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BackgroundStructural damage in rheumatoid arthritis (RA) includes bone erosion, cartilage change, and joint malalignment; historically evaluated with conventional radiography. Ultrasound (US) has been shown to be a valid tool for evaluating both cartilage change and bone erosion.ObjectivesTo obtain agreement on definitions and develop semiquantitative scoring systems for assessing structural damage by US and to validate these in a web-based reliability exercise.MethodsA Delphi survey of statements was prepared by an OMERACT US Working Group task force (USWG) based on a previously published systematic literature review (1) and circulated between group members, including definitions on normal US appearance of joint components, definitions of elementary lesions and scoring systems for bone erosions and joint malalignment. Definitions and a US scoring system for scoring cartilage change were recently developed and validated by the USWG (2) After agreement was achieved (≥75% of grades 4-5 on 1-5 Likert scale) on the statements, still images of metacarpophalangeal and proximal interphalangeal joints 2-5 in healthy controls and in RA patients with varying degrees of pathology were acquired by the USWG members. A dataset of 100 anonymized images, representing various grades of the 3 components of structural damage was created and utilized in 2 rounds of a web-based exercise. Intra- and inter-reader reliability of the scoring systems was assessed by kappa statistics.Results19 USWG members needed 4 Delphi rounds to reach agreement on a total of 9 statements. 4/12 statements were approved in the first, 2/6 in the second, 1/5 in the third and 2/2 in the fourth round. Final scoring systems and representative images are shown in Table 1 & Figure 1. 22 members participated in the web-based reliability exercise. The intra-reader reliability was almost perfect for bone erosion (kappa: 0.87) and cartilage change (kappa: 0.83) and substantial for malalignment (kappa of 0.72). The inter-reader reliability was almost perfect for bone erosion (kappa: 0.85), and substantial for cartilage change (kappa: 0.79) and malalignment (0.62).Table 1.Final definitions of scoring systems of elementary lesions of structural damage in rheumatoid arthritisAgreementBone erosionA 4-grade semiquantitative scoring system can be used to score erosions as follows: grade 0. intact cortical bone; grade 1. single small erosion (diameter: ≤2mm); grade 2. single large erosion (diameter: >2mm) or 2 small erosions; grade 3. 2 large erosions or ≥3 erosions, regardless of size. Both longitudinal and transverse scans should be considered, and the largest measure chosen for each erosion.100%Cartilage changeA 3-grade semiquantitative scoring system can be used to grade hyaline cartilage change as follows: grade 0. normal cartilage; grade 1. minimal change: focal thinning or incomplete loss of cartilage; grade 2. severe change: diffuse thinning or complete loss of cartilage.80% (2)MalalignmentA 3-grade semiquantitative scoring system can be used to grade malalignment as follows: 0. normal alignment; 1. subluxation or partial dislocation, where the two bone endings are malaligned so that one bone ending is dislocated from its normal position, but still within the articulation; 2. luxation or total dislocation, where the luxated bone ending moves beyond the articulation and the opposing bone ending. Bone position may be compared with a contralateral or similar intact joint if available.94%Figure 1.Representative images of the scoring systems for bone erosion (A), cartilage change (B) and malalignment (C)ConclusionThis first attempt to create a composite US instrument based on scoring systems encompassing all aspects of structural damage, demonstrates that US is a reliable tool for evaluating and scoring bone erosion, cartilage change and malalignment in the finger joints of RA patients.References[1]Gessl I, et al. Semin Arthritis Rheum. 2021 Jun;51(3):627-39.[2]Mandl P, et al. Rheumatology (Oxford). 2019 Oct 1;58(10):1802-11.Disclosure of InterestsPeter Mandl Speakers bureau: AbbVie, Janssen, Lilly, Novartis, Consultant of: AbbVie, Janssen, Lilly, Novartis, Grant/research support from: AbbVie, BMS, Novartis, Janssen, Lilly, MSD, UCB, Irina Gessl: None declared, Georgios Filippou: None declared, Silvia Sirotti: None declared, Lene Terslev Speakers bureau: Novartis, Pfizer, UCB, Janssen, GE, Carlos Pineda: None declared, Helen Keen Speakers bureau: Roche, AbbVie, Janssen, Consultant of: Sanofi, Marina Backhaus: None declared, David Andrew Bong: None declared, Edoardo Cipolletta: None declared, PAZ COLLADO: None declared, Christian Dejaco Speakers bureau: Roche, AbbVie, Sanofi, Lilly, Pfizer, Novartis, Janssen, Galapagos, Consultant of: Roche, AbbVie, Sanofi, Lilly, Pfizer, Novartis, Janssen, Galapagos, Andrea Delle Sedie Speakers bureau: Abbvie, Amgen, Lilly, MSD, Novartis, UCB, Paid instructor for: Abbvie, Amgen, Lilly, MSD, Novartis, UCB, Consultant of: Abbvie, Amgen, Lilly, MSD, Novartis, UCB, Christina Duftner: None declared, Hilde Berner Hammer: None declared, Annamaria Iagnocco: None declared, Zunaid Karim: None declared, Ingrid Möller Speakers bureau: Bristol-Myers Squibb, Ibsa, Pfizer, Galapagos, Esperanza Naredo Speakers bureau: Abbvie, Pfizer, Lilly, Novartis, Janssen, Celgene GmbH, Paid instructor for: Novartis, Consultant of: Novartis, Lilly, Grant/research support from: Lilly, Pfizer, Wolfgang A. Schmidt: None declared, Marcin Szkudlarek: None declared, Giorgio Tamborrini: None declared, Priscilla C Wong: None declared, Emilio Filippucci Speakers bureau: AbbVie, Amgen, Bristol -Myers Squibb, Janssen-Cilag, Lilly, Novartis, Pfizer, Roche, Union Chimique Belge Pharma, Peter Balint Speakers bureau: Abbvie, Janssen, Lilly, Novartis, Maria-Antonietta D’Agostino: None declared

BackgroundConventional radiography (CR) is widely used as the first-line investigation for calcium pyrophosphate deposition (CPPD) disease, given its widespread use and the low cost. Next to it a series of advanced imaging techniques have been evaluated for accuracy and reliability. Among them, ultrasound (US) has been thoroughly tested and demonstrated to be accurate and reliable for CPPD diagnosis. However, even if there are data on the diagnostic accuracy of US and CR alone, it is not clear if performing both diagnostic tests and in which sequential order provides an added value for the diagnosis of CPPD.ObjectivesThe aim of this study was to assess which diagnostic test performs better for the diagnosis of CPPD and if a combination of the two exams provides an additional value.MethodsThis is an ancillary study of the criterion validity of US in CPPD study1. Consecutive patients with knee osteoarthritis requiring total joint replacement were enrolled in 8 centres. Participants underwent US and CR of the affected knee prior to surgery. US was performed by experienced sonographers following the same scanning protocol described in the main study, while CR were performed in weight bearing AP and lateral views and were read by 2 experienced radiologists that reached a consensus on the presence/absence of CPPD. The evaluation of CPPD at the level of menisci and hyaline cartilage (HC) was based on the OMERACT definitions for US and on the new definitions developed by the ACR/EULAR CPPD classification criteria working group for CR [paper under submission]. Patients were classified as having CPPD considering histological examination as reference standard. Diagnostic indexes were calculated for US and CR alone and combined. Poisson models with robust estimation were used to estimate the best sequence of these diagnostic methods for a more accurate diagnosis of CPPD.Results51 pts were enrolled (63% F, mean age 74y ± 8). Diagnostic indexes of US and CR alone and combined are indicated in Table 1. Compared to histology, US demonstrated to be a sensitive tool for identification of CPPD at the knee, with a good sensitivity in all sites and in the overall evaluation. Instead, CR was less sensitive, but it was a highly specific exam for CPPD identification. Combining US and CR led to a higher sensitivity compared with CR alone, but a lower specificity compared to both CR and US alone, and it offered no additional increase in diagnostic accuracy. The Figure 1 shows the results of the appropriate sequence of use of US and CR in patients with suspected CPPD: in case of a positive CR at any of the 3 sites (menisci and HC) no additional exam is necessary, and the same in case of a positive US in at least two sites; however in case of a negative CR, US could help in a statistically significant way to identify CPPD patients, and further in case of a positive US in a single site CR can offer additional information.Table 1.diagnostic indexes of US, CR and US + CR in the identification of CPPD. MM: medial meniscus, LM: lateral meniscus, HC: hyaline cartilage, SN: sensitivity, SP: specificity, PPV: positive predictive value, NPV: negative predictive value, ACC: accuracy.USSNSPPPVNPVACCMM0.880.810.820.880.84LM0.880.730.760.860.80HC0.780.860.820.830.82Overall0.920.640.730.890.78CRMM0.32110.610.67LM0.400.960.910.630.69HC0.480.930.850.680.73Overall0.540.920.880.660.73US + CRMM0.880.810.820.880.84LM0.920.690.740.900.80HC0.870.820.800.890.84Overall0.920.560.670.880.75Figure 1.evaluation of sequence of US and CRConclusionUS confirmed a high diagnostic accuracy in identifying patients affected by CPPD at knee level, while CR demonstrated a high specificity but a low sensitivity. Performing both diagnostic tests could make sense in case of a negative CR or in case of an inconclusive US (only one positive site). To our knowledge, this is the first study that investigates the role of the combination of the two exams in CPPD. Further studies in a large number of patients and in different joints would be helpful to address this point.References[1]Filippou G. et al, Ann Rheum Dis, 2020Disclosure of InterestsNone declared

