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Research over the past decade has shown that attractant pheromones used by cerambycid beetles are often highly conserved, with the same compound being used as a pheromone component by multiple related species, even among species on different continents which have been separated for millions of years. We describe how this conservation of structures can be exploited to identify possible pheromone components for Asian target species with a high risk of invading North America. Thus, collection and analysis of volatiles from five North American species, Semanotus amethystinus (LeConte), Semanotus ligneus (F.), Semanotus litigiosus (Casey), Callidium antennatum hesperum Casey, and Callidium pseudotsugae Fisher, showed that males of the two Callidium species sex-specifically produced 3-hydroxyhexan-2-one, a previously known cerambycid pheromone component, along with a novel natural product, 1-(1H-pyrrol-2-yl)-1,2-propanedione (henceforth pyrrole). In contrast, males of the three Semanotus species produced only the pyrrole. In field bioassays, both sexes of C. antennatum hesperum were significantly attracted to the blend of the two compounds, and S. amethystinus were equally attracted to the pyrrole alone, or the blend of the two compounds. Even before completing field bioassays with these species in California, field testing of the two compounds in Japan and China had revealed that several related target species, including the invasive Callidiellum rufipenne (Motschulsky), Callidiellum villosulum (Fairmaire), and Semanotus bifasciatus (Motschulsky), were attracted to one or both compounds (data reported elsewhere), providing proof of concept of the “pheromone identification by proxy” strategy.

Objective: To assess the efficacy and safety of secukinumab in patients with rheumatoid arthritis (RA) who failed to respond to tumour necrosis factor- α (TNF-α) inhibitors. Method: This phase III double-blind, double-dummy, placebo-controlled study (NCT01770379) randomized (1:1:1) patients to subcutaneous secukinumab 150 mg, secukinumab 75 mg, or placebo at baseline, weeks 1, 2, 3, and 4, and then every 4 weeks. American College of Rheumatology (ACR) 20 response at week 24 was the primary endpoint. Secondary outcomes included the 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP), Health Assessment Questionnaire Disability Index (HAQ-DI), and ACR50 at week 24. Long-term treatment was planned for 5 years. Results: ACR20 response rates at week 24 for the secukinumab 150 mg and 75 mg groups were not statistically superior to placebo. None of the secondary endpoints was met for either secukinumab dose. Although not statistically significant, compared with placebo, numerically greater differences in least squares mean changes from baseline in HAQ-DI score and numerically higher ACR50 response rates were observed at week 24 in both secukinumab treatment groups. No new or unexpected adverse events were observed in this study compared with the large secukinumab safety database across psoriasis, psoriatic arthritis, ankylosing spondylitis, and other RA studies. Conclusions: Given that other second-line therapies have demonstrated efficacy in RA patients who failed to respond to TNF-α inhibitors, these findings may suggest that interleukin-17A inhibition with secukinumab does not provide additional benefit to these patients. This study further confirms the well-characterized safety profile of secukinumab.

Previous research has shown that rats reared in simple/impoverished environments demonstrate greater repetitive responding for sensory reinforcers (e.g., light onset). Moreover, the brains of these rats are abnormally developed, compared to brains of rats reared in more complex/enriched environments. Repetitive behaviors are commonly observed in individuals with developmental disorders. Some of these repetitive behaviors could be maintained by the reinforcing effects of the sensory stimulation that they produce. Therefore, rearing rats in impoverished conditions may provide an animal model for certain repetitive behaviors associated with developmental disorders. We hypothesize that in rats reared in simple/impoverished environments, the normal habituation process to sensory reinforcers is impaired, resulting in high levels of repetitive behaviors. We tested the hypothesis using an operant sensory reinforcement paradigm in rats reared in simple/impoverished (IC), standard laboratory (SC), and complex/enrichened conditions (EC, treatments including postnatal handling and environmental enrichment). Results show that the within-session habituation of the reinforcer effectiveness of light onset was slower in the IC and SC rats than in the EC rats. A dishabituation challenge indicated that within-session decline of responses was due to habituation and not motor fatigue or sensory adaptation. In conclusion, rearing rats in simple/impoverished environments, and comparing them to rats reared in more complex/enriched environments, may constitute a useful approach for studying certain repetitive behaviors associated with developmental disorders.

Background Results from the second CONCORD study (CONCORD-2) indicated that 5-year net survival for lung cancer was low (range, 10%-20%) between 1995 and 2009 in most countries, including the United States, which was at the higher end of this range. Methods Data from CONCORD-2 were used to analyze net survival among patients with lung cancer (aged 15-99 years) who were diagnosed in 37 states covering 80% of the US population. Survival was corrected for background mortality using state-specific and race-specific life tables and age-standardized using International Cancer Survival Standard weights. Net survival was estimated for patients diagnosed between 2001 and 2003 and between 2004 and 2009 at 1, 3, and 5 years after diagnosis by race (all races, black, and white); Surveillance, Epidemiology, and End Results Summary Stage 2000; and US state. Results Five-year net survival increased from 16.4% (95% confidence interval, 16.3%-16.5%) for patients diagnosed 2001-2003 to 19.0% (18.8%-19.1%) for those diagnosed 2004-2009, with increases in most states and among both blacks and whites. Between 2004 and 2009, 5-year survival was lower among blacks (14.9%) than among whites (19.4%) and ranged by state from 14.5% to 25.2%. Conclusions Lung cancer survival improved slightly between the periods 2001-2003 and 2004-2009 but was still low, with variation between states, and persistently lower survival among blacks than whites. Efforts to control well established risk factors would be expected to have the greatest impact on reducing the burden of lung cancer, and efforts to ensure that all patients receive timely and appropriate treatment should reduce the differences in survival by race and state. Cancer 2017;123:5079-99. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

Ground-borne vibrations induced by mine blasting are typically of low amplitudes, which are not considered a major concern for modern engineered structures. However, historic structures are often c...

