip pain greater than the target knee, and BMI ≥40 kg/m2. The primary endpoint was change from baseline to Day 28 in the WOMAC pain score. Safety outcomes included reported adverse events (AE), clinical laboratory parameters, ECG, and vital signs.A pre-defined subgroup analysis in subjects with a baseline PainDETECT score >12 indicated a positive effect. Accordingly, post-hoc analyses were undertaken to further assess the effects of APPA in subgroups of participants with higher disease severity.Results152 participants were randomized, and 149 (98%) completed the trial. The mean (SD) WOMAC pain score at baseline was 55.3 (10.2). The two groups were comparable in terms of baseline pain score, gender, age, and BMI.The primary endpoint was not met, mean difference (MD) between APPA and placebo was -0.89 (95 % CI: -5.62, 3.84, p=0.71, Figure 1A). Similarly, no significant differences were found on other key secondary endpoints (WOMAC Function and WOMAC total Figure 1B and C, respectively.) APPA was well tolerated and no differences in frequencies of reported AEs were noted, apart from a higher proportion of subjects reporting mild to moderate gastrointestinal discomfort reported with APPA compared to placebo (12% vs. 6.5 %).In the pre-defined subgroup of participants with baseline PainDETECT ≥ 13 (N=45), the difference in mean change in pain from baseline favored the APPA-group (MD: -11.20, 95 % CI: -20.29 to -2.11, p=0.02). Analysis of participants > 50 WOMAC pain at baseline (Group 1, N=95, Figure 1D), and a KL-grade of the non-target knee >2 (Group 2, N=105, Figure 1E), and a combination of these two criteria (Group 3, N=64, Figure 1F) found a positive effect of APPA compared to placebo (Group 1 MD: -2.61, 95 % CI: -8.98 to 3.76, p=0.42, Group 2 MD: -4.01, 95 % CI: -9.35 to 1.33, p=0.14, and Group 3 MD: -8.32, 95 % CI: -15.48 to -1.16, p=0.02).ConclusionTreatment with APPA 800 mg twice daily for 28 days in patients with symptomatic knee OA overall was not associated with significantly improved outcomes compared to placebo. The treatment was well-tolerated and safe. Subgroup analyses, however, showed a significant effect of APPA in patients with moderate to severe OA, indicating that further research in the effects of APPA in appropriate patients is warranted.References[1]Cross AL, Hawkes J, Wright HL, Moots RJ, Edwards SW. APPA (apocynin and paeonol) modulates pathological aspects of human neutrophil function, without supressing antimicrobial ability, and inhibits TNFα expression and signalling. Inflammopharmacology. 2020 Oct; 28(5):1223-1235.Disclosure of InterestsAsger Reinstrup Bihlet Shareholder of: NBCD A/S, Employee of: NBCD A/S, Inger Byrjalsen Employee of: NBCD A/S, Jeppe Ragnar Andersen Shareholder of: NBCD A/S, Employee of: NBCD A/S, Anna Metnik Shareholder of: NBCD A/S, Employee of: NBCD A/S, Alan Reynolds Shareholder of: AKL R&D, Employee of: AKL R&D, Nicholas Larkins Shareholder of: AKL R&D, Employee of: AKL R&D, Peter Alexandersen: None declared, Helene Rovsing: None declared, Ulla Schmidt: None declared, Robert Moots Speakers bureau: Pfizer, Amgen, Novartis, Gilead, Grant/research support from: University of Liverpool received grant support from AKL on Phase 1 trial where Prof. Rob Moots was principal investigator. UoL also received grant support from AKL on basic neutrophil research., Philip G Conaghan Speakers bureau: AbbVie, BMS, Eli Lilly, Galapagos, Gilead, Novartis, Pfizer and UCB, Consultant of: AbbVie, BMS, Eli Lilly, Galapagos, Gilead, Novartis, Pfizer and UCB

