Epidemiological, clinical, and prognostic analysis of oral squamous cell carcinoma diagnosed and treated in a single hospital in Galicia (Spain): a retrospective study with 5-year follow-up.

BACKGROUND: Oral cancer is a common neoplasm worldwide, mostly corresponding to squamous cell carcinoma (OSCC). Unfortunately, its overall prognosis remains poor, with no improvement in recent decades. In this study, we have analysed the epidemiological, clinical, and prognostic characteristics of OSCC on patients of a specific Spanish region (Galicia), in order to improve its prognosis and apply effective preventive and early diagnosis measures. MATERIAL AND METHODS: We retrospectively analysed 243 cases of OSCC, diagnosed and treated in a single hospital centre in Galicia between 2010 and 2015 (minimum of 5 years of evolution). Overall and specific survival were calculated (Kaplan-Meier) and associated variables were identified (log rank test and Cox regression). RESULTS: The mean age of the patients was 67 years, with the majority being male (69.5%), smokers (45.9%) and alcohol consumers (58.6%), who lived in non-urban areas (79.4%). Cases diagnosed at advanced stages entailed the 48.1% of the sample, and 38.7% of cases relapsed. The 5-year overall and disease-specific survival rates were 39.9% and 46.1%, respectively. Patients who consumed tobacco and alcohol had a worse prognosis. OSCC cases referred to hospital by specialist dentists had a better prognosis, as those who were previously diagnosed with an oral potentially malignant oral disorder (OPMD) or received dental care during OSCC treatment. CONCLUSIONS: In view of these findings, we conclude that OSCC in Galicia (Spain) still has a very poor overall prognosis, which is mainly related to the advanced age of the patients and the late diagnosis. Our study highlights the better survival of OSCC in relation to the referring health professional, the presence of a previous OPMD and the dental care after diagnosis. This demonstrates the importance of dentistry as a health profession involved in the early diagnosis and multidisciplinary management of this malignant neoplasm.

Clinical practice guideline of the spanish society of oral surgery for oral surgery in patients with coagulation disorders.

BACKGROUND: The number of patients treated with coagulation disorders, and more specifically with anticoagulant therapy, has increased worldwide in recent years due to increased life expectancy in developed countries. The protocols for managing this type of patient in oral surgery has varied over recent years, especially after the appearance of new direct-acting oral anticoagulants (DOACs). The assessment of risk of bleeding in this type of patient when undergoing a surgical procedure continues to be a controversial issue for patients, dentists and general practitioners. The objective of this document is to offer recommendations, based on evidence, for decision making for patients with coagulopathies who require dental surgical intervention. MATERIAL AND METHODS: Based on the indications of the "Preparation of Clinical Practice guidelines in the National Health System. Methodological manual", we gathered a group of experts who agreed on 15 PICO questions based on managing patients with coagulation disorders in dental surgical procedures, such as fitting of implants or dental extractions. RESULTS: The 15 PICO questions were answered based on the available evidence, being limited in most cases due to the lack of a control group. Two of the PICO questions were answered by the experts with a grade C recommendation, while the rest were answered with grade D. CONCLUSIONS: The results of this review highlight the need to undertake well designed clinical trials with control groups and with a representative sample size.

Risk assessment for uptake and accumulation of pharmaceuticals by baby leaf lettuce irrigated with reclaimed water under commercial agricultural activities.