Background:Axial spondyloarthritis (axSpA) is an inflammatory disease characterised by chronic back pain, and it comprises radiographic axSpA and non-radiographic axSpA (nr-axSpA).1 Secukinumab (SEC) 150 mg, with (LD) or without loading (NL), dose significantly improved the signs and symptoms of patients with nr-axSpA in the PREVENT (NCT02696031) study through Week 52.2Objectives:To report the long-term clinical efficacy and safety of secukinumab from the PREVENT study through 2 years.Methods:A detailed study design, key primary and secondary endpoints have been reported previously.2 In total, 555 patients fulfilling ASAS criteria for axSpA plus abnormal C-reactive protein (CRP) and/or MRI, without evidence of radiographic changes in sacroiliac (SI) joints according to modified New York Criteria for AS were randomised (1:1:1) to receive SEC 150 mg with LD, NL, or placebo (PBO) at baseline. LD patients received SEC 150 mg at Weeks 1, 2, 3, and 4, and then every 4 weeks (q4wk) starting at Week 4. NL patients received SEC 150 mg at baseline and PBO at weeks 1, 2, and 3, and then 150 mg q4wk. 90% patients were anti-tumour necrosis factor (anti-TNF) naïve, 57% had elevated CRP and 73% had evidence of SI joint inflammation on MRI. All images were assessed centrally before inclusion. All patients continued to receive open-label SEC 150 mg treatment after Week 52. Efficacy assessments through Week 104 included ASAS40 in anti-TNF-naïve patients, ASAS40, BASDAI change from baseline, BASDAI50, ASAS partial remission, and ASDAS-CRP inactive disease in the overall population. The safety analyses included all patients who received ≥1 dose of study treatment for the entire treatment period up to Week 104. Data are presented as observed.Results:Overall, 438 patients completed 104 weeks of study: 78.9% (146/185; LD), 77.7% (143/184; NL) and 80.1% (149/186; PBO). Efficacy results at Week 52 were sustained through Week 104 and are reported in the Table 1. The safety profile was consistent with the previous reports with no deaths reported during the entire treatment period up to Week 104.2Conclusion:Secukinumab 150 mg demonstrated sustained improvement in the signs and symptoms of patients with nr-axSpA through 2 years. Secukinumab was well tolerated with no new or unexpected safety signals.References:[1]Strand V, et al. J Clin Rheumatol. 2017; 23(7):383–91.[2]Deodhar A, et al. Arthritis Rheumatol. 2020. Online ahead of print.Figure 1.ASAS40 response was maintained through Week 104 in the overall populationTable 1.Summary of clinical efficacy (Observed data)EndpointsWeekSEC 150 mg LD(N=185)SEC 150 mg NL(N=184)PBO-SEC 150 mg(N=186)*ASAS40 in anti-TNF-naïve patients, n/M (%)52a90/137 (65.7)95/145 (65.5)85/151 (56.3)10478/123 (63.4)83/123 (67.5)83/134 (61.9)BASDAI change from baseline, mean±SD52a−3.7±2.8−3.7±2.6−3.3±2.4104−4.1±2.6−3.9±2.6−3.7±2.5BASDAI50, n/M (%)52a90/153 (58.8)92/163 (56.4)90/161 (55.9)10488/137 (64.2)84/136 (61.8)87/142 (61.3)ASAS partial remission,n/M (%)52a46/152 (30.3)56/163 (34.4)46/161 (28.6)10451/137 (37.2)50/135 (37.0)50/142 (35.2)ASDAS CRP inactive disease, n/M (%)52a49/152 (32.2)58/163 (35.6)48/160 (30.0)10450/132 (37.9)53/133 (39.8)53/142 (37.3)*For anti-TNF-naïve patients, N=164, LD; 166, NL; 171, PBO-SEC.a total number of evaluable patients including open-label SEC and standard of care (SOC; 2 patients in LD, 1 patient in NL continued on SOC). After Week 52, only patients who continued to receive open-label SEC are presented.ASAS, Assessment of SpondyloArthritis International Society; ASDAS, Ankylosing Spondylitis Disease Activity Score; BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; M, number of patients with evaluation; N, total randomised patients; n, number of patients who are responders; SD, standard deviationDisclosure of Interests:Denis Poddubnyy Speakers bureau: AbbVie, BMS, Eli Lilly, MSD, Novartis, Pfizer, UCB, Consultant of: AbbVie, Biocad, BMS, Eli Lilly, Gilead, MSD, Novartis, Pfizer, Samsung Bioepis, UCB, Grant/research support from: AbbVie, MSD, Novartis, Pfizer, Atul Deodhar Speakers bureau: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myer Squibb (BMS), Eli Lilly, GSK, Janssen, Novartis, Pfizer, and UCB, Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, GSK, Janssen, Novartis, Pfizer, and UCB, Grant/research support from: AbbVie, Eli Lilly, GSK, Novartis, Pfizer, and UCB, Xenofon Baraliakos Speakers bureau: AbbVie, BMS, Celgene, Chugai, MSD, Novartis, Pfizer, and UCB, Consultant of: AbbVie, BMS, Celgene, Chugai, Galapagos, Gilead, MSD, Novartis, Pfizer, and UCB, Grant/research support from: AbbVie and Novartis, Ricardo Blanco Speakers bureau: AbbVie, Pfizer, Roche, Bristol-Myers, Janssen, UCB pharma and MSD and Eli Lilly, Consultant of: AbbVie, Pfizer, Roche, Bristol-Myers, Janssen, UCB pharma and MSD, Grant/research support from: AbbVie, MSD, and Roche, Eva Dokoupilova Grant/research support from: AbbVie, Affibody AB, Eli Lilly, Galapagos, Gilead, GSK, Hexal AG, MSD, Novartis, Pfizer, R-Pharm, Sanofi-Aventis, and UCB, Stephen Hall Speakers bureau: Novartis, Merck, Janssen, Pfizer, Eli Lilly, and UCB, Consultant of: Novartis, Merck, Janssen, Pfizer, Eli Lilly, and UCB, Grant/research support from: AbbVie, UCB, Janssen, and Merck, Alan Kivitz Shareholder of: Pfizer, Sanofi, Novartis, Amgen, GlaxoSmithKline, Gilead Sciences, Inc., Speakers bureau: Celgene, GlaxoSmithKline, Eli Lilly, Merck, Novartis, Pfizer, Sanofi, Genzyme, Flexion, AbbVie, UCB, Consultant of: AbbVie, Boehringer Ingelheim, Flexion, Janssen, Pfizer, Sanofi, Regeneron, SUN Pharma Advanced Research, Gilead Sciences, Inc., Marleen G.H. van de Sande Speakers bureau: Novartis, MSD, Consultant of: Abbvie, Novartis, Eli Lily, Grant/research support from: Novartis, Eli Lilly, Janssen, UCB, Anna Stefanska Shareholder of: Novartis, Employee of: Novartis, Patricia Pertel Shareholder of: Novartis, Employee of: Novartis, Hanno Richards Shareholder of: Novartis, Employee of: Novartis, Juergen Braun Speakers bureau: Abbvie (Abbott), Amgen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, EBEWE Pharma, Medac, MSD (Schering-Plough), Mundipharma, Novartis, Pfizer (Wyeth), Roche, Sanofi-Aventis and UCB pharma, Eli Lilly, Consultant of: Abbvie (Abbott), Amgen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, EBEWE Pharma, Medac, MSD (Schering-Plough), Mundipharma, Novartis, Pfizer (Wyeth), Roche, Sanofi-Aventis and UCB, Eli Lilly, Grant/research support from: Abbvie (Abbott), Amgen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, Medac, MSD (Schering-Plough), Mundipharma, Novartis, Pfizer (Wyeth), Roche, Sanofi-Aventis and UCB, Eli Lilly

BACKGROUND: Mechanically ventilated patients increasingly spend hours in emergency department beds before ICU admission. This study evaluated the performance of blood gases in mechanically ventilated subjects in the emergency department and subsequent changes to mechanical ventilation settings. METHODS: This was a multi-center, prospective, observational study of subjects ventilated in the emergency department, conducted at 3 academic emergency departments from July 2011 to March 2013. We measured the rate of arterial blood gas (ABG) and venous blood gas (VBG) analysis, and we assessed the associations between the conditions of hypoxemia, hyperoxia, hypercapnia, or acidemia and changes to mechanical ventilator settings. RESULTS: Of 292 ventilated subjects, 17.1% did not have a blood gas sent in the emergency department. Ventilator changes were made significantly more frequently for subjects who had an ABG as the initial blood gas sent in the emergency department (odds ratio 2.70, 95% CI 1.46–4.99, P = .002). However, findings of hypoxemia, hyperoxia, hypercapnia, or acidemia were not correlated with ventilator adjustments. CONCLUSIONS: In this prospective observational study of subjects mechanically ventilated in the emergency department, the majority had a blood gas checked while in the emergency department. While ABGs were associated with having changes made to ventilator settings in the emergency department, clinical findings of hypoxemia, hyperoxia, hypercapnia, and acidemia were not. Inattention to blood gas results may lead to missed opportunities in guiding ventilator changes in the emergency department.

