A Constitutive Model for Describing the Tensile Response of Woven Polyethylene Terephthalate Geogrids after Damage.

A constitutive model was used to describe the tensile response of two woven Polyethylene Terephthalate (PET) geogrids, before and after mechanical damage. The model parameters of undamaged and damaged specimens were estimated via numerical regressions of test results. For each sample, the experimental and fitted tensile strengths were statistically compared using hypothesis tests. For each geogrid, tensile load-strain curves of damaged samples were drawn by applying scaling factors to the plot of the undamaged sample. The curve fittings resulted in high R2 values for undamaged and damaged specimens of the geogrids. For most samples, there was no significant mean difference between the experimental and fitted tensile strength. The model allowed us to describe the load-strain curve of a geogrid from its tensile properties: εmax, Tmax and Ji. Regardless of the type of damage (in laboratory or in situ), the model was able to describe the load-strain curves of damaged samples using data from undamaged samples and scaling factors.

Survival analysis of cancer patients in Portugal following the reference centre model implementation.

Cancer has affected around eighteen million people all over the world in 2018. In Portugal, cancer was diagnosed in sixty thousand individuals during 2018, being the second leading cause of death (one in every four deaths). Following the European Directive 2011/24/EU, the Portuguese Health System has been recognizing oncology Reference Centres (RCs), which are focused on delivering best-in-class treatment for cancer patients. This paper performs a survival analysis of cancer patients in Portugal, having hospital episodes with discharge date after the official recognition, in 2016, of the first RCs for hepatobiliary, pancreatic, sarcomas and oesophageal cancer. The aim is to assess the impact of RCs on the survival probability of these patients. For each cancer type, survival curves are estimated using the Kaplan-Meier methodology, and hazard ratios are estimated for different covariates, using multivariate Extended Cox models. The results obtained support the implementation and encourage the further extension of the RC model for oncology in Portugal, as cancer patients treated in an oncology RC, overall, have a better survival probability when compared to patients who had no episode in an RC. These results are clearer for hepatobiliary and pancreatic cancer, but also visible for sarcomas and oesophageal cancer.

Is there a time window for MRI in Wernicke encephalopathy - a decade of experience from a tertiary hospital.

OBJECTIVE: Wernicke encephalopathy (WE) is a neuropsychiatric syndrome caused by thiamine deficiency. Despite its low sensitivity, brain magnetic resonance imaging (MRI) is the most useful diagnostic technique. Our aim was to investigate whether the timing of the imaging study, and thiamine replacement can influence brain MRI findings in these patients. METHODS: Retrospective observational study of hospitalized patients between January/2008 and December/2020 with a clinical diagnosis of WE. Data from clinical presentation, diagnostic features, therapeutic approach, and outcomes were collected. RESULTS: We identified 41 patients (55 ± 13.3 years) with WE. Brain MRI was performed in 36 patients, and one third had T2/FLAIR hyperintensities suggestive of WE. We found an association between a history of poor diet and periventricular hyperintensities (p = 0.023), especially on the ventral surface of the thalamus and the periaqueductal region. It was found that the odds of having a typical imaging of WE decreased by 5.3% for each additional unit (100 mg) of thiamine administered (p = 0.046) (95% CI [0.89, 0.99]). On the other hand, the number of days from clinical presentation was not found to be a viable predictor (p = 0.254) (95% CI [0.88, 1.03]) Recovery was positively correlated with the total dose of thiamine received until discharge (p = 0.020). CONCLUSIONS: MRI hyperintensities seem to be dependent on the timing of thiamine correction and, particularly, on the thiamine dosage prescribed at admission. Nevertheless, thiamine replacement should not be delayed, as its timely prescription is associated with a better prognosis at discharge.

A biochemical perspective on the fate of virgin olive oil phenolic compounds in vivo.