The use of reclaimed water to irrigate agricultural crops has increased in recent years as a consequence of water shortage constituting a potential risk for human health. The main objective of this study was to evaluate the impact on the soil-plant system and determining the accumulation of carbamazepine (CBZ), diclofenac (DCF), ketoprofen (KTP) and naproxen (NPX) in the edible part of lettuce under commonly used agricultural practices in commercial production. For this purpose, red oak baby lettuce (Lactuca sativa L.) was irrigated with reclaimed water fortified with different concentrations of pharmaceuticals. The study was carried out in two different scenarios: soil and tray. The tray experiments were conducted with substrate and took place at three different seasons of the year. Lettuce tissue sampled from these experiments were analysed 3 times during the lettuce growing cycle (first, second and third harvest). The practices of first harvest regrowth were also evaluated. For all experiments, CBZ showed the highest accumulation in lettuce leaves of the pharmaceuticals tested, showing a correlation between irrigation exposure time and pharmaceutical uptake. Unexpectedly, DCF was the compound with the highest uptake levels after regrowth practices. Results suggested that pharmaceuticals uptake could be directly associated with the irrigation method and possible accumulation in soil and substrates, while concentration of pharmaceuticals in substrates were 10 times higher. Based on the concentration values detected in lettuce leaves, the risk assessment suggests that no compounds imply any risk to human health, except CBZ for those on vegetarian diets in the tray scenario. Although commercial agricultural practices are usually not considered with regards to risk reduction, in this experiment we demonstrated that climatic conditions are a key factor in pharmaceuticals uptake and different agricultural practices (soil cropping and drip irrigation) can limit the presence of pharmaceutical compounds in crops.

COVID-19 in children and young adults with moderate/severe inborn errors of immunity in a high burden area in pre-vaccine era.

BACKGROUND: Information regarding inborn error of immunity (IEI) as a risk factor for severe COVID-19 is scarce. We aimed to determine if paediatric patients with moderate/severe IEI got COVID-19 at the same level as the general population, and to describe COVID-19 expression. MATERIAL AND METHODS: We included patients with moderate/severe IEI aged 0-21 years old: cross-sectional study (June2020) to determine the prevalence of COVID-19; prospective study (January2020-January2021) including IEI patients with COVID-19. Assays used: nasopharyngeal swab SARS-CoV-2 PCR and SARS-CoV-2-specific immunoglobulins. RESULTS: Seven from sixty-five patients tested positive (prevalence: 10.7% (7%-13%)) after the first SARS-COV-2 wave and 13/15 patients diagnosed with COVID-19 had an asymptomatic/mild course. CONCLUSIONS: In our area, prevalence of COVID-19 in moderate/severe IEI paediatric patients after the first wave was slightly higher than in the general population. The majority of patients presented a benign course, suggesting a possible protective factor related with age despite IEI.

A new morphologic classification of the alveolar ridge after distraction osteogenesis in human patients. A 17 years retrospective case series study.

BACKGROUND: To perform a morphologic classification based on the results of bone augmentation after a distraction osteogenesis. MATERIAL AND METHODS: Thirty-four (34) patients (24 women and 10 men; mean age, 47.1 years (SD=9.5); age range, 23 to 62 years) underwent a total of 42 alveolar ridge distractions before the placement of a total of 89 dental implants. Ridge bone morphology was evaluated as the main ordinal variable. Chi-squared, Kruskal-Wallis and ANOVA one-way test were used. RESULTS: Category I (30.95%): consisted of wide alveolar rim and no bone defects Category II (28.57%): wide alveolar rim, lateral bone surface concavity. Category III (23.81%): narrow alveolar rim, lateral bone surface concavity. Category IV (2.38 %): distraction transport segment forming a bridge, without bone formed beneath and requiring guided bone regeneration. Category V (9.52%): return of the transport segment to its initial position due to the reverse rotation of the distractor screw. Category VI (4.76 %): distraction transport segment completely lost. Subcategory D (28.57%), consisted of lingual deviation of the distraction axis, occurring in any of the categories I to IV. More men (76.9 %) presented with category I (p<0.001). The use of the chisel resulted mainly in categories I and II (69.4 %) (p<0.001). GBR was only required in 23.1 % of the cases in Category I (p=0.011). The bone height achieved decreases as the category increases, due to the accompanying osteogenic limitations (p<0.001). The implants placed in category I were longer 11.5 ± 0.9 mm (CI95% 10.9-11.9 mm) compared to those placed in category III with a length of 10.4 ± 1.5 mm (CI95% 9.5-11.4 mm) (p=0.035). CONCLUSIONS: The alveolar ridge after distraction osteogenesis could be divided into six morphologic categories which provide a useful basis for decision-making regarding implant placement.

Alveolar bone loss, platelet and glycosylated haemoglobin levels in 239 patients. A clinical study.