BackgroundPolymyalgia rheumatica (PMR) is diagnosed and treated by both general practitioners (GP) and rheumatologists. How rheumatologists around the world manage the referral process of patients with PMR from GP’s has not been described. EULAR/ACR guidelines recommend initial prednisolone doses between 12.5 and 25 mg, but it is unknown if guidelines are followed in daily clinical practice1. In addition, the understanding of challenges for recruitment to clinical trials in PMR is currently limited.ObjectivesThis study aims to describe the management of referrals, treatment strategy, and recruitment to clinical trials in PMR among rheumatologists worldwide.MethodsAn English language questionnaire was drafted by a working group of rheumatologists and GP’s from 6 different countries. Questions concerned: 1: respondent, 2: referrals, 3: prednisolone, and 4: barriers to research. Questionnaires were distributed to rheumatologists via members of the International PMR/GCA study group. Answers were collected via an online survey tool (Redcap), from 2nd of November 2021 to 27th of January 2022. Countries were grouped by income and geographical region based on the World bank classifications. Data were weighted by number of inhabitants in a country, based on the United Nations age specific population count, divided by number of respondents in a country. Countries with more than 20 respondents were included.ResultsResults from 27 countries were analysed including 1000 responders in total (Figure 1). There was large variation in time from referral to first assessment, initial dose of prednisolone was high, duration of treatment was relatively short, and a large proportion of patients with newly diagnosed PMR received prednisolone prior to rheumatological evaluation (Table 1). Concerning the 15% of respondents who performed research in PMR, 52% had participated in clinical trials and 56% of the responders experienced difficulties with recruitment.Table 1.Characteristics of reponders, referrals, and treatment.Geographical regionIncomeThe worldEurope and Central AsiaNorth AmericaLatin AmericaEast Asia and PacificSouth AsiaMiddle East and AfricaHigh- income countriesLow- and middle- income countriesRespondersResponders (n), Completed questionnaire (total)875 (1000)294 (304)78 (81)136 (152)53 (53)53 (72)261 (338)446 (458)429 (542)Experience as rheumatologist (years)11 (6-20)12 (6-20)7 (4-20)11 (6-23)21 (10-30)7 (4-10)9 (5-18)11 (5-22)8 (5-12)ReferralsGP’s can discuss patients prior to referral, %647979575860677461Referred patients seen (%)100 (90-100)100 (90-100)100 (100-100)100 (100-100)100 (95-100)100 (100-100)100 (60-100)100 (100-100)100 (90-100)Evaluation > 2 weeks after referral, %26498060216185815PrednisoloneStarted prior to rheumatological evaluation (%)50 (20-50)60 (30-80)70 (50-80)50 (10-50)30 (20-50)50 (20-80)20 (0-50)50 (30-80)50 (10-70)Initial dose (mg)20 (15-40)20 (15-20)20 (15-20)20 (20-40)15 (15-15)20 (15-40)20 (15-40)15 (15-20)20 (15-40)Initial dose > 25 mg, %32964104143642Duration of treatment (months)12 (6-12)12 (12-18)12 (10-18)6 (3-12)18 (12-18)12 (6-12)6 (3-12)12 (12-18)9 (6-12)Data presented as weighted median (interquartile range) unless otherwise stated.GP: general practitionerConclusionThis is the first description of current practice in managing referrals and treatment of PMR by rheumatologists worldwide. In general, median treatment duration was according to EULAR/ACR guidelines, but initial dose of prednisolone was often higher than recommended in many parts of the world. PMR patients were often seen more than two weeks after referral, and treatment had started prior to first rheumatological evaluation.References[1]Dejaco C, Singh YP, Perel P, et al. 2015 Recommendations for the management of polymyalgia rheumatica: a European League Against Rheumatism/American College of Rheumatology collaborative initiative. Annals of the rheumatic diseases 2015; 74(10): 1799-807.AcknowledgementsThis study was endorsed by the international PMR/GCA study group.Disclosure of InterestsAgnete Overgaard Donskov: None declared, Sarah Mackie: None declared, Ellen-Margrethe Hauge Speakers bureau: AbbVie, Sanofi, Sobi, MSD, UCB, Consultant of: AbbVie, Sanofi, Sobi, MSD, UCB, Grant/research support from: Novo Nordic Foundation, Danish Rheumatism Association, Danish Regions Medicine Grants, Roche, Novartis, Celgene, MSD, Pfizer, Roche, Sobi, CARLOS TORO GUTIÉRREZ: None declared, Ib Hansen: None declared, Andrea Hemmig: None declared, Aatke van der Maas: None declared, Tamer A Gheita: None declared, Berit Dalsgaard NIelsen Paid instructor for: Roche, Karen Douglas: None declared, Richard Conway Speakers bureau: Janssen, Roche, Sanofi, Abbvie,, Elena Rezus: None declared, Bhaskar Dasgupta: None declared, Sara Monti: None declared, Eric Matteson Consultant of: Boehringer-Ingelheim,, Grant/research support from: Boehringer Ingelheim,, Sebastian E. Sattui Grant/research support from: AstraZeneca, Mark Matza: None declared, Vanessa Ocampo Speakers bureau: Abbvie, Andrea Bran: None declared, Simone Appenzeller Grant/research support from: GSK, Annelise Goecke Speakers bureau: Abbvie, Boehringer Ingelheim, Recalcine. Consultant Abbvie, Boehringer Ingelheim, NELLY COLMAN MC LEOD Speakers bureau: Laboratorios FAPASA (Farmacéutica Paraguay), Helen Keen Speakers bureau: Roche, Abbvie, Masataka Kuwana: None declared, Latika Gupta: None declared, Babur Salim: None declared, Ghita Harifi Speakers bureau: Abvie, Johnson and johnson, Lilly, Novartis, Mariama Erraoui: None declared, Nelly Ziade Speakers bureau: Abbvie, Eli Lilly, Janssen, Pfizer, Pierre Fabre, Roche, Novartis, Sanofi-Aventis, Paid instructor for: Abbvie, Eli Lilly, Sanofi-Aventis, Pfizer, Janssen, Novartis., Consultant of: Abbvie, Eli Lilly, Janssen, Pfizer, Roche, Novartis, Sandoz, Grant/research support from: Abbvie, Celgene - Algorithm, Bristol-Myers Squibb - NewBridge, Pfizer, Nizar Abdulateef Al-Ani: None declared, Adeola Ajibade: None declared, Johannes Knitza: None declared, Line Frølund: None declared, Max Yates: None declared, Victor Pimentel-Quiroz: None declared, Andre Lyrio: None declared, Maria Sandovici: None declared, Kornelis van der Geest Speakers bureau: Roche, Toby Helliwell Grant/research support from: Valneva, Elisabeth Brouwer Speakers bureau: Roche, Christian Dejaco Speakers bureau: Abbvie, Eli Lilly, Janssen, Novartis, Pfizer, Roche, Galapagos and Sanofi, Consultant of: Abbvie, Eli Lilly, Janssen, Roche, Galapagos and Sanofi, Kresten Keller: None declared

BackgroundRheumatoid arthritis (RA) is a heterogeneous chronic autoimmune disease that affects the synovial joint lining and may result in permanent joint destruction, premature death, and socio-economic burden.1 Although RA is one of Australia’s national health priority areas and gathering information about the RA burden of disease was one of the national action plans2, no published epidemiological study adequately describes RA prevalence and risk factors for frequent hospitalisations in Western Australia (WA) to date. An accurate prevalence estimate of this disease offers a framework for predicting present and growing healthcare service requirements in the future.3ObjectivesWe estimated RA period prevalence and identified risk factors of frequent RA hospitalisations, using linked administrative health and state-specific Australian Pharmaceutical Benefits Scheme (PBS) datasets in WA from 1995–2014.MethodsRA prevalence was calculated per 1000 hospital separations and biological therapy users. RA patients were identified in the WA linked health dataset using ICD codes 714.0–714.9 and M05.00–M06.99. Dispensing data on biological therapy for RA were obtained from PBS records and converted to defined daily doses/1000 population/day. Multivariate logistic regression was used to analyse risk factors for frequent RA hospitalisations (>2/year), controlling for sex, age, and geographic locations.ResultsA total of 17,125 RA patients were admitted to WA hospitals between 1995–2014. The total number of RA hospital separations was 50,353, averaging three hospitalisations per patient over 20 years. The RA period prevalence was 3.4 per 1,000 separations (0.34%), while the RA period prevalence based on biological therapy use was 0.36%. The corrected RA prevalence based on biological therapy usage was 0.36% and 0.72% for the 2005–2009 and 2010–2014 periods, respectively (Table 1). Female gender, age 60–69 years, and living in rural areas were all risk factors for frequent RA hospitalisations.Table 1.Total number of Rheumatoid Arthritis patients in Western Australia taking a standard dose daily (DDD) of RA biological therapy from 1995 to 2014.YearTotal RA bDMARDs utilisation (DDD/1000 population/day)WA general populationPrevalence of RA bDMARDs use in WA population (%)Number of RA patients use standard dose daily of bDMARDs at WA20030.011,952,7410.001420040.081,979,5420.0115820050.162,011,2070.0232920060.232,050,5810.0247620070.312,106,1390.0364320080.502,171,7000.051,09420090.602,240,2500.061,33820100.592,290,8450.061,36120110.632,353,4090.061,47520120.772,425,5070.081,85920130.662,486,9440.071,64920141.002,517,6080.102,510Abbreviations: bDMARDs, biologic disease-modifying anti-rheumatic drugs included Abatacept, Adalimumab, Certolizumab, Etanercept, Golimumab, Infliximab, Rituximab, Tocilizumab; DDD, defined daily doses; RA, Rheumatoid arthritis; WA, Western Australia.ConclusionBased on hospital and biological therapy data, the minimal prevalence of RA in Western Australia is 0.34–0.36%, which falls within the literature range. Older female RA patients in rural areas were more likely to be hospitalised, suggesting unmet needs in primary care access.References[1] Guo Q, Wang Y, Xu D, Nossent J, Pavlos NJ, Xu J. (2018) Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies. Bone Res. 6, 15.[2] Australian Institute of Health and Welfare. (2006) National indicators for monitoring osteoarthritis, rheumatoid arthritis, and osteoporosis. pp. 55. AIHW, Canberra.[3]Hanly JG, Thompson K, Skedgel C. (2015) The use of administrative health care databases to identify patients with rheumatoid arthritis. Open access rheumatology: research and reviews. 7(6), 69-75.AcknowledgementsThe authors thank the data custodians of Hospital Morbidity Data Collection, Emergency Department Data Collection, the Death Registrations and staff at the Western Australian Data Linkage Branch to assist in the provision of data. Special thanks to the University of Western Australia to support KA with an Australian Government Research Training Program PhD Scholarship and the Australian Rheumatology Association WA for Research Fellowship Award.Disclosure of InterestsKhalid Almutairi: None declared, Charles Inderjeeth Speakers bureau: Eli Lilly, David Preen: None declared, Helen Keen Speakers bureau: Pfizer Australia, Abbvie Australia, Johannes Nossent Speakers bureau: Janssen