Context Early studies suggested that experienced clinicians simply generate more accurate diagnoses than those less experienced. However, more recent studies indicate that experienced clinicians may be subject to biases in formulating and confirming hypotheses that lead to inaccuracy. Objectives The goal of this study was to identify factors associated with the ability to process information in ways that overcome premature closure and result in accurate diagnosis using a set of vignettes in which inconsistent information was introduced midway. Methods Seventy-five participants (25 Year 3 medical students, 25 internal medicine residents in their second year of residency and 25 internal medicine faculty) were recruited to solve each of four complex clinical vignettes. In each vignette, the first four rounds of information pointed toward a narrowing range of diagnostic possibilities, but patient information presented in and after the fifth round was inconsistent with prior findings. In addition to accuracy, outcome measures were length of differential diagnosis, certainty of diagnosis, persistence in data collection and tendency to switch diagnoses. Results There were no significant differences in diagnostic accuracy across the three groups, each of which differed in level of training. However, across experience levels, diagnostic accuracy was associated with the mean number of items in the differential, tendency to persist (e.g. to request a greater number of rounds of information), and openness to switch (e.g. to change the most likely diagnosis on receipt of disconfirming information). Conclusions Level of training (i.e. clinical experience) was not associated with accuracy on this task. As faculty clinicians certainly have more knowledge than their junior counterparts, it is important to identify ways in which cognitive factors can lead to more or less persistence and openness, and to teach clinicians how to overcome tendencies associated with error.

The life cycle of Stenocolus scutellaris includes oviposition in summer, larval growth and overwintering for at least two years, pupation in late spring and adult emergence in summer. the larval food mainly includes FPOM, shredded wood, algal filaments and associated debris; adults do not feed. The geographic distribution is in California's Central Valley counties, in the Sacramento/San Joaquin River systems. Various parts of the morphology of the egg, larva, pupa and adult are described and illustrated. The larval “gills” are shown to be osmoregulatory structures, not respiratory structures.

Objective Secukinumab improved the signs and symptoms of ankylosing spondylitis (AS) over 52 weeks in the phase III MEASURE 2 study. Here, we report longer-term (104 weeks) efficacy and safety results. Methods Patients with active AS were randomized to subcutaneous secukinumab 150 mg, 75 mg, or placebo at baseline; weeks 1, 2, and 3; and every 4 weeks from week 4. The primary end point was the Assessment of SpondyloArthritis international Society criteria for 20% improvement (ASAS20) response rate at week 16. Other end points included ASAS40, high-sensitivity C-reactive protein, ASAS5/6, Bath Ankylosing Spondylitis Disease Activity Index, Short Form 36 health survey physical component summary, ASAS partial remission, EuroQol 5-domain measure, and Functional Assessment of Chronic Illness Therapy fatigue subscale. End points were assessed through week 104, with multiple imputation for binary variables and a mixed-effects model repeated measures for continuous variables. Results Of 219 randomized patients, 60 of 72 (83.3%) and 57 of 73 (78.1%) patients completed 104 weeks of treatment with secukinumab 150 mg and 75 mg, respectively; ASAS20/ASAS40 response rates at week 104 were 71.5% and 47.5% with both secukinumab doses, respectively. Clinical improvements with secukinumab were sustained through week 104 across all secondary end points. Across the entire treatment period (mean secukinumab exposure 735.6 days), exposure-adjusted incidence rates for serious infections and infestations, Crohn's disease, malignant or unspecified tumors, and major adverse cardiac events with secukinumab were 1.2, 0.7, 0.5, and 0.7 per 100 patient-years, respectively. No cases of tuberculosis reactivation, opportunistic infections, or suicidal ideation were reported. Conclusion Secukinumab provided sustained improvement through 2 years in the signs and symptoms of AS, with a safety profile consistent with previous reports.

Objective To validate an ocular phantom as a realistic educational tool utilizing in vivo and phantom optic nerve sheath (ONS) images obtained by ultrasound. Methods This prospective study enrolled 51 resident physicians from the Denver Health Residency in Emergency Medicine (EM) and 10 ultrasound fellowship-trained EM attending physicians. Participants performed optic nerve sheath diameter (ONSD) measurements on five in vivo and five phantom ocular ultrasound images and rated the realism of each image on a 5-point Likert scale. Chi-square analysis was performed to evaluate the subjective “realness” of in vivo and phantom images. Results Sixty-one participants performed ONSD measurements. Mean Likert scale values were 3.43 (95% confidence interval: 3.31–3.55) for in vivo images and 3.41 (95% confidence interval: 3.28–3.54) for phantom images. There was no statistical difference in subjective “realness” between in vivo and phantom ONSD ultrasound images among EM residents. Ultrasound fellowship-trained EM attending physicians aptly differentiated between in vivo (p < 0.01) and phantom (p < 0.01) images, as compared with EM residents. Conclusion Our ocular phantom simulates in vivo posterior ocular anatomy. EM resident physicians found the phantom indistinguishable from in vivo images. Our ONS model provides an inexpensive and realistic educational tool to teach bedside ONSD sonography.

Genome-wide association studies in humans have suggested that variants of the cadherin-13 (CDH13) gene are associated with substance use disorder, subjective response to amphetamine, and attention deficit hyperactivity disorder. To examine the role of the Cdh13 and its peptide ligand adiponectin (AdipoQ) in addiction-related behaviors, we assessed Cdh13 knock-out rats and AdipoQ knock-out mice using intravenous cocaine self-administration and conditioned place preference paradigms. During intravenous cocaine self-administration, male Cdh13 heterozygous (+/−) and knock-out (−/−) rats showed increased cue-induced reinstatement compared to wild-type rats when presented with a cocaine-paired stimulus, whereas female Cdh13 rats showed no differences across genotype. Cdh13 −/− rats showed higher responding for a saccharin reinforcer and learned the choice reaction time task more slowly than wild-types. However, we found no differences between Cdh13 −/− and +/+ rats in responding for sensory reinforcement, number of premature responses in the reaction time task, tendency to approach a Pavlovian food cue, conditioned place preference and locomotor activation to cocaine (10 or 20 mg/kg). In AdipoQ −/− mice there was a significant increase in conditioned place preference to methamphetamine (1 mg/kg) but not to a range of d-amphetamine doses (0.5, 1, 2 and 4 mg/kg). Taken together, these data suggest that Cdh13 and AdipoQ regulate sensitivity to psychomotor stimulants and palatable rewards without producing major changes in other behaviors. In humans, these two genes may regulate sensitivity to natural and drug rewards, thus influencing susceptibility to the conditioned drug effects and relapse.

Analysis of human mitochondrial DNA (mtDNA) variation plays an important role in forensic genetic investigations, especially in degraded biological samples and hair shafts. There are many issues of the mtDNA phylogeny that are of special interest to the forensic community, such as haplogroup classification or the post hoc investigation of potential errors in mtDNA datasets. We have analyzed >2200 mitogenomes of African ancestry with the aim of improving the known worldwide phylogeny. More than 300 new minor subclades were identified, and the Time to the Most Recent Common Ancestor (TMRCA) was estimated for each node of the phylogeny. Phylogeographic details are provided which might also be relevant to forensic genetics. The present study has special interest for forensic investigations because current analysis and interpretation of mtDNA casework rest on a solid worldwide phylogeny, as is evident from the role that phylogeny plays in popular resources in the field (e.g. PhyloTree), software (e.g. Haplogrep 2), and databases (e.g. EMPOP). Apart from this forensic genetic interest, we also highlight the impact of this research in anthropological studies, such as those related to the reconstruction of the transatlantic slave trade.