BACKGROUND: The relation between periodontal disease and systemic pathologies is still not widespread among general practitioners. The aim of our study is to evaluate whether or not periodontal radiological diagnosis can aid the detection of blood alterations associated with acquired systemic diseases. MATERIAL AND METHODS: This is a cross sectional study. All of the participants underwent a panoramic radiograph and a complete blood test. Morphological bone loss was considered as positive in those patients who showed radiographically more than 1 tooth with bone loss greater than or equal to the middle third of the root. The statistical analysis was performed by comparing the variables using the ANOVA or U-Mann-Whitney tests for independent samples with normal conditions. The correlation coefficient was analysed using the Pearson test. RESULTS: 239 patients were included in our study (96 men and 143 women) with an average age of 64.40 years. 59.04% of the patients were determined as morphological bone loss positive and had on average 4 teeth less than negative patients (p <0.0001). Also the average platelet levels in positive patients were lower (p = 0.024) and mean levels of HBA1c (p = 0.009) were higher. CONCLUSIONS: Morphological bone loss parameter can be useful both for dentists and general practitioners to refer, subsequently, to periodontal specialist.

Quality and readability of the dental information obtained by patients on Internet: criteria for selecting medical consultation websites.

BACKGROUND: The main objective of this study is to examine the quality of the information available for patients online with regards to the apicoectomy surgical procedure, both on general and critically selected websites. The hypothesis is that general websites has less quality than other that have been pre-selected. MATERIAL AND METHODS: A search for the English term "apicoectomy" was performed online. The first 100 websites that appeared in both Google and Yahoo were analysed. Seven validated instruments were used for these two dimensions: quality (DISCERN, JAMA and EQIP), and readability (FRES, Fog Scale, FKRGL and SMOG). RESULTS: A total of 21 websites (10.5%) were selected. The readability of the websites in both groups was difficult or very difficult. With regards to the quality of the websites, the DISCERN instrument indicated an average value of 2.28 [2.14-2.39] for all of the websites, therefore indicating very low quality with serious defects; however, in the selected websites, the average quality was 3.16 [2.84-3.48], indicating potential, but not serious defects (p<0.001). There were statistically significant differences for the FRES values (p = 0.030), with a greater readability in the selected group of websites. CONCLUSIONS: We believe that it is very important for the population to become aware of and learn how to use certain exclusion criteria when selecting medical consultation websites, as in doing so, they will be able to obtain a higher quality of information from these websites.

Serotonin inputs to the dorsal BNST modulate anxiety in a 5-HT1A receptor-dependent manner.

Serotonin (5-HT) neurons project from the raphe nuclei throughout the brain where they act to maintain homeostasis. Here, we study 5-HT inputs into the bed nucleus of the stria terminalis (BNST), a major subdivision of the extended amygdala that has been proposed to regulate responses to anxiogenic environments in humans and rodents. While the dorsal part of the BNST (dBNST) receives dense 5-HT innervation, whether and how 5-HT in the dBNST normally modulates anxiety remains unclear. Using optogenetics, we demonstrate that activation of 5-HT terminals in the dBNST reduces anxiety in a highly anxiogenic environment. Further analysis revealed that optogenetic inhibition of 5-HT inputs into the dBNST increases anxiety in a less anxiogenic environment. We found that 5-HT predominantly hyperpolarizes dBNST neurons, reducing their activity in a manner that can be blocked by a 5-HT1A antagonist. Finally, we demonstrate that activation of 5-HT1A receptors in the dBNST is necessary for the anxiolytic effect observed following optogenetic stimulation of 5-HT inputs into the dBNST. These data reveal that 5-HT release in the dBNST modulates anxiety-like behavior via 5-HT1A receptors under naturalistic conditions.

Gene expression profile following an oral unsaturated fat load in abdominal obese subjects.