BackgroundOverweight and obesity are associated with greater incidence and progression of the structural defects of knee osteoarthritis, but it is unknown if weight loss is of benefit.ObjectivesTo describe the association between change in body mass index (BMI) and the incidence and progression of structural defects in knee osteoarthritis.MethodsScores from radiographic analyses of knees at baseline and at 4 to 5 years’ follow up were obtained from three independent data sets (the OAI and MOST data sets from the United States from America, and the CHECK data set from the Netherlands). The exposure of interest was change in BMI from baseline to 4 to 5 years’ follow up. To investigate the incidence of structural defects of knee osteoarthritis, we selected a total of 9732 knees (from 5802 participants) that had a Kellgren-Lawrence (KL) grade of knee osteoarthritis at baseline of ‘none’ (0) or ‘doubtful’ (1) (the ‘incidence cohort’), and determined the odds of having a KL grade at follow-up of ‘minimal’ (2), ‘moderate’ (3), or ‘severe’ (4). To investigate progression, we selected a total of 6084 knees (from 3996 participants) that had a KL grade at baseline of ‘minimal’ (2), ‘moderate’ (3), or ‘severe’ (4) (the ‘progression cohort’), and determined the odds of increasing by 1 or more KL grades by follow up. The degradation of three individual structural features of knee osteoarthritis (i.e., joint space narrowing, osteophytes on the femoral surface, and osteophytes on the tibial surface), on both the medial and lateral sides of the knee, were also investigated in both the incidence and progression cohorts. Here, degradation was defined as an increase by 1 or more Osteoarthritis Research Society International (OARSI) grades.ResultsChange in BMI was positively associated with both the incidence and progression of knee osteoarthritis, as defined by KL grade. Specifically, for each one-unit change in BMI, the adjusted odds ratio for incidence was 1.05 (95% confidence interval [CI] 1.02 to 1.09), and for progression, the same adjusted odds ratio and 95% CI was also observed. Change in BMI was also positively associated with degradation (i.e., narrowing) of joint space on the medial but not the lateral side of the knee, with an adjusted odds ratio of 1.08 (95% CI 1.04 to 1.12) in the ‘incidence cohort’ and 1.08 (95% CI 1.03 to 1.12) in the ‘progression cohort’. Degradation of the tibial and femoral surfaces (i.e., osteophytes) was also seen on the medial but not the lateral side of the knee, but only in one of the two cohorts investigated (the ‘incidence cohort’), with an adjusted odds ratio of 1.07 (95% CI 1.03 to 1.12) for osteophytes on the femoral surface, and 1.05 (95% CI 1.01 to 1.09) for osteophytes on the tibial surface.ConclusionEach one-unit reduction in BMI is associated with a 5 to 8% decrease in the odds of the incidence and progression of the structural defects of knee osteoarthritis, with lower odds of structural degradation specific to the medial – not lateral – side of the knee.AcknowledgementsWe acknowledge the provision of datasets and/or research tools from three studies: the Osteoarthritis Initiative (OAI) Study; the Multicenter Osteoarthritis Study (MOST); and the Cohort Hip and Cohort Knee (CHECK) Study.OAI is a collaborative informatics system created by the National Institute of Mental Health and the National Institute of Arthritis, Musculoskeletal and Skin Diseases (NIAMS) to provide a worldwide resource to quicken the pace of biomarker identification, scientific investigation and OA drug development. The OAI data repository is housed within the National Institute of Mental Health (NIMH) Data Archive (NDA).For the MOST data set, we wish to acknowledge the contributions of the study participants, investigators and research staff involved. MOST is comprised of four (4) cooperative grants: U01 AG18820 David T. Felson (Boston University); U01 AG18832 James Torner (University of Iowa); U01 AG18947 Cora E. Lewis (University of Alabama at Birmingham); U01 AG19069 Michael C. Nevitt (University of California, San Francisco), funded by the National Institutes of Health, a branch of the Department of Health and Human Services, and conducted by MOST investigators. This manuscript was prepared using MOST data and does not claim, infer, or imply endorsement by MOST, by the MOST investigators and their respective institutions or by the University of California of the Data Recipients’ use of the Data, of the entity or personnel conducting the research, or of any results of the research.The CHECK study is funded by the Dutch Arthritis Foundation. Involved are: Erasmus Medical Center Rotterdam; Kennemer Gasthuis Haarlem; Leiden University Medical Center; Maastricht University Medical Center; Martini Hospital Groningen /Allied Health Care Center for Rheumatology and Rehabilitation Groningen; Medical Spectrum Twente Enschede /Ziekenhuisgroep Twente Almelo; Reade Center for Rehabilitation and Rheumatology; St.Maartens-kliniek Nijmegen; University Medical Center Utrecht and Wilhelmina Hospital Assen.Disclosure of InterestsZubeyir Salis: None declared, Helen Keen: None declared, Blanca Gallego: None declared, Tuan van Nguyen: None declared, Amanda Sainsbury Speakers bureau: ZS and AS own 50% each of the shares in Zuman International, which receives royalties for books AS has written and payments for presentations, and provides paid training for higher degree students. AS additionally reports receiving presentation fees and travel reimbursements from Eli Lilly and Co, the Pharmacy Guild of Australia, Novo Nordisk, the Dietitians Association of Australia, Shoalhaven Family Medical Centres, the Pharmaceutical Society of Australia, and Metagenics, and serving on the Nestlé Health Science Optifast VLCD advisory board from 2016 to 2018., Consultant of: ZS and AS own 50% each of the shares in Zuman International, which receives royalties for books AS has written and payments for presentations, and provides paid training for higher degree students. AS additionally reports receiving presentation fees and travel reimbursements from Eli Lilly and Co, the Pharmacy Guild of Australia, Novo Nordisk, the Dietitians Association of Australia, Shoalhaven Family Medical Centres, the Pharmaceutical Society of Australia, and Metagenics, and serving on the Nestlé Health Science Optifast VLCD advisory board from 2016 to 2018.

BackgroundPatients with autoimmune connective tissue disease (CTD) and systemic vasculitis (SV) often require aggressive immune-modulating therapy to prevent organ damage. This however increases the risk for common and uncommon infections.ObjectivesTo compare the temporal rates and associated mortality of hospitalisation with opportunistic infections (OI) for CTD and SV patients in Western Australia between 1985 and 2015.MethodsAll patients hospitalized in Western Australia in the period 1985-2015 with ≥ 2 ICD based diagnostic codes for SLE (n=1432), other CTD (o-CTD; incl DM/PM, systemic sclerosis, Sjogren’s syndrome; n=2161) and Systemic vasculitis (SV; n=1599) and a microbiologically confirmed OI (Mycobacterial, Fungal and viral infections) were included. Descriptive data are given as median (IQR) and frequency (%). Incidence rates per 1000 person years (IR) were calculated during 100.410 person years.ResultsOI occurred in 12.4 % of lupus, 11.5% of SV and 10.4% of o-CTD patients (p=0.72), but overall IR rates for OI were higher for lupus patients (9.87, CI 5 .49-15.76) than for SV (5.94, CI-2.81-10.24) and o-CTD patients (3.40, CI 1.62-7.23). However, whereas the IR for OI in lupus decreased over time, the IR increased for SV and o-CTD patients (Figure 1). Viral infections were the most frequent specific OI followed by tuberculosis and mycotic infections. Cryptococcal infections were observed in lupus patients only and the limited cases of pneumocystis occurred predominantly in SV patients with no cases observed after 2000 (Figure 2). In hospital mortality during OI admission was 11.5% for SV, 5.6 % for lupus and 3.5% for o-CTD patients (p=0.004).Figure 1.Figure 2.ConclusionHospitalization rates for OI have decreased for lupus patients especially since 2005, whereas viral and mycotic OI rates have increased for both SV and o-CTD patients. Hospitalization for OI associated with significant case fatality in especially SV patients, indicating a need for increased prevention of OI.References[1]Esposito S, Bosis S, Semino M, Rigante D. Infections and systemic lupus erythematosus. Eur J Clin Microbiol Infect Dis. 2014 Sep;33(9):1467-75AcknowledgementsSupported by an unrestricted grant from The Arthritis Foundation of Western AustraliaDisclosure of InterestsNone declared

BackgroundSystemic lupus erythematosus (SLE) patients have higher fracture risk, driven by primary (chronic inflammation) and secondary (glucocorticoids treatment) osteoporosis. However, there is limited data on fracture recurrence and post-fracture mortality in this vulnerable population.ObjectivesTo describe the association between systemic lupus erythematosus (SLE) and the risk of fracture(s), 5- and 10-year recurrent fracture(s), and 5-year post-fracture mortality, compared to hospital-based controls in Western Australia (WA) from 1980 - 2014.MethodsPopulation-level cohort study of SLE patients (n=2,440, 28,002 person-years) and general population comparators (controls) (n=10,220; 161,392 person-years) identified within the Western Australia (WA) Rheumatic Disease Epidemiological Registry (WARDER). SLE patients 18-80 years old (identified by ICD-9-CM: 695.4, 710.0, ICD-10-AM: L93.0, M32.0) and controls were nearest matched (5:1) for age, sex, Aboriginality, and temporality. Follow-up was from timezero (index SLE hospitalisation) to fracture-related hospitalisation, death or 31/12/2014. Using longitudinal linked health data we determined the relative risk of (low impact) fracture-related hospitalisations (after excluding for traumatic and external factors, such as, falls from more than standing height and transport accidents), 5- and 10-year recurrent fractures, and 5-year post-fracture mortality between SLE patients and controls with multivariate Cox proportional hazards regression models from 1980-2014.ResultsCompared to general population controls, SLE patients had higher multivariate-adjusted risk (aHR 2.44, 95%CI 2.08, 2.87; PConclusionSLE patients have an increased risk of fractures, 5- and 10-year recurrent fractures, and 5-year mortality post-fracture compared to controls from the general population. After adjustment for conventional risk factors, these associations remained unchanged in the most recent period (2000-2014). This study highlights the need for improved primary prevention of a first fracture event in SLE patients.AcknowledgementsThe authors wish to thank the staff at the Western Australian Data Linkage Branch and Emergency Department Data Collection, Hospital Morbidity Data Collection, Western Australian Cancer Registry, and Death Registrations. The authors wish to thank the Australian Co-ordinating Registry, the Registries of Births, Deaths and Marriages, the Coroners, the National Coronial Information System and the Victorian Department of Justice and Community Safety for enabling COD URF data to be used for this publication.Disclosure of InterestsNone declared