Objective To determine whether sclerostin is associated with fasting glucose, insulin levels, insulin resistance or increased risk of incident type 2 diabetes. Background Type 2 diabetic patients have a higher risk of fractures. Recent studies suggest sclerostin, a regulator of osteoblast activity, is associated with diabetes. Materials and Methods Sclerostin levels were obtained from 1,778 individuals with no history of type 2 diabetes participating in the population-based Canadian Multicentre Osteoporosis Study (CaMos) cohort. Participants were followed until diagnosis of type 2 diabetes, death, or end of the study period (December 31, 2013). The relationship of sclerostin with fasting glucose, insulin levels and homeostatic model assessment-insulin resistance (HOMA-IR) was studied in linear regression models. Cox proportional hazards models were used to determine the association of sclerostin levels and the risk of incident type 2 diabetes during a mean 7.5 years of follow-up. Results Fasting glucose, fasting insulin levels and HOMA-IR were weakly correlated with sclerostin levels (Spearman's correlation coefficient: 0.11, p

ObjectiveTo evaluate the effect of secukinumab, an interleukin-17A inhibitor, on clinical signs and symptoms and radiographic changes through 2 years in patients with ankylosing spondylitis (AS).MethodsIn the phase III MEASURE 1 study, patients were randomised to receive intravenous secukinumab 10 mg/kg (at baseline, week 2 and week 4) followed by subcutaneous secukinumab 150 mg (intravenous 150 mg; n=125) or 75 mg (intravenous 75 mg; n=124) every four weeks, or matched placebo (n=122). Placebo-treated patients were re-randomised to subcutaneous secukinumab 150 or 75 mg from week 16. Clinical efficacy assessments included Assessment of SpondyloArthritis international Society 20 (ASAS20) response rates through week 104. Radiographic changes at week 104 were assessed using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS).Results97 (77.6%) and 103 (83.1%) patients in the intravenous 150 mg and intravenous 75 mg groups, respectively, completed week 104. In the full analysis set (intent-to-treat), ASAS20 response rates at week 104 were 73.7% and 68.0% in the intravenous 150 mg and intravenous 75 mg groups, respectively. Among patients with evaluable X-rays who were originally randomised to secukinumab (n=168), mean change in mSASSS from baseline to week 104 was 0.30±2.53. Serious adverse events were reported in 12.2% and 13.4% of patients in the 150 mg and 75 mg groups, respectively.ConclusionsSecukinumab improved AS signs and symptoms through 2 years of therapy, with no unexpected safety findings. Data from this study suggest a low mean progression of spinal radiographic changes, which will need to be confirmed in longer-term controlled studies.Trial registration numberNCT01358175.

Background:Axial spondyloarthritis (axSpA) spectrum covers radiographic axSpA and non-radiographic axSpA (nr-axSpA). PREVENT (NCT02696031) is the first phase III, placebo (PBO) controlled study evaluating secukinumab (SEC) 150 mg with (LD) or without loading (NL) dose, in patients (pts) with nr-axSpA.1The study had 2 independent analysis plans as per EU (Wk 16) and US (Wk 52) regulatory requirements.Objectives:To report efficacy through Wk 52 and safety up to two years for the PREVENT study.Methods:555 pts fulfilling ASAS criteria for axSpA plus abnormal CRP and/or MRI, without evidence of radiographic changes in sacroiliac (SI) joints according to modified New York Criteria for AS were enrolled. All images were assessed centrally before inclusion. Pts were randomised (1:1:1) to SEC 150 mg with LD, NL, or PBO at baseline (BL). LD pts received SEC 150 mg at Wks 1, 2, 3, and 4, and then every 4 wks (q4wk) starting at Wk 4. NL pts received SEC 150 mg at BL and PBO at Wks 1, 2, and 3, and then 150 mg q4wk. Switch to open-label (OL) SEC 150 mg or standard of care (SoC) was permitted after Wk 20. Primary endpoint was ASAS40 at Wk 16 (LD) and at Wk 52 (NL) in anti-TNF-naïve pts. Secondary endpoints (overall population) included ASAS40, BASDAI50, SI joint bone marrow edema (BME) score by MRI at Wks 16 and 52 and ASDAS-CRP inactive disease (ID) at Wk 52. Endpoints were analysed according to statistical hierarchy. Analysis used non responder imputation through Wk 52. Safety analyses included all pts who received ≥1 dose of study treatment.Results:Overall, 481 pts completed 52 wks with no major differences in retention across groups: 84.3% (156/185; LD), 89.7% (165/184; NL) and 86.0% (160/186; PBO). BL characteristics were similar across groups; 90% pts were anti-TNF-naïve, 56-58% pts had elevated CRP, 71-75% pts had evidence of SI joint inflammation by MRI. Proportion of pts who switched to OL or SoC between Wks 20 and 48 was 52.1% (LD), 49.2% (NL), and 67.4% (PBO). Primary endpoints at Wk 16 and Wk 52 were met (Table). SEC 150 mg LD or NL significantly improved secondary endpoints at Wk 16 and 52 vs PBO (Table). SEC significantly reduced SI joint MRI BME score vs PBO at Wk 16 (-1.68 and -1.03 vs -0.39;P= 0.0197 and 0.026, LD and NL respectively). No unexpected safety signals were reported.Conclusion:SEC 150 mg provided significant and sustained improvement in signs and symptoms of pts with nr-axSpA through Wk 52. MRI BME scores were reduced accordingly. There was no major difference between LD and NL. Safety of SEC was consistent with previous reports.2References:[1]Deodhar A, et al.Arthritis Rheumatol. 2019;71(suppl 10).[2]Deodhar A, et al. Arth Res Ther. 2019;21:111.TableEndpoints, % respondersWkSEC150 mg LD(N = 185)SEC150 mg NL(N = 184)PBO(N = 186)PrimaryASAS40 in anti-TNF-naïve pts1641.5‡42.2‡29.25235.4‡39.8‡19.9SecondaryASAS401640.0‡40.8‡28.05233.5‡38.0‡19.4BASDAI501637.3‡37.5‡21.05230.8‡35.3‡19.9ASDAS-CRP ID1620.5†21.7†8.15215.723.9‡10.2†P< 0.001;‡P< 0.05 vs PBO (Pvalues are adjusted for multiplicity of testing at Wks 16 and 52. UnadjustedPvalue for ASDAS-CRP ID at Wk 16). Missing values were imputed as non-response.N, number of randomised ptsDisclosure of Interests:Juergen Braun Grant/research support from: Abbvie (Abbott), Amgen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, Eli Lilly and Company, Medac, MSD (Schering Plough), Mundipharma, Novartis, Pfizer (Wyeth), Roche, Sanofi- Aventis, and UCB Pharma, Consultant of: Abbvie (Abbott), Amgen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, EBEWE Pharma, Eli Lilly and Company, Medac, MSD (Schering-Plough), Mundipharma, Novartis, Pfizer (Wyeth), Roche, Sanofi-Aventis, and UCB Pharma, Speakers bureau: Abbvie (Abbott), Amgen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, EBEWE Pharma, Eli Lilly and Company, Medac, MSD (Schering-Plough), Mundipharma, Novartis, Pfizer (Wyeth), Roche, Sanofi-Aventis, and UCB Pharma, Ricardo Blanco Grant/research support from: AbbVie, MSD, Roche, Consultant of: Abbvie, Eli Lilly, Pfizer, Roche, Bristol-Myers, Janssen, UCB Pharma and MSD, Speakers bureau: Abbvie, Eli Lilly, Pfizer, Roche, Bristol-Myers, Janssen, UCB Pharma. MSD, Eva Dokoupilova Grant/research support from: Eli Lilly, AbbVie, Novartis, Lianne S. Gensler Grant/research support from: Pfizer, Novartis, UCB, Consultant of: AbbVie, Eli Lilly, GSK, Novartis, UCB, Alan Kivitz Shareholder of: AbbVie, Amgen, Gilead, GSK, Pfizer Inc, Sanofi, Consultant of: AbbVie, Boehringer Ingelheim, Flexion, Genzyme, Gilead, Janssen, Novartis, Pfizer Inc, Regeneron, Sanofi, SUN Pharma Advanced Research, UCB, Paid instructor for: Celgene, Genzyme, Horizon, Merck, Novartis, Pfizer, Regeneron, Sanofi, Speakers bureau: AbbVie, Celgene, Flexion, Genzyme, Horizon, Merck, Novartis, Pfizer Inc, Regeneron, Sanofi, Stephen Hall Grant/research support from: Abbvie, UCB, Janssen, Merck, Hideto Kameda Grant/research support from: Abbvie, Asahi-Kasei, Chugai, Eisai, Mitsubishi-Tanabe and Novartis, Consultant of: Abbvie, Boehringer, Celgene, Eli Lilly, Janssen, Novartis, Sanofi, UCB, Speakers bureau: Abbvie, Asahi-Kasei, BMS, Chugai, Eisai, Eli Lilly, Janssen, Mitsubishi-Tanabe, Novartis and Pfizer, Denis Poddubnyy Grant/research support from: AbbVie, MSD, Novartis, and Pfizer, Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly, MSD, Novartis, Pfizer, Roche, UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Eli Lilly, MSD, Novartis, Pfizer, Roche, UCB, Marleen van de Sande Grant/research support from: Novartis, Eli Lilly, Boehringer Ingelheim, Janssen, Consultant of: Abbvie, Novartis, Eli Lilly, Speakers bureau: Novartis, MSD, Désirée van der Heijde Consultant of: AbbVie, Amgen, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Cyxone, Daiichi, Eisai, Eli-Lilly, Galapagos, Gilead Sciences, Inc., Glaxo-Smith-Kline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, UCB Pharma; Director of Imaging Rheumatology BV, Anna Wiksten Shareholder of: Novartis, Employee of: Novartis, Brian Porter Shareholder of: Novartis, Employee of: Novartis, Hanno Richards Shareholder of: Novartis, Employee of: Novartis, Sibylle Haemmerle Shareholder of: Novartis, Employee of: Novartis, Atul Deodhar Grant/research support from: AbbVie, Eli Lilly, GSK, Novartis, Pfizer, UCB, Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myer Squibb (BMS), Eli Lilly, GSK, Janssen, Novartis, Pfizer, UCB, Speakers bureau: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myer Squibb (BMS), Eli Lilly, GSK, Janssen, Novartis, Pfizer, UCB