The chemistry of the phenolic compounds found in virgin olive oil (VOO) is very complex due, not only to the different classes of polyphenols that can be found in it, but, above all, due to the existence of a very specific phenol class found only in oleaceae plants: the secoiridoids. Searching in the Scopus data base the keywords flavonoid, phenolic acid, lignin and secoiridoid, we can find a number of 148174, 79435, 11326 and 1392 research articles respectively, showing how little is devote to the latter class of compounds. Moreover, in contrast with other classes, that include only phenolic compounds, secoiridoids may include phenolic and non-phenolic compounds, being the articles concerning phenolic secoiridoids much less than the half of the abovementioned articles. Therefore, it is important to clarify the structures of these compounds and their chemistry, as this knowledge will help understand their bioactivity and metabolism studies, usually performed by researchers with a more health science's related background. In this review, all the structures found in many research articles concerning VOO phenolic compounds chemistry and metabolism was gathered, with a special attention devoted to the secoiridoids, the main phenolic compound class found in olives, VOO and olive leaf.

A Drug Screening Reveals Minocycline Hydrochloride as a Therapeutic Option to Prevent Breast Cancer Cells Extravasation across the Blood-Brain Barrier.

Among breast cancer (BC) patients, 15-25% develop BC brain metastases (BCBM), a severe condition due to the limited therapeutic options, which points to the need for preventive strategies. We aimed to find a drug able to boost blood-brain barrier (BBB) properties and prevent BC cells (BCCs) extravasation, among PI3K, HSP90, and EGFR inhibitors and approved drugs. We used BCCs (4T1) and BBB endothelial cells (b.End5) to identify molecules with toxicity to 4T1 cells and safe for b.End5 cells. Moreover, we used those cells in mixed cultures to perform a high-throughput microscopy screening of drugs' ability to ameliorate BBB properties and prevent BCCs adhesion and migration across the endothelium, as well as to analyse miRNAs expression and release profiles. KW-2478, buparlisib, and minocycline hydrochloride (MH) promoted maximal expression of the junctional protein ß-catenin and induced 4T1 cells nucleus changes. Buparlisib and MH further decreased 4T1 adhesion. MH was the most promising in preventing 4T1 migration and BBB disruption, tumour and endothelial cytoskeleton-associated proteins modifications, and miRNA deregulation. Our data revealed MH's ability to improve BBB properties, while compromising BCCs viability and interaction with BBB endothelial cells, besides restoring miRNAs' homeostasis, paving the way for MH repurposing for BCBM prevention.

Validity and reliability of the Portuguese version of the modified Migraine Disability Assessment.

BACKGROUND: Migraine Disability Assessment Scale (MIDAS) is a useful tool to measure headache-related disability. Modified MIDAS with 4-week recall period reduces recall bias and improves accuracy of the results. This study aimed at validating mMIDAS in Portuguese. METHODS: Studied population consisted of adult migraine patients attending a headache outpatient clinic. Reliability was assessed by internal consistency and reproducibility in a 3-week test-retest. Content validity was evaluated by two expert panels. Construct validity was tested by comparing mMIDAS-P index in socioeconomic and clinical patient groups and scale unidimensionality was evidenced by factor analysis. Criterion validity was tested using EQ-5D-5L and HADS. RESULTS: Ninety-two patients, 88% female, mean age of 44 years, participated. They had, in average, 9.7 headache days in previous month, pain averaging 7.5/10. About 69.9% were on a migraine prophylactic treatment, and 42.4% had severe disability; 29.4 and 13.0% showed, respectively, moderate/severe anxiety and depression. Content validity showed that mMIDAS-P is simple and clinically useful. It did not show to be determined by patient's sociodemographic characteristics and it was correlated with depression scale and EQ-5D-5L. Test-retest demonstrated high reproductive reliability and good internal consistency. CONCLUSION: mMIDAS-P is valid and reliable. We strongly recommend it for clinical and research use.

Condylar form alteration on skeletal class II patients that underwent orthognathic surgery: An overview of systematic reviews.