PURPOSE: Our aim was to evaluate the postprandial effect of an oral fat load test (OFLT) rich in unsaturated fatty acids on gene expression profile in peripheral blood mononuclear cells (PBMC) from subjects with abdominal obesity as an insulin resistance model and controls. METHODS: A total of 20 controls and 20 abdominal obese patients were studied. Metabolic parameters and oxidative stress markers were measured with standardized protocols. The whole gene expression at fasting state and after the OFLT (0, 4 and 8 h) was analysed using human HT-12-v4 expression beadchips, from Illumina. RESULTS: We found a significant decrease in plasma glucose, insulin and oxidative stress markers in abdominal obese patients and controls. We found beneficial metabolic postprandial gene expression in three genes: FKBP5, DDIT4 and DHRS9. Following an OFLT, the postprandial mRNA expression of FKBP5, and DDIT4 was downregulated while that of DHRS9 was overexpressed, both in nondiabetic normolipidemic subjects and in insulin-resistant subjects with abdominal obesity. CONCLUSIONS: Our results suggest that an OFLT rich in unsaturated fatty acids downregulates the expression of FKBP5, coding for the glucocorticoid receptor pathway, and that of DDIT4, involved in the oxidative stress response. These changes could favourably influence the insulin resistance and oxidative stress status in the postprandial state.

Increased phagocytosis and growth inhibition of Encephalitozoon cuniculi by LPS-activated J774A.1 murine macrophages.

Encephalitozoon cuniculi is an obligate macrophage parasite of vertebrates that commonly infects rodents, monkeys, dogs, birds, and humans. In the present study, we aimed to assess the phagocytosis and intracellular survival of E. cuniculi spores using untreated and lipopolysaccharide (LPS)-activated J774A.1 murine macrophages and assess the macrophage viability. The experimental groups comprised untreated spores, spores killed by heat treatment at 90 °C, and spores killed by treatment with 10% formalin. LPS-activated macrophages significantly increased the phagocytosis of spores and reduced their intracellular growth after 24 and 48 h (P < 0.01); however, after 72 h, we observed an increase in spore replication but no detectable microbicidal activity. These results indicate that LPS activation enhanced E. cuniculi phagocytosis between 24 and 48 h of treatment, but the effect was lost after 72 h, enabling parasitic growth. This study contributes to the understanding of the phagocytosis and survival of E. cuniculi in murine macrophages.

Biomarkers to predict the onset of biphosphonate-related osteonecrosis of the jaw: A systematic review.

BACKGROUND: The goal of this paper was to identify available biomarkers to predict the onset of biphosphonate-related osteonecrosis of the jaw (BRONJ). MATERIAL AND METHODS: Case-control studies comparing the different concentrations of a series of molecules detected in serum and urine as matrices of BRONJ affected patients vs. non-affected were included. PRISMA guidelines for systematic reviews were used for the present paper. Two reviewers independently screened electronic databases (Medline, Web of science, and The Cochrane Library) and performed hand searches. Risk of bias assessment of selected studies was performed by the Newcastle-Ottawa Scale. This study is registered as PROSPERO CRD42017078149. RESULTS: From a total of 601 identified studies, 7 (4 articles with high methodological quality and 3 with medium) articles were included. They investigate 2623 patients, of whom 91 (3.47%) developed BRONJ. A total of 7 biomarkers were identified and classified into 3 groups: bone turnover, angiogenesis and endocrine markers. Conflicting results were found in relation to most biomarkers. CONCLUSIONS: The present review suggests that no useful markers are currently available to evaluate BRONJ risk. Nevertheless, the present paper indicates that a paradigm shift from bone turnover biomarkers to angiogenesis and endocrine markers could shed light on this search.

Patient-centered web-based information on oral lichen planus: Quality and readability.

BACKGROUND: To assess the readability and quality of web-based information available for patients about oral lichen planus (OLP). MATERIAL AND METHODS: Three major search engines (Google, Bing and Yahoo!) were used to identify websites of particular interest to the study using the search term 'oral lichen planus'. The first 100 sites of each search engine were considered for the study. The quality of the contents was evaluated using the DISCERN instrument. The Flesch-Kinkaid Reading Grade Level (FKRGL) and the Flesh Reading Ease Score (FRES) were used to assess readability. The presence of the Health on the Net (HON) seal was also evaluated. RESULTS: Following the application of the study's exclusion criteria, only 28 websites were compiled for further analysis. The median of the DISCERN instrument was 3 [2-3] which means serious or potentially important shortcoming in the quality of the information. Readability indexes pointed to a high reading difficulty (FRES: 48.14±11.22; FKRGL:11.13±2.90). CONCLUSIONS: The information provided by the Internet to the general public regarding OLP has major deficits in terms of quality, and at the same time is difficult for a comprehensive reading. Further studies are warranted to test well-produced patient-centered information on OLP.