Objective To evaluate the effect of secukinumab (interleukin-17A inhibitor) on patient-reported outcomes in patients with active ankylosing spondylitis (AS). Methods In this phase III study, 371 patients were randomized (1:1:1) to receive intravenous (IV) secukinumab 10 mg/kg at baseline and weeks 2 and 4 followed by subcutaneous (SC) secukinumab 150 mg every 4 weeks (IV→150 mg group), or SC secukinumab 75 mg every 4 weeks (IV→75 mg group), or placebo. Patient-reported outcomes included the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), BASDAI criteria for 50% improvement (BASDAI 50), Short Form 36 (SF-36) physical component summary (PCS) score and mental component summary (MCS) score, Ankylosing Spondylitis Quality of Life (ASQoL) questionnaire, Bath Ankylosing Spondylitis Functional Index (BASFI), EuroQol 5-domain (EQ-5D) questionnaire, Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F), and Work Productivity and Activity Impairment–General Health questionnaire (WPAI-GH). Results At week 16, secukinumab IV→150 mg or IV→75 mg was associated with statistically and clinically significant improvements from baseline versus placebo in the BASDAI (−2.3 for both regimens versus −0.6; P

Background: Smoking is the leading preventable cause of death; however, small-area estimates for detailed smoking status are limited. We developed multilevel small-area estimate mixed models to generate county-level estimates for six smoking status categories: current, some days, every day, former, ever, and never. Method: Using 2012 Behavioral Risk Factor Surveillance System (BRFSS) data (our sample size = 405,233 persons), we constructed and fitted a series of multilevel logistic regression models and applied them to the U.S. Census population to generate county-level prevalence estimates. We mapped the estimates by sex and aggregated them into state and national estimates. We conducted comparisons for internal consistency with BRFSS states' estimates using Pearson correlation coefficients, and external validation with the 2012 National Health Interview Survey current smoking prevalence. Results: Correlation coefficients ranged from 0.908 to 0.982, indicating high internal consistency. External validation indicated complete agreement (prevalence = 18.06%). We found large variations in current and former smoking status between and within states and by sex. County prevalence of former smokers was highest among men in the Northeast, North, and West. Utah consistently had the lowest smoking prevalence. Conclusions: Our models, which include demographic and geographic characteristics, provide reliable estimates that can be applied to multiple category outcomes and any demographic group. County and state estimates may help understand the variation in smoking prevalence in the United States and provide information for control and prevention. Impact: Detailed county and state smoking category estimates can help identify areas in need of tobacco control and prevention and potentially allow planning for health care. Cancer Epidemiol Biomarkers Prev; 25(10); 1402–10. ©2016 AACR.

Volume loss is commonly encountered at chest imaging and may result from a number of causes, including endobronchial obstruction from mucous impaction or centrally obstructing neoplasms, previous surgical resection, and visceral pleural restriction from prior pleural inflammation or intervention. Ty

Background: Clinical trials investigating mepolizumab for eosinophilic severe asthma patients employed strict eligibility criteria. Nonetheless, patients not meeting these criteria are treated with mepolizumab in clinical practice. Aim: To investigate the extent and reasons for trial ineligibility of real-life, mepolizumab-treated severe asthma patients. To compare characteristics of these patients with trial populations. Methods: Trial criteria and patient characteristics of the SIRIUS, DREAM and MENSA trials were extracted. Baseline characteristics from mepolizumab-treated, oral glucocorticoid-dependent severe asthma patients were studied in RAPSODI (the Dutch severe asthma registry). Results: 7 of 70 mepolizumab-treated patients (10%) from RAPSODI fulfil the trial criteria, whereas 34 (48.6%) and 29 (41.4%) patients are ineligible on the basis of exclusion and inclusion criteria, respectively. Predominant deviations from criteria are summarised in table 1. Significant differences exist in age (56.5 vs 50.1 years), gender (41.4% vs 57.1% females) and FEV1 (2.49 vs 1.82 L) between the real-life and MENSA trial populations. Conclusion: Only a small part of mepolizumab-treated patients in clinical practice fulfils trial criteria and significant differences in patient characteristics exist between trial and real-life severe asthma populations, indicating limited representativeness. The RAPSODI registry was financially supported by GSK and Novartis.

Rationale: Analysis of exhaled volatile organic compounds (VOCs) by sensor-driven electronic nose (eNose) technology is a widely suggested measure for non-invasive monitoring of chronic airway diseases. While this technology allows probabilistic (clinical) advise, it is incapable of providing details regarding involved metabolites. Modelling sensor deflections by matching Gas Chromatography-Mass Spectrometry (GC-MS) samples could help to ascertain which VOCs induce a sensor response. Objective: To determine the association between eNose sensor deflections and exhaled VOCs measured by GC-MS. Methods: Paired samples of breath from asthma patients (n=22) were collected on sorbent tubes. One tube was analysed by four different eNoses and the second one by GC-MS. Pooling of resulting datasets consisted of 1) Partial Least Square Regression (PLSR) analysis and 2) clustered heat-mapping of PLSR loadings. Results: Matching data was available for 158 eNose sensors and 1025 GC-MS features, whereby PLSR resulted in R2‘s from 0.25 to 0.72. Figure 1 shows clustered heat-mapping outcomes. Conclusion: This explorative analysis revealed distinctive and associated patterns of exhaled VOCs between eNose and GC-MS. This data matching could help to identify which VOCs are responsible for clinically relevant results obtained by eNose and will facilitate valorisation of breathomics into clinical tests.