BACKGROUND: Bilateral sagittal split osteotomy (BSSO) is commonly considered as the surgical technique of election for the treatment of skeletal class II with mandibular hypoplasia. After orthognathic surgery, condylar resorption can occur as a surgical relapse, which may affect the temporomandibular joint. Objective: This study aimed to summarise published systematic review that assess if orthognathic surgery with mandibular advancement performed on skeletal class II patients results in condylar form alteration. MATERIAL AND METHODS: A literature search was performed using the electronic databases PubMed, Web of Science, Cochrane Library, Embase along with several sources of grey literature. Selection Criteria: Inclusion criteria were systematic reviews published until December 2019, of skeletal class II patients aged more than 18 years old that underwent BSSO with mandibular advancement surgery. Data collection: The electronic search identified 37 publications. Four publications fulfilled the inclusion criteria and were included in this meta-analysis. Qualitative assessment of the selected studies was performed using the Assessment of Multiple Systematic Reviews - AMSTAR 2 checklist. RESULTS: Four systematic reviews were included in this review. Despite its low incidence all studies reported condylar resorption. However, there were methodological limitations in all assessed articles. CONCLUSIONS: The alteration of the condylar form may be a consequence of BSSO with mandibular advancement surgery. Additional high quality prospective research assisted by 3D-imaging technology is needed to allow more definite conclusions. Key words:Evidence-based orthodontics, TMJ, Class II, mandibular advancement, malocclusion, Angle class II.

Antimicrobial Photodynamic Therapy in the Control of Pseudomonas syringae pv. actinidiae Transmission by Kiwifruit Pollen.

Pseudomonas syringae pv. actinidiae (Psa) is a phytopathogen responsible for bacterial canker in kiwifruit plants and can be disseminated through pollen. This study aimed to evaluate the effectiveness of antimicrobial photodynamic therapy (aPDT) in the inactivation of Psa on kiwifruit pollen using New Methylene Blue (NMB) and Methylene Blue (MB) in the presence/absence of potassium iodide (KI). Pollen germination assays were also performed to evaluate if it was affected by aPDT. Higher reduction of Psa was achieved using NMB (5.0 µM) combined with KI (100 mM) in vitro (ca. 8 log CFU mL-1 after 90 min of irradiation), while NMB alone promoted a lower reduction (3.7 log CFU mL-1). The most efficient NMB concentration with KI was used to study the photodynamic efficiency of MB (5.0 µM). MB with KI photo-inactivated Psa more efficiently than NMB, causing the same bacterial reduction (ca. 8 log CFU mL-1) in half the irradiation time (45 min). Therefore, MB was selected for the subsequent ex vivo aPDT assays in pollen. Almost all the Psa cells added artificially to the pollen (3.2 log CFU mL-1) were photo-inactivated (3.1 log CFU mL-1), whereas aPDT had a low effect on pollen natural microorganisms. When KI was added, a significant increase in aPDT effectiveness was observed (4.5 log CFU mL-1). No negative effects were observed in the pollen germination after aPDT. The results show aPDT is an effective and safe method to Psa inactivation on kiwifruit pollen, and MB use is a promising alternative in the control of Psa transmission.

Familial congenital cataract, coloboma, and nystagmus phenotype with variable expression caused by mutation in PAX6 in a South African family.

Purpose: To report on a clinical and genetic investigation of a large, multigenerational South African family of mixed ancestry with autosomal dominant congenital cataracts, coloboma, and nystagmus. Methods: Ophthalmic examination was performed in 27 individuals from the same admixed South African family. DNA was sampled from either peripheral blood or buccal swabs in all 27 individuals, and whole genome sequencing was performed in six individuals. Sanger sequencing was used to validate the probable mutation in the remaining family members. Results: Twenty-seven family members with 19 affected individuals were included in the study. The predominant phenotype, with highly variable expression, was congenital cataract (14 individuals), posterior segment coloboma (17 individuals), and nystagmus (18 individuals). Other features present included high myopia, microcornea, and strabismus. An R208W mutation in PAX6 (dbSNP rs757259413; HGMD CM930572; NM_000280.3:c.622G>A; NP_000271.1:p.Arg208Trp) was identified as being the most probable pathogenic mutation. Cosegregation of the mutation with the phenotype was confirmed in all 27 family members. Conclusions: PAX6 is a highly conserved gene crucial for normal oculogenesis, and although mutations within the gene may cause an array of ocular developmental abnormalities, most are associated with aniridia and aniridia-related ocular defects. The observation that PAX6 aniridia phenotypes are largely associated with nonsense mutations and milder non-aniridia phenotypes with missense mutations suggested that there may be specific genotype-phenotype correlations for the gene. The R208W mutation in PAX6 identified in this family challenges this theory as it has previously been reported in three unrelated families and is associated with aniridia and non-aniridia phenotypes across the four families. PAX6 with its wide phenotypic associations and highly variable expression should be considered a candidate gene in the diagnostic screen for any ocular developmental abnormality.

