A Genome-Wide Association Study of Upper Aerodigestive Tract Cancers Conducted within the INHANCE Consortium

Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in susceptibility to etiologically complex disease. We conducted a GWAS to identify common genetic variation involved in susceptibility to upper aero-digestive tract (UADT) cancers. Genome-wide genotyping was carried out using the Illumina HumanHap300 beadchips in 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls. The 19 top-ranked variants were investigated further in an additional 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies participating in the INHANCE consortium. Five common variants presented evidence for significant association in the combined analysis (p≤5×10−7). Two novel variants were identified, a 4q21 variant (rs1494961, p = 1×10−8) located near DNA repair related genes HEL308 and FAM175A (or Abraxas) and a 12q24 variant (rs4767364, p = 2×10−8) located in an extended linkage disequilibrium region that contains multiple genes including the aldehyde dehydrogenase 2 (ALDH2) gene. Three remaining variants are located in the ADH gene cluster and were identified previously in a candidate gene study involving some of these samples. The association between these three variants and UADT cancers was independently replicated in 5,092 UADT cancer cases and 6,794 controls non-overlapping samples presented here (rs1573496-ADH7, p = 5×10−8; rs1229984-ADH1B, p = 7×10−9; and rs698-ADH1C, p = 0.02). These results implicate two variants at 4q21 and 12q24 and further highlight three ADH variants in UADT cancer susceptibility.

Variability of indication criteria in knee and hip replacement: an observational study

BACKGROUND. Total knee (TKR) and hip (THR) replacement (arthroplasty) are effective surgical procedures that relieve pain, improve patients' quality of life and increase functional capacity. Studies on variations in medical practice usually place the indications for performing these procedures to be highly variable, because surgeons appear to follow different criteria when recommending surgery in patients with different severity levels. We therefore proposed a study to evaluate inter-hospital variability in arthroplasty indication. METHODS. The pre-surgical condition of 1603 patients included was compared by their personal characteristics, clinical situation and self-perceived health status. Patients were asked to complete two health-related quality of life questionnaires: the generic SF-12 (Short Form) and the specific WOMAC (Western Ontario and Mcmaster Universities) scale. The type of patient undergoing primary arthroplasty was similar in the 15 different hospitals evaluated.The variability in baseline WOMAC score between hospitals in THR and TKR indication was described by range, mean and standard deviation (SD), mean and standard deviation weighted by the number of procedures at each hospital, high/low ratio or extremal quotient (EQ5-95), variation coefficient (CV5-95) and weighted variation coefficient (WCV5-95) for 5-95 percentile range. The variability in subjective and objective signs was evaluated using median, range and WCV5-95. The appropriateness of the procedures performed was calculated using a specific threshold proposed by Quintana et al for assessing pain and functional capacity. RESULTS. The variability expressed as WCV5-95 was very low, between 0.05 and 0.11 for all three dimensions on WOMAC scale for both types of procedure in all participating hospitals. The variability in the physical and mental SF-12 components was very low for both types of procedure (0.08 and 0.07 for hip and 0.03 and 0.07 for knee surgery patients). However, a moderate-high variability was detected in subjective-objective signs. Among all the surgeries performed, approximately a quarter of them could be considered to be inappropriate. CONCLUSIONS. A greater inter-hospital variability was observed for objective than for subjective signs for both procedures, suggesting that the differences in clinical criteria followed by surgeons when indicating arthroplasty are the main responsible factors for the variation in surgery rates.