BackgroundPrior studies indicate that mast cells are involved in chronic inflammation and that their activity in the synovium may contribute to structural progression of osteoarthritis (OA), however the exact role of mast cells in OA remains unclear. Antihistamines act by blocking histamine receptors, and further are found to have anti-inflammatory effects by stabilizing mast cell membranes. Current reports describing antihistamine use in OA patients suggest that antihistamines may reduce development of OA and lead to reduced risk of structural progression.ObjectivesWe aimed to investigate whether antihistamine use during a two-year trial period was associated with differences in structural progression of OA, as compared with non-use.MethodsThis is a post-hoc analysis of two large phase III trials investigating oral salmon calcitonin in knee OA (NCT00486434 and NCT00704847). The primary outcome measure was structural progression defined as the change in minimum joint-space width measured by use of x-ray imaging from baseline to Year Two. In these trials, participants reported use of antihistamines, defined as medication coded with the ATC code R06A. In our study, we evaluated differences between groups of participants who reported use of antihistamines, versus those who did not, over the 2-year study period. Secondly, the duration of antihistamine use divided into categories of either no use, 1-49, 50-299 or >300 days of use was investigated to evaluate exposure-response relationships. The effect of use of antihistamines was evaluated using ANCOVA analysis adjusting for age, sex, BMI, and baseline JSW.ResultsOf a total study population of 2,206 participants, 1,485 completed the trial. Of these, 1,327 were non-users of antihistamines (mean age 64.4 years, 64.1% female, mean BMI 29.0 kg/m2) and 158 reported use of antihistamines of any duration during the trial (mean age 64.5 years, 75.2% female, mean BMI 28.1 kg/m2). Seventy-four participants reported use of antihistamines of a duration between 1-49 days, 21 participants between 50-299 days, and 63 reported use of 300 days or more. As illustrated in Figure 1A, the mean JSW change from baseline in the group of non-users was -0.32 mm (95% CI: -0.36 to -0.29), versus -0.19 mm (95%CI: -0.29 to -0.08, p=0.02 for difference) in the group of patients reporting antihistamine use of any duration. A trend towards an association between duration of antihistamine use and reductions in narrowing of JSW was observed (p for trend: 0.02), Figure 1B).ConclusionUse of antihistamines was associated with reduced structural progression in knee OA. Further research evaluating the role of antihistamines in OA is needed to further characterize this observation.Disclosure of InterestsAsger Reinstrup Bihlet Shareholder of: Shareholder of NBCD A/S, Employee of: Employee at NBCD A/S, Claire Prener Miller Employee of: Employee at NBCD A/S, Inger Byrjalsen Employee of: Past employee at NBCD A/S, Jeppe Ragnar Andersen Shareholder of: Shareholder of NBCD A/S, Employee of: Employee at NBCD A/S, Morten Karsdal Shareholder of: Shareholder of Nordic Bioscience A/S, Employee of: Employee at Nordic Bioscience A/S, Matthew C. Baker Shareholder of: Shareholder of Mobility Bio Inc., Employee of: Employee at Mobility Bio Inc., Tharaknath Rao Shareholder of: Shareholder of Mobility Bio Inc., Employee of: Employee of Mobility Bio Inc.

is missing (Short communication)

To investigate acute changes in biochemical markers of bone and cartilage turnover in response to moderate intensity exercise with and without joint impact in healthy human subjects.A randomized, cross-over, exploratory, clinical study was conducted. Twenty healthy subjects with no history of joint trauma completed 30 min interventions of standardized moderate intensity cycling and running as well as a resting intervention 1 week apart. Blood samples were taken immediately before, four times after exercise and again the next day. Urine was sampled, before, after and the next day. On the day of rest, samples were taken at timepoints similar to the days of exercise. Markers of type I (CTX-I), II (C2M, CTX-II) and VI (C6M) collagen degradation, cartilage oligomeric matrix protein (COMP) and procollagen C-2 (PRO-C2) was measured.NCT04542655, 02 September 2020, retrospectively registered.CTX-I was different from cycling (4.2%, 95%CI: 0.4-8.0%, p = 0.03) and resting (6.8%, 95%CI: 2.9-10.7%, p = 0.001) after running and the mean change in COMP was different from cycling (10.3%, 95%CI: 1.1-19.5%, p = 0.03), but not from resting (8.6%, 95%CI: - 0.7-17.8%, p = 0.07) after running. Overall, changes in other biomarkers were not different between interventions.In this exploratory study, running, but not cycling, at a moderate intensity and duration induced acute changes in biomarkers of bone and cartilage extra-cellular matrix turnover.