Background The earliest records in Britain for the western European house mouse (Mus musculus domesticus) date from the Late Bronze Age. The arrival of this commensal species in Britain is thought to be related to human transport and trade with continental Europe. In order to study this arrival, we collected a total of 16 ancient mouse mandibulae from four early British archaeological sites, ranging from the Late Bronze Age to the Roman period. Results From these, we obtained ancient mitochondrial DNA (mtDNA) house mouse sequences from eight house mice from two of the sites dating from the Late Bronze to Middle Iron Age. We also obtained five ancient mtDNA wood mouse (Apodemus spp.) sequences from all four sites. The ancient house mouse sequences found in this study were from haplogroups E (N = 6) and D (N = 2). Modern British house mouse mtDNA sequences are primarily characterised by haplogroups E and F and, much less commonly, haplogroup D. Conclusions The presence of haplogroups D and E in our samples and the dating of the archaeological sites provide evidence of an early house mouse colonisation that may relate to Late Bronze Age/Iron Age trade and/or human expansion. Our results confirm the hypothesis, based on zooarchaeological evidence and modern mtDNA predictions, that house mice, with haplogroups D and E, were established in Britain by the Iron Age and, in the case of haplogroup E, possibly as early as the Late Bronze Age.

Artículo escrito por un elevado número de autores, sólo se referencian el que aparece en primer lugar, el nombre del grupo de colaboración, si le hubiera, y los autores pertenecientes a la UAM, Used for both proton decay searches and neutrino physics, large water Cherenkov (WC) detectors have been very successful tools in particle physics. They are notable for their large masses and charged particle detection capabilities. While current WC detectors reconstruct charged particle tracks over a wide energy range, they cannot efficiently detect neutrons. Gadolinium (Gd) has the largest thermal neutron capture cross section of all stable nuclei and produces an 8 MeV gamma cascade that can be detected with high efficiency. Because of the many new physics opportunities that neutron tagging with a Gd salt dissolved in water would open up, a large-scale R&D program called EGADS was established to demonstrate this technique’s feasibility. EGADS features all the components of a WC detector, chiefly a 200-ton stainless steel water tank furnished with 240 photo-detectors, DAQ, and a water system that removes all impurities from water while keeping Gd in solution. In this paper we discuss the milestones towards demonstrating the feasibility of this novel technique, and the features of EGADS in detail, This work was supported by the JSPS KAKENHI Grant Numbers JP21224004, JP26000003, JP24103004 and JP17H06365. Funding support was provided by Kavli IPMU (WPI), the University of Tokyo and the US Department of Energy. We thank the “Consorcio Laboratorio Subterraneo de Canfranc” (Spain) and the Boulby Underground Research Laboratory and in particular the staff of the BUGS facility (UK) for supporting the low-background materials screening work. Some of us have been supported by funds from the European Union H2020-MSCA-RISE-GA872549-SK2HK, the Spanish Ministry of Science and Innovation (grant PGC2018-099388-B-100), the Science and Technology Facilities Council (STFC) and GridPP, UK, and the European Union’s H2020 -MSCA-RISE-2018 JENNIFER2 grant agreement no. 822070

Smoking cessation is a critical component of cancer prevention among older adults (age ≥ 65 years). Understanding smoking cessation behaviors among older adults can inform clinical and community efforts to increase successful cessation. We provide current, national prevalence estimates for smoking cessation behaviors among older adults, including interest in quitting, quitting attempts, quitting successes, receiving advice to quit from a healthcare provider, and use of evidence-based tobacco cessation treatments. The 2015 National Health Interview Survey and Cancer Control Supplement were used to estimate cigarette smoking status and cessation behaviors among older US adults across selected socio-demographic and health characteristics. We found that four in five older adults who had ever smoked cigarettes had quit and more than half who currently smoked were interested in quitting but fewer than half made a past-year quit attempt. Two-thirds of older adults said that a healthcare provider advised them to quit smoking, but just over one-third who tried to quit used evidence-based tobacco cessation treatments and only one in 20 successfully quit in the past year. Prevalence estimates for smoking cessation behaviors were similar across most characteristics. Our study demonstrates that few older adults, across most levels of characteristics examined, successfully quit smoking, underscoring the importance of assisting smoking cessation efforts. Healthcare providers can help older adults quit smoking by offering or referring evidence-based cessation treatments. States and communities can implement population-based interventions including tobacco price increases, comprehensive smoke-free policies, high-impact tobacco education media campaigns, and barrier-free access to evidence-based tobacco cessation counseling and medications., Highlights • Smoking cessation among older adults (age ≥ 65 years) is key to cancer prevention. • More than half of older adults who currently smoked were interested in quitting. • Only one in 20 older adults successfully quit smoking in the past year. • Only a third of older adults who tried to quit used a proven cessation treatment. • Clinical and community efforts can boost successful cessation among older adults.

What you need to know Providing effective feedback is an essential component of being a good teacher. When delivered well, feedback improves doctors’ and students’ skillsets and establishes lifelong learning (fig 1). A 2013 literature review described the characteristics of learners interested in feedback in terms of the self-motives framework (self assessment, self improvement, self enhancement, and self verification) and concluded that feedback‐seeking behaviour is valuable for individuals in work and educational settings as it aids their adaptation, learning, and performance.1 Fig 1 Clinical learning is an ongoing cycle of progress pivoting on feedback While the literature about feedback is broad and characterised by a lack of high quality, evidence based guidance or internationally recognised guidelines, consensus opinion and reviews of available quantitative and qualitative results indicate that effective feedback is based on observations, given in a conducive environment, characterised by a non-judgmental approach, focused on specific skills and behaviours, and limited in quantity to avoid overwhelming learners.23 This article is written for clinicians who teach and outlines how to give effective feedback to students and doctors in training, and why it is important. We provide specific strategies and approaches for clinicians and clinician educators to assist in developing and providing effective feedback to medical learners. A useful working definition of feedback is “Information describing performance in a given activity that is intended to guide future performance in that same or related activity.”4. Feedback can be either formative or summative in nature. Formative feedback is provided during or shortly after a specific encounter or experience, with the content focusing constructively on …

This chapter deals with the special areas of concern for practitioners who are required to deal with the sale or purchase of new residential properties, either recently constructed or in the course of construction. It looks at the roles of the practitioners acting for the developer and prospective buyer respectively. It also considers the arrangements for roads and sewers on a new estate and the importance of insurance against structural defects in new properties.

This chapter begins by considering leases, dealing with leases when acting for a lessee or lender, liability on covenants in leases, and lease variations. It then discusses new leases, existing leases, statutes and leases, and the Commonhold and Leasehold Reform Act 2002.

This chapter first considers matters that must be attended to before an exchange of contracts when acting for the buyer and when acting for the seller. It then discusses implementing the exchange of contracts; actions taken after exchange; and death or insolvency of contracting parties between exchange and completion.

This introductory chapter begins with an overview of conveyancing, which is the process by which legal title to property is transferred. It then discusses the conveyancing of registered land; defensive lawyering and the conveyancing process; conveyancing and information technology; and the future of conveyancing.