BackgroundAdult-onset Stills disease (AOSD) is a rare, potentially life-threatening autoinflammatory condition for which the reported prevalence shows regional variation and where comparative long-term outcome data are scarce (1).ObjectivesTo investigate annual incidence and point prevalence of AOSD in Western Australia (WA) and compare long-term health-related outcomes between AOSD patients and hospital-based controls.MethodsPopulation-based cohort study using longitudinally linked administrative health data from all hospitals in WA between 1999 and 2013. ASD patients (ICD-10-AM code M06.1) were matched to controls for age and gender. Rate and odds ratios (RR/OR) with 95% confidence intervals (CI) were used to compare ASD patients and controls for serious infections (SI), osteoporosis, joint replacement and the modified Charlson Comorbidity (mCCI).ResultsIn total 52 patients had incident AOSD for an average period incidence of 0.22/100,000 and a point prevalence of 2.4 /100.000 (per 30/12/2013). Compared to controls, ASD patients (median age 41.5 years, 59.6% females) had higher odds of prior liver disease (OR 2.67, 95%CI: 1.31-5.45), fever (OR 54.1, 95%CI: 6.6-43), rash (OR 15.7, 95%CI: 4.08-60.8) and SI (OR 4.36, 95%CI: 2.11-22.8). During 49 months of follow up, crude mortality (11.5% vs 7.5%; p=0.34), survival at one and five years (p=0.78) and m-CCI score at last observation (median 2 vs 2) were similar for ASD patients and controls. However, the odds for subsequent joint replacement (in 7 patients; 13.5%) (OR 45.5, 95%CI: 4.57-93), osteoporosis (OR 31.3, 95%CI: 3.43-97) and SI (RR 5.68, 95%CI: 6.61-8.74) were significantly higher in ASD patients.ConclusionThe epidemiology and demographics of AOSD in Western Australia fall within the internationally reported range. Compared to controls, AOSD patients presented higher rates of liver disease, rash and SI before disease onset. Mortality following AOSD was not increased for five years despite high rates of chronic arthritis requiring joint replacement, SI, and osteoporosis.References[1]Tomaras, S.; Goetzke, C.C.; Kallinich, T.; Feist, E. Adult-Onset Still’s Disease: Clinical Aspects and Therapeutic Approach. J. Clin. Med.2021, 10, 733.AcknowledgementsSupported by a grant from the Arthritis Foundation of Western AustraliaDisclosure of InterestsNone declared

BackgroundUltrasound (US) has proven to be an excellent imaging technique for detecting calcium pyrophosphate (CPP) deposition disease (CPPD); it is also widely available and inexpensive and can be performed during the clinic visit making it the preferred imaging modality for many rheumatologists. However, no validated grading systems have yet been developed allowing for a quantification of the extent of crystal deposition in CPPD.ObjectivesThe aim of this study was to develop a scoring system for the quantification of CPP deposition at a patient level according to the OMERACT framework.MethodsAs part of the OMERACT methodology, we performed a systematic literature review (SLR) and meta-analysis aimed to estimate the prevalence of CPP deposition in peripheral joints by imaging, in order to identify relevant joints for CPPD monitoring. A preliminary survey was also circulated among the members of the OMERACT US – CPPD working group to collect their own suggestions according to their personal experience. Subsequently, a Delphi survey was prepared and circulated between members of the group, including statements that reflected both the results of the SLR and of the preliminary survey. In total, 32 statements were generated regarding the type of scoring for single structures, the sites to be included, the final scoring at patient level, and the scanning technique. Participants were asked to reply on a 5-point Likert scale (1, strongly disagree to 5, strongly agree) and agreement was achieved when 4 and 5 grades reached 75% or more of concordance. In case of disagreement, new statements were proposed according to the members’ suggestions and circulated for voting in a subsequent round. After agreement of a scoring system, the validation process began. Two rounds of a web-based exercise on static images were conducted on 120 images representing equally all sites under investigation and all degrees of crystal deposition, to assess the intra- and inter-reader reliability of the new scoring system. Representative images of the scoring system were visible throughout the entire exercise in order to facilitate the scoring of the lesions.ResultsThree Delphi rounds were needed to reach agreement on all items. 32/41 members of the OMERACT US-CPPD working group replied in the first round, 26/32 in the second, and 25/26 in the third round. Twenty statements were approved in the first round, 3 in the second, and 3 in the third round. Only the knees (menisci and hyaline cartilage) and the triangular fibrocartilage of the wrist were included in the final score, using a four-grade system (0-3). It was decided that each anatomical structure should be scored separately and then also summed in order to define the joint score. The sum of the assessed joints was the total score at patient level. The final scoring system with the definitions and the relative technical notes is represented in Figure 1. 33/41 members participated to the reliability exercise. The inter-reader reliability of the scoring was substantial (kappa of 0.72), and the intra-reader reliability was almost perfect (kappa of 0.82).ConclusionThis is the first study for developing a scoring system for the extent of CPP crystal deposition in patients with CPPD. The scoring system demonstrated to be reliable in static images. The next step of the validation process is to assess the reliability of the scoring system in a patient-based exercise. This study represents a fundamental step in the OMERACT process of validating US as an outcome measure instrument, and above proposed scoring system will hopefully provide a useful tool for clinical practice and research.Disclosure of InterestsNone declared

BackgroundThe association between systemic lupus erythematosus (SLE) and cancer risk is unclear.ObjectivesDescribe the association between systemic lupus erythematosus (SLE) and the risk of cancer development and subsequent 5-year mortality in Western Australia (WA).MethodsPopulation-level cohort study of SLE patients (n=2,111) and general population comparators (n=21,110) hospitalised between 1980–2014. SLE patients (identified by ICD-9-CM: 695.4, 710.0, and ICD-10-AM: L93.0, M32.0) were nearest matched (10:1) for age, sex, Aboriginality, and temporality. Follow-up was from timezero (index SLE hospitalisation) to cancer development, death or 31/12/2014. Using longitudinal linked health data, we determined the risk of cancer development and subsequent 5-year mortality between SLE patients and comparators with Cox proportional hazards regression models.ResultsSLE patients had similar multivariate-adjusted risk (aHR 1.03, 95%CI 0.93, 1.15; P=0.583) of cancer development. Cancer development risk was higher in SLE patients ConclusionHospitalised SLE patients had increased risk of multiple cancers, but a reduced risk of breast cancer. Following cancer development, SLE patients had increased risk of 5-year mortality. Together there is scope to improve cancer prevention and surveillance in SLE patients.AcknowledgementsThe authors wish to thank the staff at the Western Australian Data Linkage Branch and Emergency Department Data Collection, Hospital Morbidity Data Collection, Western Australian Cancer Registry, and Death Registrations. The authors wish to thank the Australian Co-ordinating Registry, the Registries of Births, Deaths and Marriages, the Coroners, the National Coronial Information System and the Victorian Department of Justice and Community Safety for enabling COD URF data to be used for this publication.Disclosure of InterestsNone declared

BackgroundOver the last 20 years aggressive therapy for inflammatory joint diseases (IJD) has become standard of care following the acceptance of Methotrexate as anchor drug and extensive of use biologic therapy since 2003. Immunosuppression increases the risk for common and uncommon infections (1).ObjectivesTo compare the temporal rates and associated mortality of hospitalisation with opportunistic infections (OI) (Table 1) for IJD patients in Western Australia between 1985 and 2015.MethodsAll patients hospitalized in Western Australia in the period 1980-2015 with ≥ 2 diagnostic codes for rheumatoid arthritis (RA, n=8490), psoriatic arthritis (PsA, n=601), axial spondylarthritis (AS, n=1419). Overall incidence rates (IR) with microbiologically confirmed OI (Mycobacterial, Fungal and viral infections)(Table 1) during 306.514 person years were expressed per 1000 person years and compared across IJD by incidence rate ratios (IRR) with 95% CI. IR trend rates across 5-year periods for each IJD were analyzed by least square regression (R2). Mortality rate ratio (MRR) was number of deaths per 1000 observation years in patients with OI compared to patients in same disease category hospitalized without OI.Table 1.Diagnostic codes applied to define conditions and opportunistic infections in hospital discharge database.ICD9CMICD10AMRA714.0-714.9M05.0-M06.9AS720.0M45, M08.10-M08.19PsA696.0M07.0-M07.3, L40.5 Tuberculosis010.x-018.xA15–A19 Non-tuberculous mycobacteria031.xA30-A31 Cryptococcosis117.5B45 Aspergillosis117.3B44 Histoplasmosis115B39 All mycosis114.0 - 118.9B35.0 - B49.9 Pneumocystosis136.3B59 Cytomegaloviral disease078.5B25 Influenza487.x, 488.xJ09, J10 Herpes zoster053.xB02 Varicella052.xB01ResultsThe IR for all OI in RA patients (5.19, CI 4.8-5.6) was significantly higher than for PsA (IRR 0.56, CI 0.41-0.76 and AS (IRR 0.64, CI 0.53-0.79) with lower IRR observed especially for tuberculosis and H Zoster in PsA (0,49 and 0,47) and AS patients (0,43 and 0,49). H Zoster, TBC and other mycobacteria were the most frequent cause of OI with cryptococcal and pneumocystis only seen in RA. The IR for TBC decreased over time in RA (R2 0.51, p=0.08), and AS (R2 0.47, p=0.09) while the IR for H. zoster decreased in RA only (R2 0.46, p=0.09) (Figure 1). In-hospital mortality rate in patients with OI was 4.9 % for RA, 2.6 % for PsA and 2.2% for AS, but MRR for RA (1.15; 0.71-1.97), PsA (1.64; 0.82-3.57) and AS patients (1.35; 0.68-2.89) was not significantly increased.Figure 1.Incidence rate per 1000 personyears over time for hospitalisation with opportunistic infections in RA patients.ConclusionThe IR for hospitalization with OI is twice as high for RA patients compared to AS and PsA patients. Admission rates for most OI including have decreased in RA patients over the two decades where more intensive treatment became standard of care. This suggests efficacy of preventative measures. Hospital admission with OI associated with a moderate risk of death, but did not incur a higher risk of death than admission for other medical complications in IJD patientsReferences[1]Wang D, Yeo AL, Dendle C, Morton S, Morand E, Leech M. Severe infections remain common in a real-world rheumatoid arthritis cohort: A simple clinical model to predict infection risk. Eur J Rheumatol 2021; 8(3): 133-8.AcknowledgementsSupported by an unrestricted grant from the Arthritis Foundation of Western Australia.Disclosure of InterestsNone declared

Clathrin heavy chain is the structural component of the clathrin triskelion, but unique functions for the two distinct and highly conserved clathrin light chains (CLCa and CLCb, also known as CLTA and CLTB, respectively) have been elusive. Here, we show that following detachment and replating, CLCa is uniquely responsible for promoting efficient cell spreading and migration. Selective depletion of CLCa, but not of CLCb, reduced the initial phase of isotropic spreading of HeLa, H1299 and HEK293 cells by 60–80% compared to siRNA controls, and wound closure and motility by ∼50%. Surface levels of β1-integrins were unaffected by CLCa depletion. However, CLCa was required for effective targeting of FAK (also known as PTK2) and paxillin to the adherent surface of spreading cells, for integrin-mediated activation of Src, FAK and paxillin, and for maturation of focal adhesions, but not their microtubule-based turnover. Depletion of CLCa also blocked the interaction of clathrin with the nucleation-promoting factor WAVE complex, and altered actin distribution. Furthermore, preferential recruitment of CLCa to budding protrusions was also observed. These results comprise the first identification of CLCa-specific functions, with implications for normal and neoplastic integrin-based signaling and cell migration.

