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To assess the role of rare copy number variations in Alzheimer's disease (AD), we conducted a case–control study using whole-exome sequencing data from 522 early-onset cases and 584 controls. The most recurrent rearrangement was a 17q21.31 microduplication, overlapping the CRHR1 , MAPT , STH and KANSL1 genes that was found in four cases, including one de novo rearrangement, and was absent in controls. The increased MAPT gene dosage led to a 1.6–1.9-fold expression of the MAPT messenger RNA. Clinical signs, neuroimaging and cerebrospinal fluid biomarker profiles were consistent with an AD diagnosis in MAPT duplication carriers. However, amyloid positon emission tomography (PET) imaging, performed in three patients, was negative. Analysis of an additional case with neuropathological examination confirmed that the MAPT duplication causes a complex tauopathy, including prominent neurofibrillary tangle pathology in the medial temporal lobe without amyloid-β deposits. 17q21.31 duplication is the genetic basis of a novel entity marked by prominent tauopathy, leading to early-onset dementia with an AD clinical phenotype. This entity could account for a proportion of probable AD cases with negative amyloid PET imaging recently identified in large clinical series.

Parasitic helminths cause significant damage as they migrate through host tissues to complete their life cycle. While chronic helminth infections are characterized by a well-described Type 2 immune response, the early, tissue-invasive stages are not well understood. Here we investigate the immune pathways activated during the early stages of Heligmosomoides polygyrus bakeri (Hpb), a natural parasitic roundworm of mice. In contrast to the Type 2 immune response present at later stages of infection, a robust Type 1 immune signature including IFNg production was dominant at the time of parasite invasion and granuloma formation. This early response was associated with an accumulation of activated Natural Killer (NK) cells, with no increase of other innate lymphoid cell populations. Parabiosis and confocal microscopy studies indicated that NK cells were recruited from circulation to the small intestine, where they surrounded parasitic larvae. NK cell recruitment required IFNγ receptor signaling, but was independent of CXCR3 expression. The depletion of tissue-infiltrating NK cells altered neither worm burden nor parasite fitness, but increased vascular injury, suggesting a role for NK cells in mediating tissue protection. Together, these data identify an unexpected role for NK cells in promoting disease tolerance during the invasive stage of an enteric helminth infection.

The SORL1 protein plays a protective role against the secretion of the amyloid β peptide, a key event in the pathogeny of Alzheimer’s disease. We assessed the impact of SORL1 rare variants in early-onset Alzheimer’s disease (EOAD) in a case–control setting. We conducted a whole exome analysis among 484 French EOAD patients and 498 ethnically matched controls. After collapsing rare variants (minor allele frequency ≤1%), we detected an enrichment of disruptive and predicted damaging missense SORL1 variants in cases (odds radio (OR)=5.03, 95% confidence interval (CI)=(2.02–14.99), P =7.49.10 −5 ). This enrichment was even stronger when restricting the analysis to the 205 cases with a positive family history (OR=8.86, 95% CI=(3.35–27.31), P =3.82.10 −7 ). We conclude that predicted damaging rare SORL1 variants are a strong risk factor for EOAD and that the association signal is mainly driven by cases with positive family history.