The heterogeneous nature of osteoarthritis (OA) and the need to subtype patients is widely accepted in the field. The biomarker CRPM, a metabolite of C-reactive protein (CRP), is released to the circulation during inflammation. Blood CRPM levels have shown to be associated with disease activity and response to treatment in rheumatoid arthritis (RA). We investigated the level of blood CRPM in OA compared to RA using data from two phase III knee OA and two RA studies (N = 1591). Moreover, the association between CRPM levels and radiographic progression was investigated. The mean CRPM levels were significantly lower in OA (8.5 [95% CI 8.3–8.8] ng/mL, n = 781) compared to the RA patients (12.8 [9.5–16.0] ng/mL, n = 60); however, a significant subset of OA patients (31%) had CRPM levels (≥ 9 ng/mL) comparable to RA. Furthermore, OA patients (n = 152) with CRPM levels ≥ 9 ng/mL were more likely to develop contra-lateral knee OA assessed by X-ray over a two-year follow-up period with an odds ratio of 2.2 [1.0–4.7]. These data suggest that CRPM is a blood-based biochemical marker for early identification OA patients with an inflammatory phenotype.

BackgroundThe heterogeneous nature of osteoarthritis (OA) and the need to subtype patients is widely accepted. The biomarker CRPM, a metabolite of C-reactive protein (CRP), is released to the circulation during inflammation. Blood CRPM levels have shown to be associated with disease activity and response to treatment in rheumatoid arthritis (RA). We hypothesized that circulating levels of CRPMs could be used to identify OA patients with an inflammatory phenotype. We investigated the level and the prognostic effect of CRPM using combined data from two phase III OA and two RA studies (N = 1591). The association between serum CRPM levels and radiographic progression was investigated in knees of OA patients without radiographic OA in contra-lateral knee at baseline by dividing the patients into cases (knees with two-year radiographic progression) and controls (knees without radiographic progression). ResultsThe mean CRPM levels were significantly lower in OA (8.5 [95% CI 8.3-8.8] ng/mL) compared to the RA patients (15.6 [9.5-21.6] ng/mL); however, a significant subset of OA patients (31%) had CRPM levels ≥ 9ng/mL, as 75% of patients with early RA. Furthermore, OA patients with CRPM levels ≥ 9ng/mL were more likely to progress on X-ray over a two-year follow-up period; CRPM was prognostic for contralateral incidence knee OA with an odds ratio of 2.2 [1.0 - 4.7]. ConclusionA subset of OA patients, approximately 30%, appear to have tissue inflammation comparable to that of RA patients, reflected by the level of CRPM. Furthermore, high CRPM levels were prognostic of incident knee OA. These data suggest that CRPM is a blood-based biochemical marker for early identification OA patients with an inflammatory phenotype.