The αvβ3 integrin is known to be highly upregulated during cancer progression and promotes a migratory and metastatic phenotype in many types of tumors. We hypothesized that the αvβ3 integrin is transferred through exosomes and, upon transfer, has the ability to support functional aberrations in recipient cells. Here, for the first time, it is demonstrated that αvβ3 is present in exosomes released from metastatic PC3 and CWR22Pc prostate cancer cells. Exosomal β3 is transferred as a protein from donor to nontumorigenic and tumorigenic cells as β3 protein or mRNA levels remain unaffected upon transcription or translation inhibition in recipient cells. Furthermore, it is shown that upon exosome uptake, de novo expression of an αvβ3 increases adhesion and migration of recipient cells on an αvβ3 ligand, vitronectin. To evaluate the relevance of these findings, exosomes were purified from the blood of TRAMP mice carrying tumors where the expression of αvβ3 is found higher than in exosomes from wild-type mice. In addition, it is demonstrated that αvβ3 is coexpressed with synaptophysin, a biomarker for aggressive neuroendocrine prostate cancer. Implications: Overall this study reveals that the αvβ3 integrin is transferred from tumorigenic to nontumorigenic cells via exosomes, and its de novo expression in recipient cells promotes cell migration on its ligand. The increased expression of αvβ3 in exosomes from mice bearing tumors points to its clinical relevance and potential use as a biomarker. Mol Cancer Res; 14(11); 1136–46. ©2016 AACR.

Recent college graduates in the United States are increasingly pursuing a year of service in programs such as Teach for America, AmeriCorps, and Volunteers Exploring Vocation. A cohort of 689 volunteers participating in 18 Volunteers Exploring Vocation programs across the nation was surveyed both at the beginning and end of their year of service. Principal component analysis was used to analyze the two surveys. Repeated measures captured volunteers’ motivations for entering the programs and opportunities important to them upon exiting programs. Upon entering, program participants were motivated by opportunities for discovery about themselves in relation to community and for exploring spirituality and careers, but were not anticipating friendships and social life as central to their volunteer year. Important to volunteers at the end of the year were opportunities to express compassion, to gain skills while working for social justice, and to explore careers in the context of friendships and social life. Consideration of these findings may increase the number of emerging young adult professionals who find meaning and purpose in their careers as agents for social justice on behalf of communities in need.

In this article, we interpreted, in light of Mezirow’s theory of transformative learning, interviews with 13 educators regarding their work with marginalized adult learners in prisons in the northeastern United States. Transformative learning may have been aided by the educators’ response to unplanned activating events, humor, and respect, and being a role model, and counselor. Teachers presented activating events that they perceived as supporting resistant learners in altering their meaning schemes and revising their frames of reference. Administrators of educational programs for marginalized adult learners can help prison educators develop these pedagogical practices. Practitioners and researchers may wish to explore humor in restricted learning environments as well as the challenge mandatory prison classrooms present for the field of formal adult learning and transformative learning theory.

The margins of mainland Europe, and especially those areas coming under the influence of North Atlantic weather systems, are ideally placed to record changing palaeoclimates. Cores from an infilled lake basin at Crudale Meadow in Mainland, Orkney, revealed basal deposits of calcareous mud (‘marl’) beneath sedge peat. Stable isotope, palynological and molluscan analyses allowed the establishment of palaeoenvironmental changes through the Devensian Lateglacial and the early Holocene. The δ18Omarl record exhibited the existence of possibly four climatic oscillations in the Lateglacial (one of which, within event cf. GI-1c, is not often commented upon), as well as the Preboreal Oscillation and other Holocene perturbations. The cold episodes succeeding the Preboreal Oscillation were demarcated conservatively and one of these (event C5, ∼11.0 ka) may have previously been unremarked, while the putative 9.3 and 8.2 ka events seem not to produce corresponding palynologically visible floristic changes. The events at Crudale Meadow are consistent with those recorded at other sites from Britain, Ireland and elsewhere, and can be correlated with isotopic changes shown by the Greenland ice cores. The multi-proxy approach enriches the environmental reconstructions from the site, although the synchronicity of the response of the various proxies is sometimes equivocal, depending upon the time period concerned, taphonomy, and the nature of the deposits. The site may contain the most northerly Lateglacial isotope record from northwest Europe, and it has yielded one of the best archives for the demonstration of abrupt early Holocene events within Britain.

Integrin engagement on lymphocytes initiates "outside-in" signaling that is required for cytoskeleton remodeling and the formation of the synaptic interface. However, the mechanism by which the "outside-in" signal contributes to receptor-mediated intracellular signaling that regulates the kinetics of granule delivery and efficiency of cytolytic activity is not well understood. We have found that variations in ICAM-1 expression on tumor cells influence killing kinetics of these cells by CD16.NK-92 cytolytic effectors suggesting that changes in integrin ligation on the effector cells regulate the kinetics of cytolytic activity by the effector cells. To understand how variations of the integrin receptor ligation may alter cytolytic activity of CD16.NK-92 cells, we analyzed molecular events at the contact area of these cells exposed to planar lipid bilayers that display integrin ligands at different densities and activating CD16-specific antibodies. Changes in the extent of integrin ligation on CD16.NK-92 cells at the cell/bilayer interface revealed that the integrin signal influences the size and the dynamics of activating receptor microclusters in a Pyk2-dependent manner. Integrin-mediated changes of the intracellular signaling significantly affected the kinetics of degranulation of CD16.NK-92 cells providing evidence that integrins regulate the rate of target cell destruction in antibody-dependent cell cytotoxicity (ADCC).

The current study explores the relationship between participation in college service-learning (SL) experiences, in both academic courses and co-curricular programs, and post-college civic engagement. Using data from a purposeful sample of 1,066 alumni from 30 campuses who participated in the 20th Anniversary Bonner Scholars Study, we explored the extent to which SL experiences during the college years were related to civic outcomes post-graduation, particularly in terms of civic-minded orientations, volunteering, and civic action. When evaluating various attributes of SL programs (e.g., curricular, co-curricular programming, types of reflection, dialogue across difference, interactions with others), two components were particularly salient. Dialogue with others across difference was the strongest predictor of cultivating civic outcomes after college. In addition, both structured and informal reflection independently contributed to civic outcomes (i.e., civic-mindedness, voluntary action, civic action). The results suggested the Pathways to Adult Civic Engagement (PACE) model, which can be used to examine SL programming in higher education and to guide future research to understand how variations in SL program attributes influence civic outcomes years after graduation. The well-being of American democracy is dependent upon the active participation of its citizens and professionals in both political and community life. This voluntary impulse for engagement is shaped, in part, by traditions learned in families, clubs, religious organizations, and schools (Daloz, Keen, Keen, & Parks, 1996; Wilson, 2000). Each of these social organizations is vital to cultivating civic commitments (Kim, Flanagan, & Pykett, 2015). Higher education has a unique responsibility to prepare graduates with the necessary disciplinary knowledge for their careers as well as with the skills and dispositions to be active citizens through both their personal and professional lives (Sullivan & Rosen, 2008). The National Task Force on Civic Learning and Democratic Engagement (2012) and the Association of American Colleges & Universities (Reich, 2014) recently reiterated to institutions of higher education that their mission should focus on civic engagement. Research suggests that the college years are indeed a crucial period in the development of civic identity and engagement (Colby, Ehrlich, Beaumont, & Stephens, 2003; Kneflekamp, 2008; Mitchell, Richard, Battistoni, Rost-Banik, Netz, & Zakoske, 2015). Civic outcomes for college students include a wide and complex range of dimensions, including civic knowledge, skills, dispositions, and behaviors related to civic identity, sense of social responsibility, and intentions to participate in politics as well as community engagement and voluntary action (Beaumont, 2012; Hatcher, 2011; Hatcher, Bringle, & Hahn, 2016). Understanding the conditions under which higher education institutions are best able to support civic outcomes among graduates would enrich student learning, help college administrators enact coordinated and impactful academic and co-curricular service-learning (SL) programs, and support the engagement of alumni in the public sphere. SL, defined broadly as a course-based activity or as a co-curricular program (Jacoby, 2015), is on the rise in American higher education. Concomitantly, research on SL is increasingly prevalent. There have been a number of critiques regarding the quality of SL research in higher education (Butin, 2013; Finley, 2011; Giles & Eyler, 2013). The research on SL often is focused on one course or one program and rarely uses multi-campus sampling strategies. Oftentimes, the research fails to identify clearly the various dimensions of the SL course design (Finley, 2011), thus attributing the outcomes to SL rather than to the specific characteristics of, or variations within, the SL experience itself (Giles & Eyler, 2013). …

This paper presents evidence of the discovery of a new Middle Pleistocene site in central southern England, with undisturbed evidence of hominin occupation well-dated to an interstadial towards the end of Marine Isotope Stage 8, c. 250,000 BP. The site consists of a preserved remnant of a river terrace and its alluvial floodplain overlain by chalk-rich bankside deposits, all abutting a Chalk bedrock riverbank. It preserves an area of occupation with activity focused on the riverbank, complemented by occasional activity on a palaeo-landsurface developed on the surface of the alluvial floodplain. Lithic technology at the site consists almost entirely of handaxe manufacture, allowing attribution to an Acheulian industrial tradition. Mammalian and other palaeo-environmental remains are present and associated with the occupation horizons, including large mammal bones showing signs of hominin interference. Dating was based on OSL determinations on the sediments and amino acid racemisation of molluscan remains, supported by biostratigraphic indications. Besides being a rare instance of an undisturbed Palaeolithic palaeo-landscape covering several hectares, the site contributes to wider Quaternary research concerns over the ability of Middle Pleistocene hominins to tolerate colder climatic episodes in higher latitudes, and over settlement history and changing lithic industrial traditions of northwest Europe in relation to climate change and British peninsularity. It is suggested that the Harnham evidence may represent an insular population that had persisted in southern Britain since MIS 10/9, which became locally extinct during the glacial maximum 8.2 marking the end of MIS 8.