Background In the Netherlands, the HPV-vaccine uptake was 52% during the 2009 catch-up campaign (birth cohorts 1993–1996). This increased to 61% in the regular immunization program (birth cohorts 2000–2001). However for birth cohorts 2003–2004 the uptake declined to 45.5%. With this study we aimed to gain insight into social, economic and cultural determinants that are associated with HPV-vaccination uptake and which subgroups with a lower HPV-vaccination uptake can be identified. In addition, we investigated whether the influence of these factors changed over time. Methods To study the determinants of HPV-vaccine uptake we performed a database study using different aggregation levels, i.e. individual level, postal code level and municipality level. All Dutch girls who were invited for HPV-vaccination through the National Immunization Program in the years 2012, 2014 and 2017 (i.e. birth cohorts 1999, 2001 and 2004, respectively) were included in the study population. We conducted multilevel logistic regression analyses to analyze the influence of the determinants on HPV-vaccination uptake, taking into account that the delivery of HPV-vaccine was nested within municipalities. Results Results showed that in particular having not received a MMR-vaccination, having one or two parents born in Morocco or Turkey, living in an area with lower socioeconomic status and higher municipal voting proportions for Christian political parties or populist parties with liberal-conservative views were associated with a lower HPV-vaccination uptake. Besides some changes in political preferences of the population and changes in the association between HPV uptake and urbanization level we found no clear determinants which could possibly explain the decrease in the HPV-vaccination uptake. Conclusions In this study we identified current social, economic and cultural determinants that are associated with HPV-vaccination uptake and which low-vaccination subgroups can be identified. However, no clear determinants were found which could explain the decrease in the HPV-vaccination uptake. Tailored information and/or consultation for groups that are associated with a lower HPV-vaccination uptake might help to increase the HPV-vaccination uptake in the future.

ObjectiveAlarmins S100A8 and S100A9 are major products of activated macrophages regulating cartilage damage and synovial activation during murine and human osteoarthritis (OA). In the current study, we investigated whether S100A8 and S100A9 are involved in osteophyte formation during experimental OA and whether S100A8/A9 predicts osteophyte progression in early human OA.MethodsOA was elicited in S100A9−/− mice in two experimental models that differ in degree of synovial activation. Osteophyte size, S100A8, S100A9 and VDIPEN neoepitope was measured histologically. Chondrogenesis was induced in murine mesenchymal stem cells in the presence of S100A8. Levels of S100A8/A9 were determined in plasma of early symptomatic OA participants of the Cohort Hip and Cohort Knee (CHECK) cohort study and osteophytes measured after 2 and 5 years.ResultsOsteophyte size was drastically reduced in S100A9−/− mice in ligaments and at medial femur and tibia on days 21 and 42 of collagenase-induced OA, in which synovial activation is high. In contrast, osteophyte size was not reduced in S100A9−/− mice during destabilised medial meniscus OA, in which synovial activation is scant. S100A8 increased expression and activation of matrix metalloproteinases during micromass chondrogenesis, thereby possibly increasing cartilage matrix remodelling allowing for larger osteophytes. Interestingly, early symptomatic OA participants of the CHECK study with osteophyte progression after 2 and 5 years had elevated S100A8/A9 plasma levels at baseline, while C-reactive protein, erythrocyte sedimentation rate and cartilage oligomeric matrix protein were not elevated at baseline.ConclusionsS100A8/A9 aggravate osteophyte formation in experimental OA with high synovial activation and may be used to predict osteophyte progression in early symptomatic human OA.

Survival after trauma has considerably improved. This warrants research on non-fatal outcome. We aimed to identify characteristics associated with both short and long-term health status (HS) after trauma and to describe the recovery patterns of HS and psychological outcomes during 24 months of follow-up. Hospitalized patients with all types of injuries were included. Data were collected at 1 week 1, 3, 6, 12, and 24 months post-trauma. HS was assessed with the EuroQol-5D-3L (EQ-5D-3L) and the Health Utilities Index Mark 2 and 3 (HUI2/3). For the screening of symptoms of post-traumatic stress, anxiety and depression, the Impact of Event Scale (IES) and the Hospital Anxiety and Depression Scale (HADS) subscale anxiety (HADSA) and subscale depression (HADSD) were used. Recovery patterns of HS and psychological outcomes were examined with linear mixed model analyses. A total of 4,883 patients participated (median age 68 (Interquartile range 53-80); 50% response rate). The mean (Standard Deviation (SD)) pre-injury EQ-5D-3L score was 0.85 (0.23). One week post-trauma, mean (SD) EQ-5D-3L, HUI2 and HUI3 scores were 0.49 (0.32), 0.61 (0.22) and 0.38 (0.31), respectively. These scores significantly improved to 0.77 (0.26), 0.77 (0.21) and 0.62 (0.35), respectively, at 24 months. Most recovery occurred up until 3 months. At long-term follow-up, patients of higher age, with comorbidities, longer hospital stay, lower extremity fracture and spine injury showed lower HS. The mean (SD) scores of the IES, HADSA and HADSD were respectively 14.80 (15.80), 4.92 (3.98) and 5.00 (4.28), respectively, at 1 week post-trauma and slightly improved over 24 months post-trauma to 10.35 (14.72), 4.31 (3.76) and 3.62 (3.87), respectively. HS and psychological symptoms improved over time and most improvements occurred within 3 months post-trauma. The effects of severity and type of injury faded out over time. Patients frequently reported symptoms of post-traumatic stress. ClinicalTrials.gov identifier: NCT02508675.