Anatomical characteristics of the styloid process in internal carotid artery dissection: Case-control study.

Introduction Pathophysiology of cervical artery dissection is complex and poorly understood. In addition to well-known causative and predisposing factors, including major trauma and monogenic connective tissue disorders, morphological characteristics of the styloid process have been recently recognized as a possible risk factor for cervical internal carotid artery dissection. Aims To study the association of the anatomical characteristics of styloid process with internal carotid artery dissection. Methods Retrospective, multicenter, case-control study of patients with internal carotid artery dissection and age- and sex-matched controls. Consecutive patients with internal carotid artery dissection and controls with ischemic stroke or transient ischemic attack of any etiology excluding internal carotid artery dissection, who had performed computed tomography angiography, diagnosed between January 2010 and September 2016. Two independent observers measured styloid process length and styloid process distance to internal carotid artery. Results Sixty-two patients with internal carotid artery dissection and 70 controls were included. Interobserver agreement was good for styloid process length and styloid process-internal carotid artery distance (interclass correlation coefficient = 0.89 and 0.76, respectively). Styloid process ipsilateral to dissection was longer than left and right styloid process in controls (35.8 ± 14.4 mm versus 30.4 ± 8.9 mm and 30.3 ± 8.2 mm, p = 0.011 and p = 0.008, respectively). Styloid process-internal carotid artery distance ipsilateral to dissection was shorter than left and right distance in controls (6.3 ± 1.9 mm versus 7.2 ± 2.1 mm and 7.0 ± 2.3 mm, p = 0.003 and p = 0.026, respectively). Internal carotid artery dissection was associated with styloid process length (odds ratio = 1.04 mm-1, 95% confidence interval = 1.01-1.08, p = 0.015) and styloid process-internal carotid artery distance (OR = 0.77 mm-1, 95% confidence interval = 0.64-0.92, p = 0.004). Conclusion Longer styloid process and shorter distance between styloid process and cervical internal carotid artery are associated with cervical internal carotid artery dissection.

Base resolution maps reveal the importance of 5-hydroxymethylcytosine in a human glioblastoma.

Aberrant genetic and epigenetic variations drive malignant transformation and are hallmarks of cancer. Using PCR-free sample preparation we achieved the first in-depth whole genome (hydroxyl)-methylcytosine, single-base-resolution maps from a glioblastoma tumour/margin sample of a patient. Our data provide new insights into how genetic and epigenetic variations are interrelated. In the tumour, global hypermethylation with a depletion of 5-hydroxymethylcytosine was observed. The majority of single nucleotide variations were identified as cytosine-to-thymine deamination products within CpG context, where cytosine was preferentially methylated in the margin. Notably, we observe that cells neighbouring tumour cells display epigenetic alterations characteristic of the tumour itself although genetically they appear "normal". This shows the potential transfer of epigenetic information between cells that contributes to the intratumour heterogeneity of glioblastoma. Together, our reference (epi)-genome provides a human model system for future studies that aim to explore the link between genetic and epigenetic variations in cancer progression.