A multidisciplinary investigation was undertaken to establish the palaeoecology of three different fluvial depositional environments in the basal sediments of a richly fossiliferous channel infill at Whittlesey, eastern England, which is dated by amino acid racemization (AAR) to marine oxygen isotope stage (MIS) 7. Molluscan and coleopteran data indicate that the river flowed throughout the year, supporting extensive adjacent marshland. Palaeobotanical and insect evidence indicates that extensive deciduous woodland was present, and the ostracod evidence indicates that saline habitats were available locally, suggesting that sea level at the time was not much different to today. Pollen and insect data do not differentiate thethree different depositional environments, in contrast to the molluscan and ostracod evidence. Temperature estimates based on insect and ostracod data indicate a 'mutual mutual' mean July temperature of 16-21??C and-1 to 3??C for January. This is the first fully interglacial fluvial fossil assemblage described so far for the River Nene catchment that is reliably dated to MIS 7. Of particular note is the molluscan assemblage, which contains eight exotic species, including Theodoxus danubialis - a species described previously in the United Kingdom only in MIS 11 deposits associated with the River Thames catchment. Also of note is the insect assemblage, which in contrast contains no exotic species - unlike other MIS 7 insect assemblages recorded so far in the United Kingdom. Together these faunal assemblages may suggest a hitherto uninvestigated phase of a British interglacial stage, which the AAR data indicate could be late in MIS 7. The possibility that this so far unique interglacial fossil assemblage is the result of acombination of local preservation potential and environmental factors, however, cannot be ruled out. ?? 2013 Elsevier Ltd and INQUA.

International audience; Lateglacial to Holocene subfossil chironomids from the St-Omer basin at St-Momelin (northern France) were analysed. At the end of the Lateglacial, stratigraphic and chironomid sequences indicate a shallow, oligotrophic and slow-flowing freshwater stream, with abundant aquatic macrophytic vegetation. Cold-water adapted taxa indicate a cold climate. During the early Holocene, from about 9500 to 7700 conventional radiocarbon yr BP, climate improvement is marked by an increase in warm-water adapted taxa and a decrease in cold-water fauna. However, the cold-water fauna persist, probably because of both the instability and continentality of the climate. During the mid Holocene, from about 7700 to 6000 BP, the marine transgression strongly influenced the river's hydrological regime and consequently the chironomid assemblages. At that time, eutrophic, warm and shallow stagnant-water conditions occured throughout the basin. From 6000 to 3200 BP, the St-Momelin basin was subjected to a marine regression. Chironomids indicate a hydrological regime marked by an alternance of phases with either a dominance of rheophilous or limnophilous fauna. During this period, equivalent percentages of warm- and cold-adapted taxa may be explained by cold-water input in context of a temperate climate.

Low research self-efficacy and anxiety about succeeding in quantitative research courses may be limiting graduate students' research skills development and mute the calling to serve society as a professional researcher. Onwuegbuzie and Wilson's (2003) review of the literature on statistics anxiety concluded that anxiety towards statistics course performance negatively affected students' interpretation and application of data. One reason for this anxiety may be related to an earlier crystallization of negative math self-efficacy beliefs, especially for young women (Betz & Hackett, 1987, Hackett, 1985; Lapan, Shaughnessy, & Boggs, 1996). Onwuegbuzie and Wilson also identified several effective means for reducing statistics anxiety, these methods include integrating humor, gimmicks, and journals into the class; discussing anxiety experiences with other students; untimed exams; faculty reassurance and support; and cooperative groups and projects focused on a developing a final professional product. These pedagogical formats are designed to increase students' perception of the worth and value of applied statistics in turn, reducing the base level of anxieties students are expected to experience. More contemporary research in the field (Onwuegbuzie, Leech, Murtonen, & Tahtinen, 2010), has explored the effect of teaching statistics within a mixed-methods course (methodology that simultaneously utilizes both quantitative and qualitative research methods) which is reflective of a growing trend in the use of mixed-methods, especially for interdisciplinary work. The necessity for students and researchers to understand statistics is critical for success in their respective fields, therefore research into techniques for reducing statistics anxiety is of significance. The research conducted by Unrau and Beck (2004) and Timmerman, Feldon, Maher, Strickland, and Gilmore (2013) showed providing students with the opportunity to work with real data (data sets which are raw, legitimate data as compared to datasets designed to show specific preplanned statistical effects) contributed to the development of research skills. Zerden, Powers, and Wretman (2014) did just that by integrating a hands-on semester long learning exercises for social work master's level students to highlight components of research design. Students in the course designed, participated, analyzed, and reflected upon the experience of being both the researcher and the participant. Students who engaged in the hands-on learning experiences developed stronger research skills than those who were not in the hand-on learning experience. We also see the integration of hands-on learning for research methods is being used in multiple institutions. For example, a national survey of social work research methods instructors found that 61% of social work instructors were explicitly using exercises to reduce statistics anxiety (Maschi, Wells, Yoder, Slater, McMillan, & Ristow, 2014). These results are meaningful as historically social work students have not been expected to have a strong statistical/mathematical background. If the techniques used in the aforementioned studies are effective for social work students it would be logical to assume the same techniques would also be effective for students in other social sciences (e.g., psychology and education). Hands-on projects in qualitative, quantitative, and mixed-methods research classes may help ameliorate some of the students' negative self-efficacy beliefs about math, reduce anxieties about graduate methods classes, increase perceptions of the value and worth of quantitative and qualitative research, and open up career possibilities, all of which are desirable learning outcomes. A more structured approach to hands-on learning is the use of service-learning, the integration of formal community-service directly into academic coursework and learning objectives. Service-learning experiences in the community spark reflection in curricular or co-curricular classes or programs and have been found to promote undergraduate student development (Finley & McNair, 2013) in multiple disciplines ranging from basic writing composition to civic engagement/responsibility (see Butin, 2010; Conway, Amel, & Gerwien, 2009; Zlotkowski, 2011). …

'Gyrating-' or 'G'-clathrin are coated endocytic structures located near peripheral sorting endosomes (SEs), which exhibit highly dynamic but localized movements when visualized by live-cell microscopy. They have been implicated in recycling of transferrin from the sorting endosome directly to the cell surface, but there is no information about their formation or regulation. We show here that G-clathrin comprise a minority of clathrin-coated structures in the cell periphery and are brefeldin A (BFA)-resistant. Arf6-GTP substantially increases G-clathrin levels, probably by lengthening coated bud lifetimes as suggested by photobleaching and photoactivation results, and an Arf6(Q67L)-GTP mutant bearing an internal GFP tag can be directly visualized in G-clathrin structures in live cells. Upon siRNA-mediated depletion of Arf6 or expression of Arf6(T27N), G-clathrin levels rise and are primarily Arf1-dependent, yet still BFA-resistant. However, BFA-sensitive increased G-clathrin levels are observed upon acute incubation with cytohesin inhibitor SecinH3, indicating a shift in GEF usage. Depletion of both Arf6 and Arf1 abolishes G-clathrin, and results in partial inhibition of fast transferrin recycling consistent with the latter's participation in this pathway. Collectively, these results demonstrate that the dynamics of G-clathrin primarily requires completion of the Arf6 guanine nucleotide cycle, but can be regulated by multiple Arf and GEF proteins, reflecting both overlapping mechanisms operative in their regulation and the complexity of processes involved in endosomal sorting.

This article discusses the potential value of geoarchaeological and paleoenvironmental data for the contextualization of human activity at the site of Domuztepe, southeast Turkey. The data come from cores excavated on a series of transects centered on the hoyuk and from samples collected for paleoenvironmental assessment and radiocarbon dating. The results indicate that the site is situated on an alluvial plain of some stratigraphic complexity. Deep (up to 9 m) sediment sequences consisting of peats, marls, silts, clays, sands, and gravels appear on all sides of the hoyuk. Soil and water conditions during the Holocene on the Narli plain were quite probably different from present conditions, which are partly attributable to recent drainage and irrigation, with climatic changes also playing a significant role. The evidence suggests there were both periods of relatively wet local conditions with deep freshwater close to the site and episodes of drier, brackish conditions. Episodes of peat formation are recorded during the later Pleistocene (19,000―21,000 b.p. [calibrated]) and Early Holocene (9,500 b.p. [calibrated]). It seems unlikely that the site of Domuztepe was originally located on any topographic high point. While the extent of cultivatable land in the close vicinity of the settlement is unclear on the basis of the current data, local wetlands would have provided a range of resources, including plants, clays, and marls, evidenced in both the architecture and the cultural and environmental material from the excavations. The deposition of the alluvial silts and clays seems to have occurred during the later Holocene, with Roman pottery in these deposits providing a terminus post quem for the uppermost clays. These sediments probably mask the actual depth and extent of the archaeological remains at Domuztepe and might also obscure other early archaeological sites on the Narli plain.

SummaryCells are dependent on correct sorting of activated receptor tyrosine kinases (RTKs) for the outcome of growth factor signaling. Upon activation, RTKs are coupled through the endocytic machinery for degradation or recycled to the cell surface. However, the molecular mechanisms governing RTK recycling are poorly understood. Here, we show that Golgi-localized gamma ear-containing Arf-binding protein 3 (GGA3) interacts selectively with the Met/hepatocyte growth factor RTK when stimulated, to sort it for recycling in association with “gyrating” clathrin. GGA3 loss abrogates Met recycling from a Rab4 endosomal subdomain, resulting in pronounced trafficking of Met toward degradation. Decreased Met recycling attenuates ERK activation and cell migration. Met recycling, sustained ERK activation, and migration require interaction of GGA3 with Arf6 and an unexpected association with the Crk adaptor. The data show that GGA3 defines an active recycling pathway and support a broader role for GGA3-mediated cargo selection in targeting receptors destined for recycling.

This paper provides the first detailed, multi-proxy environmental record for the character of Lateglacial conditions in the lowest Pleistocene terrace of the main valley floor of the River Trent at Holme Pierrepont near Nottingham. The analysis of pollen, plant, insect and mollusc remains preserved within organic channels near the base of the terrace, named the Holme Pierrepont Sand and Gravel by the British Geological Survey (historically known as the Floodplain Terrace), provided evidence of cool, though not fully arctic climatic conditions and a largely treeless landscape, roamed by large herbivores. Radiocarbon dating indicates that these sediments were deposited during the Loch Lomond Stadial (Younger Dryas GS-1). Comparison of these dates from Holme Pierrepont with those from morphostratigraphically similar deposits in the wider Trent catchment suggests that the Holme Pierrepont Sand and Gravel may have been laid down in two separate pulses of braidplain aggradation either side of the ‘Last Glacial Maximum’. It has been demonstrated from historical documentation and riverine archaeological evidence that the middle Trent has been particularly sensitive to changing flood frequency and magnitude associated with climatic oscillations during the late Holocene; this study demonstrates that such sensitivity appears to extend back into the late Pleistocene. The timing of fluvial aggradation recorded at Holme Pierrepont agrees broadly with that recorded from other sites across England and north-west Europe.