IntroductionTrauma is a major public health problem worldwide that leads to high medical and societal costs. Overall, improved understanding of the full spectrum of the societal impact and burden of injury is needed. The main purpose of the Brabant Injury Outcome Surveillance (BIOS) study is to provide insight into prevalence, predictors and recovery patterns of short-term and long-term health-related quality of life (HRQoL) and costs after injury.Materials and methodsThis is a prospective, observational, follow-up cohort study in which HRQoL, psychological, social and functional outcome, and costs after trauma will be assessed during 24 months follow-up within injured patients admitted in 1 of 10 hospitals in the county Noord-Brabant, the Netherlands. Data will be collected by self-reported questionnaires at 1 week (including preinjury assessment), and 1, 3, 6, 12 and 24 months after injury. If patients are not capable of filling out the questionnaires, proxies will be asked to participate. Also, information about mechanism and severity of injury, comorbidity and indirect and direct costs will be collected. Mixed models will be used to examine the course of HRQoL, functional and psychological outcome, costs over time and between different groups, and to identify predictors for poor or good outcome.RelevanceThis study should make a substantial contribution to the international collaborative effort to assess the societal impact and burden of injuries more accurately. The BIOS results will also be used to develop an outcome prediction model for outcome evaluation including, besides the classic fatal, non-fatal outcome.Trial registration numberNCT02508675.

Aims Mobile Airways Sentinel NetworK (MASK) belongs to the Fondation Partenariale MACVIA-LR of Montpellier, France and aims to provide an active and healthy life to rhinitis sufferers and to those with asthma multimorbidity across the life cycle, whatever their gender or socio-economic status, in order to reduce health and social inequities incurred by the disease and to improve the digital transformation of health and care. The ultimate goal is to change the management strategy in chronic diseases. Methods MASK implements ICT technologies for individualized and predictive medicine to develop novel care pathways by a multi-disciplinary group centred around the patients. Stakeholders Include patients, health care professionals (pharmacists and physicians), authorities, patient’s associations, private and public sectors. Results MASK is deployed in 23 countries and 17 languages. 26,000 users have registered. EU grants (2018) MASK is participating in EU projects (POLLAR: impact of air POLLution in Asthma and Rhinitis, EIT Health, DigitalHealthEurope, Euriphi and Vigour). Lessons learnt (i) Adherence to treatment is the major problem of allergic disease, (ii) Self-management strategies should be considerably expanded (behavioural), (iii) Change management is essential in allergic diseases, (iv) Education strategies should be reconsidered using a patient-centred approach and (v) Lessons learnt for allergic diseases can be expanded to chronic diseases.