Satisfação do acompanhamento do doente adulto que recorre ao serviço de urgência / Satisfaction of the follow-up of the adult patient who resorts to the emergency service

preocupação com a qualidade e com a satisfação tem aumentado exponencialmente nos últimos anos e é, hoje em dia, uma das exigências impostas às instituições de saúde. Paralelamente, o aumento da complexidade das práticas, o maior envolvimento dos doentes e dos seus acompanhantes e, a necessidade de uma melhor integração nos cuidados exigem das instituições maior eficácia e eficiência. Manter continuamente a qualidade e a melhoria requer uma avaliação contínua e uma das estratégias para avaliar a qualidade dos cuidados é conhecer o nível de satisfação, enquanto utilizadores dos serviços de saúde, tendo em conta as experiências e as expectativas dos mesmos. Neste sentido, para identificar a satisfação dos acompanhantes dos doentes adultos que recorrem a um serviço de urgência, foi realizado um estudo misto, do tipo descritivocorrelacional e transversal, numa amostra de 235 acompanhantes de doentes. Esta investigação teve como finalidade contribuir para a implementação de medidas de melhoria contínua do funcionamento e dos serviços de saúde prestados. O objetivo principal foi avaliar o nível de satisfação global, dos acompanhantes do doente adulto que recorre ao Serviço de Urgência, relativamente à sua perceção sobre os cuidados prestados. Para a recolha de dados, foi aplicado um questionário, elaborado com base nos resultados do Sistema de Avaliação da Qualidade Apercebida e da Satisfação dos Utentes de um Hospital ­ QMETRICS (Serviços de Consultadoria, Gestão e Avaliação da Qualidade e da Satisfação, SA). Os resultados obtidos permitiram verificar que, relativamente à satisfação global do serviço prestado, a maioria (86,4%) dos acompanhantes ficaram satisfeitos ou muito satisfeitos. Os itens registados com maior nível de satisfação foram os aspetos gerais, admissão de doentes, tempo de espera para ser atendido na triagem e o desempenho/atendimento do pessoal de saúde. Por outro lado, as áreas apontadas como mais problemáticas foram o tempo de espera na secretaria para efetuar a admissão no hospital, a primeira observação médica, realização e conhecimento dos resultados dos exames/tratamentos. Verificou-se que 86,0% dos acompanhantes referiram que se fosse necessário voltariam ao mesmo hospital e 79,6% aconselhá-lo-iam a um familiar/amigo. Concluiu-se ainda que osacompanhantes expectam que o atendimento no serviço de urgência seja rápido, dotado de profissionalismo humanismo, simpatia, compreensão, e célere no tratamento. O tempo de espera foi a crítica mais apontada, sendo sugerida pelos questionados o seu encurtamento. Verificou-se que as características sociodemográficas não interferem com a satisfação dos acompanhantes dos doentes adultos. Conclui-se quanto maior é a satisfação dos acompanhantes, relativamente aos aspetos gerais do hospital, o conforto e qualidade das instalações, respeito pela privacidade, sinalética, limpeza, triagem, tempos de espera e as visitas, maior é a sua satisfação com os cuidados globais prestados; quanto menos tempo os inquiridos esperam para a triagem e desde a triagem até à primeira observação médica, mais satisfeitos ficam, e quanto mais satisfeitos estão com a qualidade técnica dos profissionais e com as relações interpessoais mais satisfeitos se encontram com os cuidados globais.