Purpose Osteoarthritis Research Society International (OARSI) Expert Consensus Guidelines recommend topical non-steroidal anti-inflammatory drugs as first-line medications for osteoarthritis (OA) knee pain, but several voluminous daily applications are required to achieve efficacy. There is a need to develop new and improved topical analgesics with a faster onset, longer duration of action, and the requirement to apply less gel. This trial investigated the safety and efficacy of a new 3.06% diclofenac gel (AMZ001) in subjects with knee OA. Methods In total, 444 subjects (AMZ001 twice daily (BID) [n = 121], AMZ001 once daily (QD) + placebo QD [n = 121], placebo BID [n = 121], or Voltaren 1% 4-times daily [n = 81]) were enrolled. All except Voltaren 1% (single-blinded) were applied topically in a double-blind manner for a total of 4-weeks. The primary endpoint was the change from baseline to week 4 in the WOMAC pain sub-score in the target knee. Secondary and exploratory endpoints included additional efficacy measures (WOMAC total score, WOMAC function and stiffness sub-scores, WOMAC pain weight-bearing and non-weight-bearing sub-scores, ICOAP, chair-stand test, OMERACT-OARSI responder rate, PGA, WPAI, EQ-5D, rescue medication use, satisfaction questionnaire) and safety. Results Treatment with AMZ001 QD was effective at reducing WOMAC pain sub-scores vs placebo (estimated treatment difference [ETD]: −4.61 [95% confidence interval (CI): −9.09, −0.12]; p = 0.0440); however, BID application was not (ETD: −3.76 [95% CI: −8.21, 0.68]; p = 0.0969). For several secondary endpoints, changes from baseline to week 4 conferred nominally statistically significant improvements in favor of AMZ001 vs placebo, including PGA score (AMZ001 BID vs placebo, ETD: −0.61 [95% CI: −1.11, −0.11]; p = 0.0162; AMZ001 QD vs placebo, ETD: −0.63 [95% CI: −1.13, −0.13]; p = 0.0134), WPAI overall work impairment score (AMZ001 QD vs placebo, ETD: −10.44 [95% CI: −20.84, −0.04]; p = 0.0492), and EQ-5D VAS score (AMZ001 BID vs placebo, ETD: 4.70 [95% CI: 0.55, 8.85]; p = 0.0264). Post-hoc analysis excluding 11–14 subjects per group with pain scores that decreased between screening and baseline suggests a consistent effect of both AMZ001 QD (ETD: −5.84 [95% CI: −10.71, −0.97]; p = 0.0189) and BID (ETD: −5.35 [95% CI: −10.16, −0.54]; p = 0.0292) in reducing WOMAC pain sub-scores vs placebo. In general, treatment satisfaction was high, as measured by the satisfaction questionnaire. The frequency and incidence of adverse events (AEs) was greatest in the placebo group. Most AEs (>99%) were of mild or moderate severity. There were no serious AEs. There were no notable effects of any treatment on vital signs, ECGs, physical examination findings, or other laboratory assessments. Conclusions Treatment with AMZ001 BID for 4 weeks improved WOMAC pain sub-scores; however, only QD application conferred nominally statistically significant improvements vs placebo. AMZ001 was generally well tolerated.

Objectives Clinical trials of new disease-modifying treatments for osteoarthritis should demonstrate a positive effect on a functional outcome or reduction in joint failure in order to be considered successful. Total joint replacement (TJR) surgery may be considered as joint failure, but great variation in the incidence of TJR complicates its use as a study endpoint. Factors predicting elevated risk of TJR could potentially be used to enrich such outcome-trials. Methods Using cumulative data from two phase three clinical trials with urine samples from 1255 knee OA patients followed for two years, we assessed the value of a series of baseline clinical variables including the uCTX-II biomarker, as predictors of joint-space narrowing, Kellgren-Lawrence-grade progression, and total joint replacement. Results A prediction-model incorporating age, sex, BMI, CTX-II and KL-grade predicted TJR within the two-year period with an AUC of 0.75 (95% CI: 0.72–0.77). The participants with a cumulative KL-grade between knees of 5, 6, or 7 had a more than 3 times higher risk of TJR in the study period compared to lower (HR: 3.03, 95% CI: 1.54 to 5.96, p = 0.001). Age was associated with increased TJR risk (per 5 years of age: HR: 1.28, 95% CI: 1.03–3.79, p = 0.05). Baseline u-CTX-II was associated with elevated risk of radiographic progression in terms of both JSN and KL-grade. Conclusions A composite model combining baseline age, sex, BMI, u-CTX-II and KL-grade was able to acceptably predict TJR during a two-year period. In the absence of baseline radiographic OA severity, u-CTX-II independently contributed to prediction of TJR. Baseline urine CTX-II was associated with risk of radiographic progression.

© 2019, The Author(s). The original HTML version of this Article was updated shortly after publication to add links to the Peer Review file. In addition, affiliations 16 and 17 incorrectly read ‘School of Medicine Sydney, University of Notre Dame Australia, Sydney, WA, 6160, Australia’ and ‘St Vincent’s Clinical School, University of New South Wales Medicine, University of New South Wales, Sydney, NSW, 2052, Australia.’ This has now been corrected in both the PDF and HTML versions of the Article.