Aminostratigraphic studies of continental deposits in the UK have hitherto relied almost exclusively on data from the aragonitic shells of non-marine molluscs for dating Pleistocene sequences. This is usually based on the d/l value of a single amino acid, d-alloisoleucine/l-isoleucine (A/I), in the total shell proteins. Two genera of freshwater gastropods (Valvata and Bithynia) are used to explore the value of using multiple amino acids from the intra-crystalline fraction, which should be more protected from the effects of diagenesis than the inter-crystalline component. Results are compared from both the aragonitic shells and opercula composed of calcite, a more stable form of calcium carbonate. In order to put the amino acid data from the West Runton Freshwater Bed into perspective, statistical analyses are used to compare them with results from the Hoxnian (MIS 11) site at Clacton-on-Sea, Essex. Twelve protein decomposition indicators revealed that the results from the shells were not as clear-cut as those from the opercula. Five indicators from the Valvata shell suggest that West Runton is older than Clacton (at a 95% significance level), but two actually suggested a younger age. Seven indicators show that the Bithynia shells from West Runton are older than congeneric shells from Clacton. In marked contrast, all 12 indicators isolated from the opercula demonstrate that West Runton is significantly older than Clacton. The data are also compared with results from Waverley Wood, an important archaeological site in the English Midlands falling within the ‘Cromerian Complex’. Contrary to earlier interpretations, the new amino acid data from Bithynia opercula indicate that West Runton is older than Waverley Wood, a relationship now consistent with the available biostratigraphy.

We report here detection of novel intracellular clathrin-coated structures revealed by continuous high-speed imaging of cells expressing green fluorescent protein fusion proteins. These structures, which we operationally term 'gyrating clathrin' (G-clathrin), are characterized by localized but extremely rapid movement, leading to the hypothesis that they are coated buds on waving membrane tubules. G-clathrin structures have structurally and functionally distinct features. They lack detectable adaptor proteins AP-1 and AP-2 but contain GGA1 [Golgi-localized, gamma-ear-containing, Arf (ADP-ribosylation factor)-binding protein] as well as the cation-dependent mannose-6-phosphate receptor. While they accumulate internalized transferrin (Tf), they do not contain detectable levels of cargos targeted for the late endosome/lysosome pathway such as EGF and dextran. Pulse-chase studies indicate that Tf appears in G-clathrin structures in the cell periphery after sorting endosomes (SEs), but before filling of the perinuclear endocytic recycling compartment. Furthermore, the inhibitors LY294002 and wortmannin, which inhibit direct recycling of Tf from SEs to the plasma membrane, also block its appearance in G-clathrin. These observations suggest that peripheral G-clathrin contributes to rapid recycling, a kinetically defined compartment that has largely eluded structural identification. More generally, the rapid continuous live cell imaging reported here reveals new aspects of membrane trafficking.

New sampling of Mollusca from Portelet, Jersey, Channel Islands, has allowed characterization of local conditions during deposition of the pre-Kesselt Weichselian loess. The Portelet fauna also allows a reassessment of the distribution of the Columella fauna in western Europe. Comparison of the Portelet fauna with those of eastern France and central Europe shows a decrease of the number of species present in this far-western locality which appears to be either a result of the operation of a typical ‘peninsula’ effect comparable to that seen in other zoological groups or a consequence of their occurrence in a marginal part of the European loess belt.

The potential contribution of co-curricular service-learning to develop engaged citizens is relatively unexplored. Much of the available research on college-level service-learning has studied the effect of service-learning in single courses on a variety of student outcome measures and there are at least two large, multi-campus studies of curricular service-learning (Astin, Vogelgesang, Ikeda, & Yee, 2000; Eyler & Giles, 1999). This article reports on analysis of longitudinal surveys completed at 23 liberal arts colleges by participants in four-year, co-curricular service-programs, collectively called the Bonner Scholar Program, sponsored by the Bonner Foundation. The terms "service-learning" and "civic engagement" merit definition. The National Service-Learning Clearinghouse (2005) defined service-learning as a "teaching and learning strategy that integrates meaningful community service with instruction and reflection to enrich the learning experience, teach civic responsibility, and strengthen communities." A frequent tendency in the field is to use the phrase service-learning and assume the reference is to academic service-learning based in coursework. Giles and Eyler's (1999) seminal study of programs that linked academic study with service acknowledged the value of co-curricular learning and, in defining service-learning, also mentioned "non-course-based programs that include a reflective component and learning goals" (p. 5). The terms service-learning and civic engagement have recently been used interchangeably in the field. The Bonner Scholar Program (BSP) studied here defines civic engagement as intentional participation in direct service, democratic process, and public policy (Hoy, 2006). Multi-campus studies have demonstrated that college-based, curricular service-learning contributes to academic, civic, and personal outcomes. Eyler and Giles (1999) demonstrated that one-semester service-learning classes had significant, consistent, and modest effects on student personal, civic, cognitive and academic outcomes in multicampus pre-and post-tests (p. xvii). In another large, longitudinal study, Astin, Vogelgesang, Ikeda, and Yee (2000) compared the effects of classroom-based service-learning and other forms of community service. Students who participated in one or more service-learning classes and community service experiences which were enhanced by opportunities for reflective dialogue were more likely to evidence personal and academic growth that lasted through the end of the senior year than were students who participated only in academic service-learning (p. 41-42). Little research exists on sustained co-curricular service-learning. This study explored two research questions to address that gap. Does co-curricular service-learning have an impact on desired outcomes of the college experience, particularly an appreciation of diversity and of dialogue across boundaries of perceived difference? A second question is reported separately. Do characteristics of liberal arts colleges (specifically, more or less internationally-focused, faith-oriented, diverse, urban or "elite") increase the effects of participation in co-curricular service-learning on college outcomes? The Study Study Context Yearly, the BSP funds approximately 1,500 Bonner Scholars across 23-25 campuses, almost all traditionally-aged college students, and engages them in a four-year program that requires service while offering extensive training and support. Many participating colleges are located in Appalachia. (1) Ten to twenty students are selected yearly on each campus and are required to complete a minimum of ten hours of service, training, and reflection each week. In addition, the program provides financial support for two to three full-time service experiences for at least seven weeks in the summer or during co-op terms, including international service. By graduation, each Bonner Scholar has served at least 1,680 hours. …

Data on fluvial sequences from around the world, collected as part of IGCP 449, has allowed comparison between such records with the purpose of searching for meaningful patterns. A key finding has been that fluvial incision rates, as measured by the vertical separations of well-dated terrace deposits one from another, and from the modern valley floor (which can be used as a proxy for uplift), are often very similar in different parts of the world but vary significantly between systems on different types of crust. The collection that this paper introduces, coupled with previous IGCP 449 publications cited, confirms that the aim of a worldwide compilation of fluvial archives has been achieved, with a number of syntheses already published.

At Whittlesey, eastern England, Pleistocene interglacial sediments (unit G3) deposited in marine oxygen isotope stage (MIS) 7 appear to be truncated by a sequence comprising: (i) a limestone-rich gravel containing organic mud beds (unit F1); (ii) vertically aggrading gravel beds with sand-clay-lined bases (unit F2); and (iii) interbedded sands and gravels (units F4–F6) with associated overbank deposits (unit G4). Preliminary investigations of the floral and faunal assemblages of the organic muds were consistent in providing evidence for deposition under cool conditions. This apparent single cool/cold-phase sequence therefore could have been deposited in either MIS 6 or MIS 5d−2. The presence of sand beds in units F5, F6 and G4 and of molluscs in the organic mud beds of unit F1 provided the opportunity for obtaining age estimates using optically stimulated luminescence (OSL) and amino acid racemization (AAR). Rather than a single cool/cold-phase sequence the age-estimate data revealed multiphase aggradation, with the AAR data indicating the possibility that the organic muds in unit F1 were deposited earlier in MIS 7 than the interglacial deposits of unit G3. Therefore, the succession could be: unit F1 was truncated initially by unit G3, with unit F2 subsequently incising both unit F1 and unit G3. The OSL age estimates indicate that units F5, F6 and G4 are Early to Middle Devensian in age (MIS 5d-2), and therefore unit F2 was deposited sometime between late MIS 7 and MIS 5d. This paper has demonstrated the utility of using dual age-estimate techniques in dating complex fluvial sequences. Furthermore, the organic mud beds of unit F1 could provide important new information on the complex character of the MIS 7 interglacial. In addition, the OSL data and the fluvial style recorded by units F4–F6 and G4 allow comparisons to be made with recent investigations of nearby Devensian deposits.

Phosphoinositide 3-kinase C2alpha (PI3K-C2alpha) is a type II PI-3-kinase that has been implicated in several important membrane transport and signaling processes. We previously found that overexpression of PI3K-C2alpha inhibits clathrin-mediated membrane trafficking and induces proliferation of novel clathrin-coated structures within the cytoplasm. Using fluorescently tagged fusions of PI3K-C2alpha and clathrin, we explored the behavior of these structures in intact cells. Both proteins are present in the structures, and using rapid image acquisition and fluorescence photoactivation probes, we find that they exhibit localized, rapid mobility (5-20 microm/s). The movement is micro-tubule-based as revealed by use of inhibitors, and PI3K-C2alpha accumulates on microtubules rapidly and reversibly following cytoplasmic acidification, which also blocks movement. Dynactin mediates the movement of these clathrin-PI3K-C2alpha structures, since disruption of dynactin function by overexpression of its p50 subunit also inhibits movement. Finally, immunoprecipitation experiments reveal an interaction between endogenous PI3K-C2alpha and dynactin subunits. Together, these results reveal a molecular linkage between PI3K-C2alpha and the microtubule motor machinery, with implications for membrane trafficking in intact cells.

Despite gout and hyperuricaemia being major comorbid health issues worldwide, there is a knowledge gap regarding their impact in the Australian community.To determine the prevalence and associations of self-reported medically diagnosed gout and hyperuricaemia in an Australian population-based cohort.The North West Adelaide Health Study is a longitudinal cohort study consisting of three stages of data collection. Each stage comprised a self-complete questionnaire, clinic assessment and computer-assisted telephone interview. In Stage 3 (2008-2010), participants were asked if a doctor had ever diagnosed them with gout. Additional data included demographics, comorbidities, laboratory data and Short Form 36 (SF-36). Participants were defined as having gout if they had self-reported medically diagnosed gout or were taking any gout-specific medication (allopurinol, colchicine, probenecid). Hyperuricaemia was defined as a serum uric acid (SUA) level0.42 mmol/L in men and0.34 mmol/L in women.The overall prevalence of gout was 5.2%. Males were significantly more likely to have gout than females (8.5 vs 2.1%, P0.001). The overall prevalence of hyperuricaemia was 16.6%, with being male again identified as a significant risk factor (17.8 vs 15.4%, P0.01). Both gout and hyperuricaemia were associated with male sex, body mass index and renal disease after multivariable adjustment. There was no significant difference reported in quality of life (mean SF-36) scores in participants with gout compared to unaffected individuals.The prevalence of gout and hyperuricaemia is high in the South Australian population. This study emphasises the need for optimal diagnosis and management of gout in Australia.