Management options for low-dose methotrexate-induced oral ulcers: A systematic review.

BACKGROUND: Oral ulcers caused by methotrexate (MTX) at low doses are a known side effect of this drug. Although increasingly more patients are medicated with MTX, these painful ulcers, without traumatic origin and resistant to any type of treatment, are not usually identified by health professionals as a side effect of the medication. MATERIAL AND METHODS: In the absence of a consensus protocol for the effective treatment of oral lesions produced by MTX, the objective of this article was to review and analyse the information from articles related to oral ulcers produced by low-dose MTX and to record the clinical management performed and the MTX dose given to the patient. Data sources - Medline, Web of Science, and Cochrane Library. Participants - Patients treated with low-dose MTX (less than 25 mg/week). Interventions - Management of oral lesions caused by MTX. Study eligibility criterion, study appraisal and synthesis method: An initial search was carried out in the aforementioned databases with the terms 'methotrexate AND oral OR ulcer'. The search was carried out using both medical subject heading (MeSH) terms and a free search between January 2003 and January 2018. Of the results obtained, two independent researchers analysed abstracts that met the search criteria, that is, those that mentioned oral ulcers produced by MTX at low doses. Next, both researchers read the complete article and determined whether it met the following inclusion criteria: written in English, specified the dose of MTX prescribed for the patient and specified the protocol of action for the ulcers. A third investigator acted as a mediator in cases of dispute. Agreement was calculated using Cohen's kappa coefficient, with a k value of 0.82. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guide for systematic reviews was used. RESULTS: The initial search resulted in a total of 66 articles, of which 30 were selected to assess their inclusion in this study. Finally, 16 met the inclusion criteria. Using the Pierson and Newcastle-Ottawa scales and Bradford Hill criteria modified for studies of case series and "in relation to a case", 2 were rated as high quality, 2 were rated as low quality and 12 were rated as medium quality. The limitations of this study are based on the fact that all of the articles available to carry out the systematic review were "in relation to a case or series of cases", with the heterogeneity of data that this implies. CONCLUSIONS: Evidence on the management of oral ulcers in the oral cavity produced by MTX at low doses is scarce due to the heterogeneity of data and the measures adopted in the selected studies. Therefore, it seems that this management is relegated to the perception of the clinician rather than to a specific protocol of action. Studies with a longer follow-up duration and larger sample size are needed to guide different health professionals on the management of these lesions.

20 years of alveolar distraction: A systematic review of the literature.

BACKGROUND: The Vertical Alveolar Distraction Osteogenesis (VADO) technique is an excellent solution for bone and soft tissue neoformation in areas in which there has been significant bone atrophy that hinders normal rehabilitation using dental implants. The goal of this systematic review is to analyze the most relevant articles published on VADO in the literature over the past 20 years. MATERIAL AND METHODS: The review was performed by using the keywords: "alveolar ridge", "distraction ostegenesis" and "dental implant". This search produced a total result of 240 articles. The clinical studies and cases reported in humans amounted to 113 articles, 18 articles referred to studies developed on animals and 33 review articles. The presentation of this systematic analysis follows the criteria described in the PRISMA declaration. RESULTS: 22 articles complied with the inclusion criteria and 7 articles more were added manually, reaching a total sample of 29 studies. Following the analysis of the studies, they were classified into 18 high-quality, 10 mediumquality and 1 low-quality study. Only 4 studies achieved a maximum score of 9 (according to NewCastle Ottawa Scale, NOS). CONCLUSIONS: VADO is a technique with greater potential in vertical gain. The performance of dental implants has a success and survival rate similar to dental implants placed on bones that are not subject to increase techniques.

Survival study of leukoplakia malignant transformation in a region of northern Spain.