Objective Gender is a risk factor in the onset of osteoarthritis (OA). The aim of the study was to investigate gender differences in contact area (CA) and congruity index (CI) in the medial tibiofemoral (MTF) joint in 2 different cohorts, quantified automatically from magnetic resonance imaging (MRI). Design The CA and CI markers were validated on 2 different data sets from Center for Clinical and Basic Research (CCBR) and Osteoarthritis Initiative (OAI). The CCBR cohort consisted of 159 subjects and the OAI subcohort consisted of 1,436 subjects. From the MTF joint, the contact area was located and quantified using Euclidean distance transform. Furthermore, the CI was quantified over the contact area by assessing agreement of the first- and second-order general surface features. Then, the gender differences between CA and CI values were evaluated at different stages of radiographic OA. Results Female CAs were significantly higher than male CAs after normalization, male CIs were significantly higher than female CIs after correcting with age and body mass index ( P < 0.05), consistent across the 2 data sets. For the OAI data set, the gender differences were present at all stages of radiographic OA. Conclusion This study demonstrated the gender differences in CA and CI in MTF joints. The higher normalized CA and lower CI values in female knees may be linked with the increased risk of incidence of radiographic OA in females. These differences may help further understand the gender differences and/or to establish gender specific treatment strategies.

Baggrundspapiret giver et indblik i udviklingen af en fælleseuropæisk forsvarsindustri. I baggrundspapiret drøftes EU's fornyede rolle i industrisamarbejdet i lyset af tre strategiske visioner for Europa, og afslutningsvis fremhæves en række industri- og sikkerhedspolitiske udfordringer, som udviklingen medfører for Europa og Danmark.

Background Osteoarthritis (OA) can lead to joint failure and ultimately total joint replacement (TJR). Identifying risk-factors of developing joint failure is of interest for clinicians and researchers. Currently late-stage clinical trial design for evaluating new treatments in OA is evolving with the possible utilization of accelerated approval pathways. This may require outcome studies with longer duration, in which joint failures may qualify as an endpoint. However, TJRs are relatively rare events and are known to be biased by doctor/patient interactions as well as local practice guidelines, and consequently, there is a need for objective non-invasive measures, such as soluble biomarkers (BM), to enrich the population for this outcome. BM may act as important tools in investigating the association between biochemical/pathological processes and risk of joint failure. Degradation of collagens type I and II are known to be involved in OA disease progression, and the biomarkers CTX-I (C-telopeptide of crosslinked collagen type I), a marker of bone degradation, and CTX-II (C-telopeptide of crosslinked collagen type II), a marker of cartilage degradation, may reflect disease progression with clinical relevance for the risk of joint failure. Objectives To evaluate baseline (BL) BM sCTX-I and uCTX-II as predictors of TJR. Methods Data from two clinical trials investigating oral salmon calcitonin (SMC) in OA, NCT00486434 and NCT00704847, was analyzed post-hoc. Data was dichotomized by the bottom and top quartile of the respective BM concentration at BL to compare the number TJRs of the knee or hip in groups with high vs. low sCTX-I or uCTX-II, respectively. For means of visualization, plotted in Kaplan-Meier curves. Cox Proportional Hazard Regression was performed to determine the association of BL sCTX-I and uCTX-II to the incidence of TJR while adjusting for co-variates; age, BMI, and gender. Data from both treatment groups were analyzed. Only the first reported incident was included in the analysis for each subject. Results A total of 68 TJRs of knee or hip were reported, of which 49 were knees and 18 were hips. One patient underwent two TJRs, resulting in 67 subjects with events. Results from the Cox Proportional Hazard Regression adjusted for covariates of age, BMI, and sex (table 1), indicate that high BL sCTX-I compared to low was associated with a 3.4 times higher risk of undergoing an arthroplasty of the knee or hip within a two-year period (p=0.04). High BL uCTX-II compared to low was associated with a 3.1 times higher risk of undergoing a TJR of the knee or hip during the study period (p=0.04), and an 8.9-fold increased risk of undergoing a knee replacement during the study period (p=0.02). TJR events over time in groups of high or low uCTX-II through the study are illustrated in figure 1. Conclusion High levels of sCTX-I and uCTX-II at BL were associated with increased risk of undergoing TJR of the knee or hip during the two year study. Our findings support the role of sCTX-I and uCTX-II as important biomarkers in clinical OA trials evaluating incidence of TJRs. Disclosure of Interests Jonathan Bjerre-Bastos Employee of: I am a full-time employee in Nordic Bioscience, Anne-Christine Bay-Jensen Shareholder of: I own shares of Nordic Bioscience, Employee of: I am a full-time employee in Nordic Bioscience, Morten Karsdal Shareholder of: I own shares of Nordic Bioscience, Employee of: I am a full-time employee in Nordic Bioscience, Inger Byrjalsen Employee of: I am a full-time employee in Nordic Bioscience, Jeppe Ragnar Andersen Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, Bente Juel Riis Shareholder of: Yes, I own shares in Nordic Bioscience, Employee of: I am a full-time employee in Nordic Bioscience, Claus Christiansen Shareholder of: Yes, I own shares in Nordic Bioscience, Employee of: I am a full-time employee in Nordic Bioscience, Asger Reinstrup Bihlet Shareholder of: Yes, I own shares in Nordic Bioscience., Employee of: I am a full-time employee in Nordic Bioscience