To elucidate the Middle and Late Pleistocene environmental history of south-central England, we report the stratigraphy, sedimentology, palaeoecology and geochronology of some deposits near the foot of the Chiltern Hills scarp at Marsworth, Buckinghamshire. The Marsworth site is important because its sedimentary sequences contain a rich record of warm stages and cold stages, and it lies close to the Anglian glacial limit. Critical to its history are the origin and age of a brown pebbly silty clay (diamicton) previously interpreted as weathered till.\ud \ud The deposits described infill a river channel incised into chalk bedrock. They comprise clayey, silty and gravelly sediments, many containing locally derived chalk and some with molluscan, ostracod and vertebrate remains. Most of the deposits are readily attributed to periglacial and fluvial processes, and some are dated by optically stimulated luminescence to Marine Isotope Stage (MIS) 6. Although our sedimentological data do not discriminate between a glacial or periglacial interpretation of the diamicton, amino-acid dating of three molluscan taxa from beneath it indicates that it is younger than MIS 9 and older than MIS 5e. This makes a glacial interpretation unlikely, and we interpret the diamicton as a periglacial slope deposit.\ud \ud The Pleistocene history reconstructed for Marsworth identifies four key elements: (1) Anglian glaciation during MIS 12 closely approached Marsworth, introducing far-travelled pebbles such as Rhaxella chert and possibly some fine sand minerals into the area. (2) Interglacial environments inferred from fluvial sediments during MIS 7 varied from fully interglacial conditions during sub-stages 7e and 7c, cool temperate conditions during sub-stage 7b or 7a, temperate conditions similar to those today in central England towards the end of the interglacial, and cool temperate conditions during sub-stage 7a. (3) Periglacial activity during MIS 6 involved thermal contraction cracking, permafrost development, fracturing of chalk bedrock, fluvial activity, slopewash, mass movement and deposition of loess and coversand. (4) Fully interglacial conditions during sub-stage 5e led to renewed fluvial activity, soil formation and acidic weathering.

Artefacts of Cromerian (MIS 13) age recovered from extensions to the classic site of Waverley Wood Farm Pit, Warwickshire, give new insights into the Lower Palaeolithic and Pleistocene geological record of the English Midlands. The Baginton Formation in the area to the south and southwest of Coventry has been the major source of Lower Palaeolithic artefacts in the Midlands since the first discoveries in the 1930s. Current sand and gravel workings at Waverley Wood and Wood Farm Pits near the village of Bubbenhall, have provided artefacts of quartzite, andesite and flint together with sparse large mammal material. Some of the Lower Palaeolithic finds were in situ in the succession providing, for the first time, firm evidence of their geological provenance. The variety and number of the artefacts allows detailed evaluation of the largest group of Lower Palaeolithic tools to be found in the West Midlands. The petrology of some of the tools and associated clasts in the gravels at the base of the Baginton Formation allow speculation on the origin of the rock types from northwest and eastern England which may have been brought to the West Midlands by a pre-Anglian glaciation or just possibly by human transport. Copyright © 2006 John Wiley & Sons, Ltd.

Pleistocene fluvial sediments of the Northmoor Member of the Upper Thames Formation exposed at Latton, Wiltshire, record episodic deposition close to the Churn–Thames confluence possibly spanning the interval from Marine Isotope Stages (MIS) 7 to 2. The sequence is dominated by gravel facies, indicating deposition by a high-energy, gravel-bed river. A number of fine-grained organic sediment bodies within the sequence have yielded palaeoenvironmental and biostratigraphical data from Mollusca, Coleoptera, vertebrates, pollen and plant macrofossils. The basal deposit (Facies Association A) contains faunal material indicating temperate conditions. Most of the palaeontological evidence including a distinctive small form of mammoth (Mammuthus cf. trogontherii), together with the U-series age estimate of >147.4?±?20?kyr suggest correlation with MIS 7. The overlying deposits (Facies Associations B and C) represent deposition under a range of climatic conditions. Two fine-grained organic deposits occurred within Association B; one (Association Ba) in the northern part of the pit as a channel fill and the other (Association Bb) in its southern part as a scour-fill deposit. The coleopteran assemblages from Ba, indicate that it accumulated under temperate oceanic conditions, while Bb, which also yielded a radiocarbon age estimate of 39?560?±?780 14C?yr?BP, was formed under much colder and more continental climatic conditions. The sequence is considered to represent deposition within an alluvial fan formed at the Churn–Thames confluence; a depositional scenario which may account for the juxtaposition of sediments and fossils of widely differing age within the same altitudinal range.

Middle Pleistocene deposits at Hackney, north London comprise a thick unit of organic sands and silts occupying a channel near the confluence of the River Thames in south-eastern England and its left-bank tributary the River Lea. They represent a short time interval, perhaps no more than a few years, within a late Middle Pleistocene interglacial. The organic sediments are overlain by unfossiliferous sands and gravels indicating deposition on the floodplain of a braided river under cool or cold climatic conditions. The fossil plant, insect, mollusc and vertebrate remains from the interglacial deposits all indicate climatic conditions with summers warmer than the present in SE England, and winters with a similar thermal climate. The biostratigraphic evidence suggests that the time period represented by the organic unit is part of MIS 9, although the geochronological evidence for such an age is inconclusive. The palaeontological evidence strongly suggests that this temperate stage was warmer than the succeeding temperate stage MIS 7 or the Holocene, and approaching the Ipswichian (MISs 5e) in its warmth. The multidisciplinary description of the Hackney deposits is one of the first to reconstruct terrestrial conditions in Marine Isotope Stage 9 in Western Europe.

Remodeling of cell membranes takes place during motile processes such as cell migration and cell division. Defects of proteins involved in membrane dynamics, including clathrin and dynamin, disrupt cytokinesis. To understand the function of clathrin-containing structures (CCS) in cytokinesis, we have expressed a green fluorescent protein (GFP) fusion protein of clathrin light chain a (GFP-clathrin) in NRK epithelial cells and recorded images of dividing cells near the ventral surface with a spinning disk confocal microscope. Punctate GFP-CCS underwent dynamic appearance and disappearance throughout the ventral surface. Following anaphase onset, GFP-CCS between separated chromosomes migrated toward the equator and subsequently disappeared in the equatorial region. Movements outside separating chromosomes were mostly random, similar to what was observed in interphase cells. Directional movements toward the furrow were dependent on both actin filaments and microtubules, while the appearance/disappearance of CCS was dependent on actin filaments but not on microtubules. These results suggest that CCS are involved in remodeling the plasma membrane along the equator during cytokinesis. Clathrin-containing structures may also play a role in transporting signaling or structural components into the cleavage furrow.

Polarization and segregation of the T-cell receptor (TCR) and integrins upon productive cytotoxic T-lymphocyte (CTL) target cell encounters are well documented. Much less is known about the redistribution of major histocompatibility complex class I (MHC-I) and intercellular adhesion molecule-1 (ICAM-1) proteins on target cells interacting with CTLs. Here we show that human leucocyte antigen-A2 (HLA-A2) MHC-I and ICAM-1 are physically associated and recovered from both the raft fraction and the fraction of soluble membranes of target cells. Conjugation of target cells with surrogate CTLs, i.e. polystyrene beads loaded with antibodies specific for HLA-A2 and ICAM-1, induced the accumulation of membrane rafts, and beads loaded with ICAM-1-specific antibodies caused the selective recruitment of HLA-A2 MHC-I at the contact area of the target cells. Disruption of raft integrity on target cells led to a release of HLA-A2 and ICAM-1 from the raft fraction, abatement of HLA-A2 polarization, and diminished the ability of target cells bearing viral peptides to induce a Ca(2+) flux in virus-specific CTLs. These data suggest that productive engagement of ICAM-1 on target cells facilitates the polarization of MHC-I at the CTL-target cell interface, augmenting presentation of cognate peptide-MHC (pMHC) complexes to CTLs. We propose that ICAM-1-MHC-I association on the cell membrane is a mechanism that enhances the linkage between antigen recognition and early immunological synapse formation.

Ubiquitination of the chemokine receptor CXCR4 serves as a targeting signal for lysosomal degradation, but the mechanisms mediating ubiquitination and lysosomal sorting remain poorly understood. Here we report that the Nedd4-like E3 ubiquitin ligase AIP4 mediates ubiquitination of CXCR4 at the plasma membrane, and of the ubiquitin binding protein Hrs on endosomes. CXCR4 activation promotes CXCR4 colocalization with AIP4 and Hrs within the same region of endosomes. Endosomal sorting of CXCR4 is dependent on Hrs as well as the AAA ATPase Vps4, the latter involved in regulating the ubiquitination status of both CXCR4 and Hrs. We propose a model whereby AIP4, Hrs, and Vps4 coordinate a cascade of ubiquitination and deubiquitination events that sort CXCR4 to the degradative pathway.

The Pleistocene marine and associated periglacial deposits of the coasts of southern England from Cornwall to Sussex, the British Channel Islands, and northern France from Brittany and Normandy to the Pas de Calais are described. The deposition of almost all marine deposits is ascribed to temperate conditions, although large igneous erratic boulders may have been emplaced by shore-ice rafting at the end or beginning of cold stages. The balance of the evidence from a variety of dating methods including U-series dating, amino-acid geochronology and biostratigraphy of associated terrestrial formations indicates that deposits of the last three pre-Holocene temperate marine oxygen isotope stages (stages 9, 7 and substage 5e) can readily be identified along much of both coastlines of the Channel. Deposits attributable to stages 11 and 13 are uncommon and best seen in the staircase of marine terraces backing the Hampshire–Sussex coastal plain and perhaps in western Brittany and the Boulonnais. The height above modern sea-level of the marine deposits is thought to be the result of slow uplift of the coastal zone caused by the isostatic response to sediment unloading during accelerated phases of erosion in cold stages, although deep-seated tectonics also may have been partly responsible for uplift. However, the height above modern sea-level of a deposit alone is not on its own an indicator of age. Periglacial head deposits are mainly exposed along the coasts, with the sections showing frost shattered debris moved downslope by cryoreptation (frost-creep). The age of these deposits is uncertain, although they appear to be principally of marine oxygen isotope stages 4 and 2 in age. Some remnants of marine oxygen isotope stage 6 or 8 head deposits are present both in England and northern France. In a few places with good dating control, head deposits dating to the marine oxygen isotope stage 12 can be recognised. The age of the head deposits in most sections is based on their stratigraphical relationship with loess, palaeosols and on the dating of the underlying raised beaches. Copyright © 2003 John Wiley & Sons, Ltd.