BACKGROUND: Oral leukoplakia is the most common potentially malignant disorder (PMD) of the oral cavity. The objectives of this study are to determine the clinicopathologic features in a group of patients with oral leukoplakia of Northern Spain (Galicia), determining the factors associated to clinical risk and analyzing the malignant transformation of these patients. MATERIAL AND METHODS: We included 85 patients. We recorded sex and age, habits like alcohol and tobacco, size, clinical appearance, site, number of lesions, and presence or absence of dysplasia. We assess the association between risk factors and transformation and developed a logistic regression analysis. Finally we used the Kaplan-Meier and log-rank test for the survival analysis. RESULTS: 7 patients (8.2%) had malignant transformation. The mean follow-up of the patients was 4.13 years versus 5.58 years of those who developed carcinoma. Only location and initial dysplasia have a statistically significant relationship with malignant transformation, but when applied the long rank test only the presence of dysplasia remains statistically significant(P<0,026). Oral Cancer Free Survival was 81.9% (0.150) at 11 years for the group without dysplasia. CONCLUSIONS: We found that the presence of dysplasia is the only risk factor that is statistically related to the development of a carcinoma.

Familial seborrhoeic keratosis associated with multiple 'pure reticulated acanthomas' and infundibulocystic basal cell carcinomas.

BACKGROUND: A variety of genodermatoses with multiple cutaneous tumours and germline genetic alterations, such as PTCH1 mutations, have been described. Other cutaneous syndromes have been associated with somatic gene mutations, such as FGFR3 in familial seborrhoeic keratosis. OBJECTIVES: To describe the clinical, dermoscopic and histopathological features of multiple cutaneous lesions, mostly infundibulocystic basal cell carcinomas (ICBCCs) and pure reticulated acanthomas, present in a family affected by familial seborrhoeic keratosis. In addition, we tested for possible germline alterations in FGFR3 and PTCH1. METHODS: Ten members of one family were clinically examined and 92 skin biopsy specimens were evaluated. Blood samples from six individuals were analysed for FGFR3 and PTCH1 germline alterations. We reviewed the literature concerning genetic FGFR3 alterations in seborrhoeic keratosis. RESULTS: Individuals of all generations affected by familial seborrhoeic keratosis also presented other skin tumours that corresponded histologically to reticulated acanthomas without apocrine or sebaceous differentiation, as well as ICBCCs. In addition, two novel germline variants, p.Pro449Ser (c.1345C>T) in FGFR3 and p.Pro725Ser (c.2173C>T) in exon 14 of PTCH1 were identified in five participants. CONCLUSIONS: We characterize for the first time the clinical, dermoscopic and histopathological features of multiple reticulated acanthomas without apocrine or sebaceous differentiation, for which we propose the term 'pure reticulated acanthoma', and ICBCCs associated with familial seborrhoeic keratosis. We identified FGFR3 and PTCH1 germline polymorphisms whose influence in the development of reticulated acanthomas is unknown.

The use of topical corticosteroides in the treatment of oral lichen planus in Spain: A national survey.

BACKGROUND: Explore the treatment of oral lichen planus with topical corticosteroids by the healthcare professionals in Spain. MATERIAL AND METHODS: A questionnaire targeted health professionals who treat OLP, in particular maxillofacial surgeons, dermatologist and dentist. The dissemination of the questionnaires was conducted through professional associations and dental and medical societies. The questionnaire was previously evaluated by means of a cognitive pre-test procedure to ensure that the questions were opportune and appropriate, understandable and accep-table among the professionals. RESULTS: Of the 890 questionnaires sent a total of 190 questionnaires were answered by 90 dentists, 60 dermatologists and 40 by maxillofacial surgeons. The most frequent treatment was 0.1%triamcinolone acetonide in orobase 3 times a day. The effectiveness of the topical corticosteroid treatment was 6.68 (SD= 2.26) in a scale of 1 to 10. The 30% of the dentists and 10.49% of maxillofacial surgeons combined treatment with other drugs. The most frequent one (80%) was nystatin (100,000 IU per millimetre). Dermatologists did not use other treatments in combination with corticosteroids Conclusions: There is a need for national guidelines in treatment for oral lichen planus (treatment criteria, drug, dose, treatment time and method of application of corticosteroid) that can be applied by all professionals who treat this disease.

Nematic liquid crystal reorientation around multi-walled carbon nanotubes mapped via Raman microscopy.