Objective The aim of this study was to compare radiographic progression in patients with ankylosing spondylitis (AS) treated for up to 2 years with secukinumab (MEASURE 1) with a historical cohort of biologic-naïve patients treated with NSAIDs (ENRADAS). Methods Baseline and 2-year lateral cervical and lumbar spine radiographs were independently evaluated using mSASSS by two readers, who were blinded to the chronology and cohort of the radiographs. The primary endpoint was the proportion of patients with no radiographic progression (mSASSS change ≤ 0 from baseline to year 2). The Primary Analysis Set included patients with baseline (≤ day 30) and post-baseline day 31–743 radiographs. Sensitivity analyses were performed to assess the robustness of the comparison between the two cohorts, as follows: Sensitivity Analysis Set 1 included all patients with baseline (≤ day 30) and year 2 (days 640–819) radiographs; Sensitivity Analysis Set 2 included all patients with baseline and post-baseline (> day 30) radiographs. Results A total of 168 patients (84%) from the MEASURE 1 cohort and 69 (57%) from the ENRADAS cohort qualified for the Primary Analysis Set. Over 2 years, the LS (SE) mean change from baseline in mSASSS for the primary analysis was 0.55 (0.139) for MEASURE 1 vs 0.89 (0.216) for ENRADAS (p = 0.1852). Mean changes from baseline in mSASSS were lower in MEASURE 1 vs ENRADAS for the primary and sensitivity analyses. The proportion of patients with no radiographic progression was consistently higher in the MEASURE 1 vs ENRADAS cohort across all cutoffs for no radiographic progression (change in mSASSS from baseline to year 2 of ≤ 0, ≤ 0.5, ≤ 1, and ≤ 2), but the differences were not statistically significant. Conclusion Secukinumab-treated patients demonstrated a numerical, but statistically non-significant, higher proportion of non-progressors and lower change in mSASSS over 2 years versus a cohort of biologic-naïve patients treated with NSAIDs. Electronic supplementary material The online version of this article (10.1186/s13075-019-1911-1) contains supplementary material, which is available to authorized users.

Background Evaluation of long-term efficacy and safety for treatments for ankylosing spondylitis (AS) is important. Secukinumab, a fully human monoclonal antibody that directly inhibits interleukin-17A, has shown significant and sustained improvement in the signs and symptoms of AS through 3 years in the MEASURE 2 study (NCT01649375).1 Objectives We report the 5-year end-of-study results of subcutaneous (s.c.) secukinumab 150 mg in the MEASURE 2 study. Methods AS patients (pts; N = 219) were randomised to receive s.c. secukinumab 150 mg, 75 mg or placebo at baseline, Weeks (Wks) 1, 2 and 3 and every 4 wks from Wk 4. At Wk 16, placebo-treated pts were re–randomised to receive secukinumab 150/75 mg. Efficacy results are reported for pts initially randomised to secukinumab 150 mg and those who switched from placebo to secukinumab 150 mg at Wk 16 (N = 106). An optional dose escalation from secukinumab 75 mg to 150 mg was initiated beginning Wk 140. Outcome measures at Wk 260 included ASAS20/40, BASDAI50, BASMI, BASFI, SF-36 PCS and ASAS partial remission. Analyses stratified by anti-TNF status (anti–TNF-naive and anti-TNF inadequate response [IR]) were performed. Safety analysis included all pts who received ≥1 dose of secukinumab. Results are reported as observed. Results The retention rate to Wk 260 was 77% (82/106) for secukinumab 150 mg. Sustained efficacy was observed with secukinumab 150 mg across all endpoints through 5 years (Table). Improvements were maintained regardless of prior exposure to anti–TNF therapy with greater responses in anti–TNF-naive pts. A total of 49 pts on secukinumab 75 mg (46.7%) escalated dose to 150 mg after Wk 140; efficacy responses improved in pts whose dose was escalated. Over the entire study period, the mean exposure (±SD) to secukinumab was 1459.1 ± 597.8 days. Exposure-adjusted incidence rates (per 100 pt-years) with any secukinumab dose for selected adverse events were: Candida infections (1.0), Crohn’s disease (0.5), major adverse cardiovascular events (0.7), uveitis (0.5), and malignant/unspecified tumours (0.5). Conclusion Secukinumab 150 mg provided sustained improvement in the signs, symptoms, and physical function in pts with AS through 5 years of treatment. The safety profile of secukinumab remained consistent with previous reports.1–3 References [1] Marzo-Ortega, et al. RMD Open. 2017;3:e000592; 2. Marzo-Ortega, et al. Ann Rheum Dis. 2016;75:812–3; 3. Baraliakos X,et al. Clin Exp Rheumatol2017. Disclosure of Interests Helena Marzo-Ortega Grant/research support from: Janssen, Novartis and Pfizer, Consultant for: AbbVie, Celgene, Janssen, Eli-Lilly, Novartis and UCB, Speakers bureau: AbbVie, Celgene, Janssen, Eli-Lilly, Novartis and UCB, Joachim Sieper Consultant for: Abbvie, Bohringer Ingelheim, Janssen, Lilly, Merck, Mylan, Novartis, Pfizer, UCB., Speakers bureau: Abbvie, Bohringer Ingelheim, Janssen, Lilly, Merck, Mylan, Novartis, Pfizer, UCB., Alan Kivitz Shareholder of: Novartis, Consultant for: Abbvie, Janssen, Pfizer, UCB, Genzyme, Sanofi, Regeneron, Boehringer Ingelheim, Sun Pharma Advanced Research, Flexion., Paid instructor for: Celgene, Horizon, Merck, Novartis, Pfizer, Genzyme, Sanofi, Regeneron, Speakers bureau: Celgene, Horizon, Merck and Genetech, Flexion, Ricardo Blanco Grant/research support from: Abbvie, MSD and Roche, Consultant for: Abbvie, Pfizer, Roche, Bristol-Myers, Janssen and MSD, Speakers bureau: Abbvie, Pfizer, Roche, Bristol-Myers, Janssen and MSD, Martin Cohen Consultant for: AbbVie, Amgen, Celgene, Lilly, Novartis, Pfizer, Sandoz, Sanofi and UCB, Speakers bureau: AbbVie, Amgen, Celgene, Janssen, Merck, Novartis and Pfizer, Karel Pavelka: None declared, Eumorphia Maria Delicha Employee of: Novartis, Anna Stefanska Shareholder of: Novartis, Employee of: Novartis, Hanno Richards Shareholder of: Novartis Pharma AG, Employee of: Novartis Pharma AG, Susanne Rohrer Shareholder of: Novartis, Employee of: Novartis

Background: Ankylosing spondylitis (AS) is an inflammatory disease resulting in progressive disability due to structural damage in the spine. The identification of predictors of progression would allow treating physicians to personalize treatments but requires an approach accounting for a relatively short follow-up of clinical studies, large between-patient variability, and low sensitivity of X-ray images which generate intra-patient variability when repeated measurements are taken. Objectives: 1) To identify patient characteristics predicting faster structural damage progression. 2) To quantify the progression over four years of secukinumab treatment, depending on dose/exposure. Methods: Data came from the phase 3 randomized placebo-controlled trial MEASURE 1 (NCT01358175)1 in which patients were treated with secukinumab (intravenous loading of 10 mg/kg at weeks 0, 2, and 4, followed by secukinumab subcutaneously at a dose of either 75 mg or 150 mg every 4 weeks) over 208 weeks. Only patients treated with secukinumab with at least two assessments of structural damage were included. We explored the effect of multiple baseline demographic traits, disease stage, severity, bone cartilage biomarkers as well as prior and current treatment on change in modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) using a longitudinal Bayesian mixture model with random effects, which accounted simultaneously for the probability of progression, magnitude of progression and inter-patient variability. Posterior predictive check was performed. Results: Out of 249 patients randomized to secukinumab, 167 had their structural damage assessed at least twice. These patients contributed in total 409 assessments of change in structural damage between weeks 0, 52, 104 and 208. Of the factors tested, a higher baseline BASMI score was associated with faster progression rate in a statistically significant way (+0.60 in mSASSS/year for each additional standard deviation of baseline BASMI (SD=1.74), 95% interval 0.03 to 1.14). Trends were also detected for association between faster mSASSS progression and younger age, prior exposure to TNFα inhibitor, HLA-B27 positivity, and higher osteocalcin levels. Increased exposure to secukinumab was associated with slower structural damage progression (-0.23 in mSASSS/year for each additional standard deviation in exposure, 95% interval -0.58 to 0.10). Model estimation suggested that secukinumab 150 mg was associated with a yearly progression of -0.2 (95% interval -1.2 to 0.8) in the first two years of treatment and 0.1 mSASSS (95% interval -0.8 to 1.0) in the third and fourth year of treatment. Analogously, secukinumab 75mg (currently not approved for clinical use) was associated with a progression of -0.2 mSASSS/year (95% interval -1.3 to 0.9) in the first two years of treatment and 0.5 mSASSS/year (95% interval -0.5 to 1.6) in the third and fourth year of treatment. Conclusion: Potential predictors of structural progression suggested by the model were higher baseline BASMI, younger age, prior exposure to TNFα inhibitor, HLA-B27 positivity, and higher osteocalcin at baseline, although only baseline BASMI showed statistical significance. Further analyses using larger, deeper and real-world data are needed to confirm these findings and to estimate progression rates in AS patients in daily practice. Reference [1] Baeten D, Sieper J, Braun J, et al. Secukinumab, an Interleukin-17A Inhibitor, in Ankylosing Spondylitis. N Engl J Med. 2015;373(26):2534-2548. Disclosure of Interests: Olivier Luttringer Shareholder of: Novartis, Employee of: Employee of Novartis Pharma AG, Todd Fox Employee of: Novartis, Brian Porter Shareholder of: Novartis, Employee of: Novartis, Abhijit Shete Shareholder of: Novartis Pharma AG, Employee of: Novartis Pharma AG, Hanno Richards Shareholder of: Novartis Pharma AG, Employee of: Novartis Pharma AG, Witold Wiecek Consultant for: Employee of CERTARA Strategic Consulting., Zuzanna Angehrn Shareholder of: Owns funds which might occassionaly invest in pharmaceutical companies’ stocks., Consultant for: Employee of CERTARA strategic consulting., Helene Karcher Consultant for: Former employee of Analytica Laser, a Certara company. Former independent consultant. Current employee of PAREXEL., Employee of: Former employee of Novartis., Billy Amzal Consultant for: Employee of CERTARA Strategic Consulting., Employee of: Former employee of Novartis.