Background Osteoarthritis (OA) leads to joint failure and total joint replacement (TJR, either hip (H) or knee (K)). Worsening of pain and joint space narrowing are believed to be surrogates for joint failure; however, we hypothesize that TJR, as a reflection of joint failure, can be used as an endpoint in event-driven clinical trials within a reasonable duration. We explored the incidence of TJR in the Prospective Epidemiologic Risk Factor (PERF I) study. Methods A total of 5855 Danish postmenopausal women aged 49–88 enrolled in the PERF I study during 1999–2001 (baseline). Three-, six- and twelve-year follow-up data from the Danish National Patient Registry was collected, including occurrence of TJR and OA diagnosis. At baseline the women were asked whether they had OA. Results The women with a TJR diagnosis before or after baseline were on average 1 year older (p

Background: Development of new disease-modifying drugs in OA (DMOADs) is complicated by heterogeneous study populations and insensitive endpoints of structural change and symptoms, and discordance between structural disease severity and reported symptoms. In such trials, counterintuitively, mild structural disease may be associated with severe symptoms and vice versa. Research to uncover factors distorting the perceived severity of symptoms is needed to better characterize the clinical relevance of structural improvement, if any, in DMOAD trials. Anxiety and depressive (AD) disorders are known to affect pain sensitivity and perception, and as common co-morbidities of OA, these conditions may partly explain the observed discordance between structure and symptoms. If established, exclusion of patients with AD in DMOAD trials could potentially improve the understanding of structural benefit in a clinical context. Objectives: The main objective of this analysis was to investigate the impact of AD on the association between structural features of OA and patient-reported pain. Methods: Baseline data from two phase 3 trials investigating oral salmon calcitonin in OA, NCT00486434 and NCT00704847 (total N=2206), was analyzed in a post-hoc cross-sectional analysis. Patients with self-reported current or previous depression, anxiety or post-traumatic stress syndrome (PTSD) were selected and compared to a control group, matched by sex, age, BMI and JSW. Spearman’s correlation coefficient between JSW and WOMAC pain was calculated for both groups. Multiple regression analyses of both groups with WOMAC pain as the outcome variable, and age, sex, body mass index (BMI) and baseline JSW or KL-grade as explanatory variables were performed. Results: In the AD group, 149 patients had AD in medical history of which 123 reported the condition as ongoing at baseline. The study groups of AD and matched controls (MC) were comparable in terms of age, sex, BMI, JSW, KL-grade and WOMAC pain. Associations between pain and JSW In the AD group, no significant correlation between JSW and WOMAC Pain score was found, while BMI was found to be weakly associated with WOMAC pain (R= 0.19, p=0.02) in the multiple regression analysis. In the MC group, a statistically significant (p=0.004), correlation (R= -0.24) was found between JSW and pain indicating that lower JSW was associated with higher pain, with JSW accounting for approximately 6% of the total natural variation behind reported pain. In addition, a positive significant association between male sex and WOMAC pain (R=0.18, p=0.04) was found. The univariate linear relationship between JSW and pain is illustrated in Figure 1, and multivariate analyses are shown in Table 1. Associations between pain and KL-Grade In the model evaluating associations between KL-grade and symptoms, there was no correlation between KL-grade and symptoms in the AD group. Similar to the findings relating to JSW, in the MC group, a weak (R=0.16), borderline statistically significant association (p=0.07) was found between KL-grade and WOMAC pain. Conclusion: A marked structure-symptoms discordance was found in OA patients with AD, while a statistically significant correlation was seen in matched controls without AD. The results suggest that exclusion of trial patients with anxiety and depression in medical history may improve the accuracy of pain reporting in clinical OA trials. Disclosure of Interests: Jonathan Jetsmark Bjerre-Bastos Employee of: Nordic Bioscience, Inger Byrjalsen Employee of: Nordic Bioscience, Morten Asser Karsdal Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, Jeppe Ragnar Andersen Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, Asger Bihlet Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience

Background Biomarkers of rheumatoid arthritis (RA) disease activity typically measure inflammation or autoimmunity (e.g. CRP, RF). C1M and C3M, metabolites of type I and III collagen, are markers reflecting tissue metabolism. These markers have been documented to provide additional prognostic and predictive value compared to commonly used biomarkers. We investigated the relationship of high serum levels of C1M or C3M to radiographic progression, and benchmarked them to CRP and RF. Methods Placebo treated patients of the OSK1, 2 and 3 studies (Phase III clinical trials testing efficacy of fostamatinib) with baseline serum biomarkers C1M, C3M, CRP and RF were included (nBL = 474). Van der Heijde mTSS was calculated at baseline and 24-week (n24 = 261). Progression was defined as moderate or rapid by ΔmTSS ≥0.5 or ≥ 5 units/year. Patients were divided into subgroups; low (L), high (H) or very high (V) C1M, C3M and CRP, or RF negative, positive and high positive. Difference in clinical parameters were analyzed by Mann-Whitney or χ2tests, and modelling for prediction of progression by logistic regression including covariates (age, gender, BMI, and clinical assessment scores). Results Levels of C1M, C3M, CRP and RF were significantly (p

Background Excessive cartilage degradation is a known characteristic of osteoarthritis (OA). Biochemical markers, such as uCTX-II, have been shown to be associated with disease severity, yet the tissue origin of CTX-II has been disputed. This analysis investigates the association between OA knee joints at different radiographic stages and pain categories with levels of uCTX-II and biomarkers of bone resorption and formation. Methods Baseline data of two randomised clinical trials (NCT00486434 and NCT00704847) in patients with radiographic OA and presence of pain were analysed post hoc. A subgroup with available urine samples and evaluable radiographs for both knees (N = 1241) was analysed. Urine CTX-I, urine CTX-II and serum osteocalcin were analysed for associations with combined Kellgren-Lawrence (KL) scores, gender and pain for both knees to assess the contribution of joints at different stages. Results Pain, BMI, age, gender and KL grade were all significantly associated with uCTX-II. The association between pain and CTX-II appeared to be driven by weight-bearing pain. The level of uCTX-II incrementally increased with higher radiographic severity of each knee. Levels of bone markers CTX-I and osteocalcin were both significantly associated with BMI and gender, but neither were associated with radiographic severity. Biomarker levels between male or female groups of identical KL scores were found to be higher in females compared to males in some but not all KL score groups. Conclusions These results indicate that levels of uCTX-II are independently associated with radiographic severity of OA and pain intensity. CTX-II was associated with weight-bearing pain, but not non-weight-bearing pain, independent of co-variates. Bilateral OA knee joints appear to contribute to uCTX-II levels in an incremental manner according to radiographic severity of single joints. The data suggest that biomarker differences between genders should be taken into account when evaluating these markers in the context of structural features of OA.

Study descriptions. (DOCX 30 kb)