We have studied the formation of topological defects in liquid crystal (LC) matrices induced by multiwalled carbon nanotubes (MWCNTs) and external electric fields. The defects are ascribable to a distortion of the LC molecular director in proximity of the MWCNT surface. The system is analyzed macroscopically using spectroscopic variable angle ellipsometry. Concurrently, confocal micro-Raman spectroscopy is used to study the system state at the microscale. This allows to acquire a three-dimensional, spatially-resolved map of the topological defect, determining scale length variations and orientation topography of the LC molecules around the MWCNT.

Dexketoprofen/tramadol: randomised double-blind trial and confirmation of empirical theory of combination analgesics in acute pain.

BACKGROUND: Combination analgesics are effective in acute pain, and a theoretical framework predicts efficacy for combinations. The combination of dexketoprofen and tramadol is untested, but predicted to be highly effective. METHODS: This was a randomised, double-blind, double-dummy, parallel-group, placebo-controlled, single-dose trial in patients with moderate or severe pain following third molar extraction. There were ten treatment arms, including dexketoprofen trometamol (12.5 mg and 25 mg) and tramadol hydrochloride (37.5 mg and 75 mg), given as four different fixed combinations and single components, with ibuprofen 400 mg as active control as well as a placebo control. The study objective was to evaluate the superior analgesic efficacy and safety of each combination and each single agent versus placebo. The primary outcome was the proportion of patients with at least 50 % max TOTPAR over six hours. RESULTS: 606 patients were randomised and provided at least one post-dose assessment. All combinations were significantly better than placebo. The highest percentage of responders (72%) was achieved in the dexketoprofen trometamol 25 mg plus tramadol hydrochloride 75 mg group (NNT 1.6, 95% confidence interval 1.3 to 2.1). Addition of tramadol to dexketoprofen resulted in greater peak pain relief and greater pain relief over the longer term, particularly at times longer than six hours (median duration of 8.1 h). Adverse events were unremarkable. CONCLUSIONS: Dexketoprofen trometamol 25 mg combined with tramadol hydrochloride 75 mg provided good analgesia with rapid onset and long duration in a model of moderate to severe pain. The results of the dose finding study are consistent with pre-trial calculations based on empirical formulae. TRIAL REGISTRATION: EudraCT (2010-022798-32); Clinicaltrials.gov (NCT01307020).

Efficacy of intravenous thrombolysis according to stroke subtypes: the Madrid Stroke Network data.

OBJECTIVES: To identify possible differences in the early response to intravenous thrombolysis (IVT) or in stroke outcome at 3 months, based on stroke subtype in patients with acute ischaemic stroke (IS). METHODS: Multicentre stroke registry data were used, with prospective inclusion of consecutive patients with acute IVT-treated IS in five acute stroke units. We compared clinical improvement (National Institutes of Health Stroke Scale, NIHSS) at 24 h and at day 7 as well as functional outcome at 3 months (Modified Rankin Scale, mRS) amongst the different stroke subtypes (ICD-10). RESULTS: In total, 1479 patients were included; 178 (12%) had large vessel disease (LVD) with carotid stenosis ≥ 50%, 175 (11.8%) had other LVD, 638 (43%) had cardioembolism, 60 (4.1%) had lacunar infarction, 72 (4.9%) were patients with IS of other/unusual cause and 356 (24.1%) had unknown/multiple causes. Patients with lacunar infarction had lower stroke severity (median NIHSS 6) whilst cardioembolic IS was the most severe (median NIHSS 14) (P < 0.001). No differences in NIHSS improvement were found at 24 h. LVD patients with carotid stenosis (odds ratio 0.544; 95% CI 0.383-0.772; P = 0.001) were less likely to improve at day 7 after adjustment for age, gender, vascular risk factors and stroke severity. However, adjusted multivariate analysis showed no influence of stroke subtype on stroke outcome (mRS) at 3 months. Age, systolic blood pressure on admission and stroke severity were independently associated with mRS > 2 at 3 months. CONCLUSION: Although LVD patients with arterial stenosis ≥ 50% improve less than the other aetiologies at day 7, stroke aetiological subtype does not determine differences in IS outcome at 3 months after IVT.