We assembled genome-wide data from 271 ancient Iberians, of whom 176 are from the largely unsampled period after 2000 BCE, thereby providing a high-resolution time transect of the Iberian Peninsula. We document high genetic substructure between northwestern and southeastern hunter-gatherers before the spread of farming. We reveal sporadic contacts between Iberia and North Africa by ~2500 BCE and, by ~2000 BCE, the replacement of 40% of Iberia's ancestry and nearly 100% of its Y-chromosomes by people with Steppe ancestry. We show that, in the Iron Age, Steppe ancestry had spread not only into Indo-European-speaking regions but also into non-Indo-European-speaking ones, and we reveal that present-day Basques are best described as a typical Iron Age population without the admixture events that later affected the rest of Iberia. Additionally, we document how, beginning at least in the Roman period, the ancestry of the peninsula was transformed by gene flow from North Africa and the eastern Mediterranean., J.M.F., F.J.L.-C., J.I.M., F.X.O., J.D., and M.S.B. were supported by HAR2017-86509-P, HAR2017-87695-P, and SGR2017-11 from the Generalitat de Catalunya, AGAUR agency. C.L.-F. was supported by Obra Social La Caixa and by FEDER-MINECO (BFU2015- 64699-P). L.B.d.L.E. was supported by REDISCO-HAR2017-88035-P (Plan Nacional I+D+I, MINECO). C.L., P.R., and C.Bl. were supported by MINECO (HAR2016-77600-P). A.Esp., J.V.-V., G.D., and D.C.S.-G. were supported by MINECO (HAR2009-10105 and HAR2013-43851-P). D.J.K. and B.J.C. were supported by NSF BCS-1460367. K.T.L., A.W., and J.M. were supported by NSF BCS-1153568. J.F.-E. and J.A.M.-A. were supported by IT622-13 Gobierno Vasco, Diputación Foral de Álava, and Diputación Foral de Gipuzkoa. We acknowledge support from the Portuguese Foundation for Science and Technology (PTDC/EPH-ARQ/4164/2014) and the FEDER-COMPETE 2020 project 016899. P.S. was supported by the FCT Investigator Program (IF/01641/2013), FCT IP, and ERDF (COMPETE2020 – POCI). M.Si. and K.D. were supported by a Leverhulme Trust Doctoral Scholarship awarded to M.B.R. and M.P. D.R. was supported by an Allen Discovery Center grant from the Paul Allen Foundation, NIH grant GM100233, and the Howard Hughes Medical Institute. V.V.-M. and W.H. were supported by the Max Planck Society.

Industry trades report the digital marketing skills gap continues to widen. In response to this need, Experiential Learning Theory (ELT) and a partnership with a leader in marketing technology was applied to create the Applied Marketing & Media Education Norm (AMEN). AMEN provides a model matching the employment needs of the digital marketing space while creating a means for academic programs to remain current with technology. AMEN also offers unique advantages when it comes to bridging theory-based and skills-based education models through applied projects and software certifications. This produces positive outcomes for the students, faculty, department, university, and industry.

Africa was the birth-place of Homo sapiens and has the earliest evidence for symbolic behaviour and complex technologies. The best-attested early flowering of these distinctive features was in a glacial refuge zone on the southern coast 100-70 ka, with fewer indications in eastern Africa until after 70 ka. Yet it was eastern Africa, not the south, that witnessed the first major demographic expansion, ~70-60 ka, which led to the peopling of the rest of the world. One possible explanation is that important cultural traits were transmitted from south to east at this time. Here we identify a mitochondrial signal of such a dispersal soon after ~70 ka - the only time in the last 200,000 years that humid climate conditions encompassed southern and tropical Africa. This dispersal immediately preceded the out-of-Africa expansions, potentially providing the trigger for these expansions by transmitting significant cultural elements from the southern African refuge., Portuguese foundation for science and technology (FCT), through the project PTDC/EPH-ARQ/4164/2014 partially funded by European Regional Development Fund (FEDER) (COMPETE 2020 project 016899), through a personal grant to D.V. and P.S. was supported by FCT, ESF and POPH through the FCT Investigator Programme (IF/01641/2013). P.S., D.V. and E.C.-S. acknowledge FCT IP and ERDF (COMPETE2020 – POCI) for the CBMA strategic programme UID/BIA/04050/2013 (POCI-01-0145-FEDER-007569). T.R. is supported by a FCT grant (SFRH/BPD/108126/2015) and acknowledges the project [NORTE-01-0145-FEDER-000013], supported by NORTE 2020-Portugal 2020, through FEDER for institutional support. M.B.R. and M.S. received support from a Leverhulme Doctoral Scholarship programme. E.C.-S. acknowledges project UID/MAT/00144/2013 funded by FCT (Portugal) with MEC and FEDER under PT2020. Authors acknowledge the use of cluster SEARCH funded through Search-ON2: HPC infrastructure of UMinho, (NORTE-07-0162-FEDER-000086), co-funded by ON.2-O Novo Norte under NSRF through ERDF

Neutral current (NC) interactions of atmospheric neutrinos on oxygen form one of the major backgrounds in the search for supernova relic neutrinos with water-based Cherenkov detectors. The NC channel is dominated by neutrino quasi-elastic (NCQE) scattering off nucleons inside $^{16}$O nuclei. In this paper we report the first measurement of NCQE cross section using atmospheric neutrinos at Super-Kamiokande (SK). The measurement used 2,778 live days of SK-IV data with a fiducial volume of 22.5 kiloton water. Within the visible energy window of 7.5-29.5 MeV, we observed $117$ events compared to the expected $71.9$ NCQE signal and $53.1$ background events. Weighted by the atmospheric neutrino spectrum from 160 MeV to 10 GeV, the flux averaged NCQE cross section is measured to be $(1.01\pm0.17(\text{stat.})^{+0.78}_{-0.30}(\text{sys.}))\times10^{-38}$ cm$^2$., Comment: 11 pages, 9 figures, submitted to PRD