he concern for quality and satisfaction has increased exponentially in the recent years and it is today one of the requirements imposed on Health Institutions. At the same time, the increasing complexity of practices, the greater involvement of patients and their companions and the need for a better integration of care require the institutions to be more effective and efficient. In order to maintain continuous quality and improvement continuous assessment is required; and the strategy to assess the quality of care is to learn the level of satisfaction, of users of health services, taking into account their experiences and expectations. Therefore, a mixed study was done in order to identify the level of satisfaction of those who accompany adult patients resorting to the Emergency Unit. This was a descriptivecorrelational and cross-sectional study with a sample of 235 adults accompanying patients. This research aimed to contribute to the implementation of measures for the continuous improvement measures of health care services. The main aim was to evaluate the level of overall satisfaction of those accompanying the adult patient to the Emergency Unit, regarding their perception of the health care provided. For data collection, a questionnaire was applied, which was built in order to present the results of the Perceived Quality Assessment System and the satisfaction of the Hospital Utilizers - QMETRICS, adapted to the population under study and what we sought to obtain from the study. The results obtained showed that, regarding the overall satisfaction of the service, the majority (86.4%) of the adults accompanying patients were satisfied or very satisfied. The items that registered the highest level of satisfaction refer to general aspects, admission of patients, waiting time to be assisted in triage, health personnel performance / assistance. On the other hand, the areas identified as being the most problematic were the waiting period at the secretary's office for hospital admission, the first medical observation, waiting time for undergoing examinations / treatments and waiting for its results. It was verified that 86.0% of the adults accompanying patients said that, if necessary, they would return to the hospital under study and 79.6% would advise it to a family member / friend. It was concluded that the adults accompanying patients expect the services in the Emergency service to be quick, and characterised by professionalism, humanism, sympathy and understanding, and rapid treatment. The waiting period was most criticised aspect and it was suggested by those enquired that it should be shortened. It was verified that the sociodemographic characteristics do not interfere with the level satisfaction of adults who are accompanying adult patients. It was concluded that the greater the satisfaction of the accompanying adult regarding general aspects of the hospital, the comfort and quality of the facilities, the respect for privacy, the signage, hygiene, the triage, the waiting periods and the visits, the greater is his/her satisfaction concerning the global care provided; the less time those enquired wait for triage and until the first medical observation, the more satisfied they will be; and the more satisfied they are with the technical quality of the professionals and with the interpersonal relationships, the more satisfied they are concerning the overall care provided

The genome of a Late Pleistocene human from a Clovis burial site in western Montana.

Clovis, with its distinctive biface, blade and osseous technologies, is the oldest widespread archaeological complex defined in North America, dating from 11,100 to 10,700 (14)C years before present (bp) (13,000 to 12,600 calendar years bp). Nearly 50 years of archaeological research point to the Clovis complex as having developed south of the North American ice sheets from an ancestral technology. However, both the origins and the genetic legacy of the people who manufactured Clovis tools remain under debate. It is generally believed that these people ultimately derived from Asia and were directly related to contemporary Native Americans. An alternative, Solutrean, hypothesis posits that the Clovis predecessors emigrated from southwestern Europe during the Last Glacial Maximum. Here we report the genome sequence of a male infant (Anzick-1) recovered from the Anzick burial site in western Montana. The human bones date to 10,705 ± 35 (14)C years bp (approximately 12,707-12,556 calendar years bp) and were directly associated with Clovis tools. We sequenced the genome to an average depth of 14.4× and show that the gene flow from the Siberian Upper Palaeolithic Mal'ta population into Native American ancestors is also shared by the Anzick-1 individual and thus happened before 12,600 years bp. We also show that the Anzick-1 individual is more closely related to all indigenous American populations than to any other group. Our data are compatible with the hypothesis that Anzick-1 belonged to a population directly ancestral to many contemporary Native Americans. Finally, we find evidence of a deep divergence in Native American populations that predates the Anzick-1 individual.

Identification of a candidate gene for astigmatism.

PURPOSE: Astigmatism is a common refractive error that reduces vision, where the curvature and refractive power of the cornea in one meridian are less than those of the perpendicular axis. It is a complex trait likely to be influenced by both genetic and environmental factors. Twin studies of astigmatism have found approximately 60% of phenotypic variance is explained by genetic factors. This study aimed to identify susceptibility loci for astigmatism. METHODS: We performed a meta-analysis of seven genome-wide association studies that included 22,100 individuals of European descent, where astigmatism was defined as the number of diopters of cylinder prescription, using fixed effect inverse variance-weighted methods. RESULTS: A susceptibility locus was identified with lead single nucleotide polymorphism rs3771395 on chromosome 2p13.3 (meta-analysis, P = 1.97 × 10(-7)) in the VAX2 gene. VAX2 plays an important role in the development of the dorsoventral axis of the eye. Animal studies have shown a gradient in astigmatism along the vertical plane, with corresponding changes in refraction, particularly in the ventral field. CONCLUSIONS: This finding advances the understanding of refractive error, and provides new potential pathways to be evaluated with regard to the development of astigmatism.