BackgroundA relation between osteoarthritis (OA) and increased cholesterol levels is apparent.ObjectivesIn the present study we investigate OA pathology in apolipoprotein E-deficient (ApoE-/-) mice with and without a cholesterol-rich diet, a model for high systemic low density lipoprotein (LDL) cholesterol levels independent of weight.MethodsWild type (WT), ApoE-/-, S100A9-/- and ApoE-/-S100A9-/- mice received a standard or cholesterol-rich diet. Experimental OA was induced by intra-articular injection of collagenase and animals were sacrificed at day 10 and 36. Joint pathology was investigated by immunohistochemistry and RNA expression and protein production by synovium were determined using RT-PCR and luminex, respectively. Data are depicted as mean ± standard deviation.ResultsAlthough minimal differences in cartilage damage were found between the WT and ApoE-/- mice, an increase in synovial thickening was found in the latter. At end-stage OA, ApoE-/- mice on a standard diet showed increased ectopic bone formation, particularly at the medial collateral ligament, compared to OA in WT mice. Furthermore, a significant increase in synovial gene expression of both S100A8 and S100A9 and S100A8/S100A9 protein levels was found in ApoE-/- mice as well as increased levels of the chemokine KC, suggesting an activated inflammatory status of synovial cells.In both ApoE-/- and WT mice, addition of a cholesterol-rich diet resulted in excessive bone formation in the medial collateral ligament at end point. Interestingly, at the early time point, proteoglycan-deposition was already significantly increased in ApoE-/- mice compared with WT mice. Mice deficient for both ApoE and S100A9 also showed increased ectopic bone formation, but no increase in KC-levels, suggesting a role for S100-proteins in cholesterol-mediated synovial activation.ConclusionsIncreased cholesterol levels result in synovial activation and ectopic bone formation in experimental OA. Excessive LDL levels strongly elevate synovial activation and ectopic bone formation in early-stage collagenase-induced OA.Disclosure of InterestNone declared

Background A relation between osteoarthritis (OA) and the metabolic syndrome has long been established. One of the characteristics of the metabolic syndrome is increased cholesterol levels. In a recent study, we showed that LDL accumulation by LDL receptor deficient mice resulted in increased ectopic bone formation during experimental osteoarthritis [1]. Objectives In the present study we investigate OA pathology in ApoE deficient (ApoE–/–) mice with and without a cholesterol-rich diet, which is a model for extremely high systemic LDL cholesterol levels. Methods Wild type (WT) and ApoE–/– mice received a normal or cholesterol-rich diet for 54 days. At day 18, experimental OA was induced by intra-articular injection of collagenase and animals were sacrificed at day 28 and 54. Joint pathology was investigated by histology. LDL levels were measured in serum and synovial wash-outs. Results ApoE–/– mice on a normal diet showed markedly higher LDL levels than WT mice (8.90 mmol/L and 0.40 mmol/L, respectively; p<0.001). While no differences between the two groups were found at the early time point (day 28), end point OA (day 54) in ApoE–/– mice showed a strong increase of ectopic bone formation, mainly at the medial collateral ligament (fold increase 5.4; p<0.001) compared to WT mice. No significant differences in cartilage damage were found between the two groups, a slight increase in synovial thickening, however, was found in ApoE–/– mice (1.9 versus 1.1 in WT mice; p<0.05), suggesting an activated status of synovial lining cells. In addition, we investigated whether a cholesterol-rich diet could increase joint pathology after induction of OA. The diet increased LDL levels even more in ApoE–/– mice (fold increase 2.1, compared to ApoE–/– mice on a normal diet; p<0.001) and already at day 28, histological differences between the two groups were observed. Synovial thickening was four times increased (p<0.001) and also ectopic bone formation in the medial collateral ligament was strongly increased at this early time point (fold increase 2.7; p<0.01). Interestingly, the addition of a cholesterol-rich diet to ApoE–/– mice did not enhance ectopic bone formation at day 54 and even decreased it by 40% in the medial collateral ligament compared to ApoE–/– mice on normal diet. On the other hand, cartilage damage at the medial side of the femoral chondile was strongly increased compared to ApoE–/– on normal diet (fold increase 1.6; p<0.05). Conclusions LDL cholesterol accumulation by ApoE deficiency or a cholesterol-rich diet results in increased synovial thickening and ectopic bone formation in experimental OA. Excessive LDL levels induced by a combination of ApoE deficiency and a cholesterol-rich diet unexpectedly decrease ectopic bone formation, but increase cartilage damage at end stage OA. References de Munter et al. Arthritis Research & Therapy 2013, 15:R175. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.2489