Identification of new susceptibility loci for osteoarthritis (arcOGEN): a genome-wide association study.

BACKGROUND: Osteoarthritis is the most common form of arthritis worldwide and is a major cause of pain and disability in elderly people. The health economic burden of osteoarthritis is increasing commensurate with obesity prevalence and longevity. Osteoarthritis has a strong genetic component but the success of previous genetic studies has been restricted due to insufficient sample sizes and phenotype heterogeneity. METHODS: We undertook a large genome-wide association study (GWAS) in 7410 unrelated and retrospectively and prospectively selected patients with severe osteoarthritis in the arcOGEN study, 80% of whom had undergone total joint replacement, and 11,009 unrelated controls from the UK. We replicated the most promising signals in an independent set of up to 7473 cases and 42,938 controls, from studies in Iceland, Estonia, the Netherlands, and the UK. All patients and controls were of European descent. FINDINGS: We identified five genome-wide significant loci (binomial test p≤5·0×10(-8)) for association with osteoarthritis and three loci just below this threshold. The strongest association was on chromosome 3 with rs6976 (odds ratio 1·12 [95% CI 1·08-1·16]; p=7·24×10(-11)), which is in perfect linkage disequilibrium with rs11177. This SNP encodes a missense polymorphism within the nucleostemin-encoding gene GNL3. Levels of nucleostemin were raised in chondrocytes from patients with osteoarthritis in functional studies. Other significant loci were on chromosome 9 close to ASTN2, chromosome 6 between FILIP1 and SENP6, chromosome 12 close to KLHDC5 and PTHLH, and in another region of chromosome 12 close to CHST11. One of the signals close to genome-wide significance was within the FTO gene, which is involved in regulation of bodyweight-a strong risk factor for osteoarthritis. All risk variants were common in frequency and exerted small effects. INTERPRETATION: Our findings provide insight into the genetics of arthritis and identify new pathways that might be amenable to future therapeutic intervention. FUNDING: arcOGEN was funded by a special purpose grant from Arthritis Research UK.

A combined functional annotation score for non-synonymous variants.

AIMS: Next-generation sequencing has opened the possibility of large-scale sequence-based disease association studies. A major challenge in interpreting whole-exome data is predicting which of the discovered variants are deleterious or neutral. To address this question in silico, we have developed a score called Combined Annotation scoRing toOL (CAROL), which combines information from 2 bioinformatics tools: PolyPhen-2 and SIFT, in order to improve the prediction of the effect of non-synonymous coding variants. METHODS: We used a weighted Z method that combines the probabilistic scores of PolyPhen-2 and SIFT. We defined 2 dataset pairs to train and test CAROL using information from the dbSNP: 'HGMD-PUBLIC' and 1000 Genomes Project databases. The training pair comprises a total of 980 positive control (disease-causing) and 4,845 negative control (non-disease-causing) variants. The test pair consists of 1,959 positive and 9,691 negative controls. RESULTS: CAROL has higher predictive power and accuracy for the effect of non-synonymous variants than each individual annotation tool (PolyPhen-2 and SIFT) and benefits from higher coverage. CONCLUSION: The combination of annotation tools can help improve automated prediction of whole-genome/exome non-synonymous variant functional consequences.

Do genome-wide association scans have potential for translation?

The success of genome-wide association studies (GWAS) in identifying replicating associations has greatly contributed to understanding of the genetic aetiology of complex diseases. This review discusses and provides examples of the potential of GWAS findings to be translated into clinical practice, i.e., diagnosis, prediction, prognosis, novel treatments and response to treatment of common diseases. The biological insights afforded by newly-identified robust associations represent the largest, albeit indirect, translational contribution of GWAS.