Dapagliflozina

Dapagliflozin is a new oral antidiabetic agent whose mechanism of action increases renal glucose excretion, independently of insulin secretion or insulin action. The efficacy of dapagliflozin is dependent on renal function. The use of dapagliflozin has been licensed to improve glycaemic control in patients with type 2 diabetes mellitus as: - monotherapy when diet and exercise alone do not provide adequate glycaemic control in patients for whom the use of metformin is considered inappropriate due to intolerance. - Add-on combination therapy with other glucose-lowering agents including insulin, when these, together with diet and exercise, do not provide adequate glycaemic control. Funding has been restricted to the use of dapagliflozin, prior approval, as dual therapy in combination with metformin. This report aims to assess the efficacy and safety of dapagliflozin in the treatment of type 2 diabetes mellitus, rate the added therapeutic value of dapagliflozin in type 2 diabetes mellitus and identify its current place in therapy. A systematic literature search was carried out, for the purpose of this evaluation, using PubMed, Embase, Cochrane and IDIS databases as well as other secondary sources of evidence-based medicine, therapeutic bulletins and national and international drug agencies. Following the critical reading and analysis of the selected articles, a summary is made out of the scientific evidence available, using Scottish Intercollegiate Guidelines Network (SIGN) criteria. Only one randomised clinical trial, out of the ten trials found, was considered to be a suitable comparison (versus a dual therapy in combination with the sulfonylurea glipizide in patients inadequately controlled with metformin, diet and exercise). No trials have evaluated variables of relevance to patients, except for safety variables. The main efficacy variable in the trials was the change from baseline in HbA1c, except for a study which evaluated the change from baseline in total body weight as main variable. Baseline characteristics of the patients enrolled in the trials significantly differ from those of the population with diabetes in our society which tend to be of an older age and have a longer history of type 2 diabetes mellitus. The major limitation of dapagliflozin derives from its mechanism of action, since its efficacy decreases as renal function declines. The use of dapagliflozin is not recommended in patients with moderate to severe renal impairment ((CrCl<60ml/min or GFG <60 ml/min/1.73 m2) nor in elderly patients, in which a decrease in renal function can be expected. The assessment of safety includes the incidence and rate of discontinuations due to adverse events, episodes of hypoglycaemia, signs or symptoms of genital and urinary tract infections, dehydration, hypovolaemia and hypotension. Further pharmacoepidemiological studies are to be carried out to clarify the long-term effects of dapagliflozin on renal function and the potential effect in the development of breast and bladder tumours. Dapagliflozin as monotherapy has not been evaluated against adequate comparators (sulfonylureas, pioglitazone, gliptins). In combination therapy with metformin, the efficacy of dapagliflozin was shown to be non-inferior to glipizide plus metformin, resulting in a mean reduction of 0.52% in HbA1c, with a difference of 0.00 among both groups (95% CI: -0.11 a 0.11). There are no comparative data against other second-line treatment options. As shown in the studies, the overall incidence of adverse events with dapagliflozin as monotherapy (21.5%) was similar to that observed with placebo, and greater to that observed with metformin (15.4%). Hypoglycaemia of any type was the adverse event more frequently reported. The incidence of severe hypoglycaemic events observed in most of the studies was low. The overall incidence of adverse events observed in the study that compared dapagliflozin+metformin against glipizide+metformin was similar for both groups (27%) and incidence of hypoglycaemic events with dapagliflozin (3.5%) was significantly lower to that observed with glipizide (40.8%). Reductions of body weight of about 2 to 3 kg and a slight decrease in blood pressure (1 to 5 mmHg) have been observed in all studies in the groups treated with dapagliflozin together with diet and exercise. Dosing scheme (every 24 hours) is similar to other oral antidiabetic agents and its cost is similar to that for gliptines and higher to that for sulfonylureas or generic pioglitazone. Funding has been limited to the use of dapagliflozin as dual therapy regimen in combination with metformin as an option for patients with contraindication or intolerance to sulfonylureas, such a those experiencing frequent hypoglycaemic events, weight loss associated risks, as long as they are under 75 years of age and have no moderate to severe renal impairment. In the light of the above, we consider dapagliflozin means no therapeutic innovation in the therapy of type 2 diabetes mellitus over other therapeutic alternatives available.

A combined analysis of the short-term effects of photochemical air pollutants on mortality within the EMECAM project.

In recent years, some epidemiologic studies have attributed adverse effects of air pollutants on health not only to particles and sulfur dioxide but also to photochemical air pollutants (nitrogen dioxide and ozone). The effects are usually small, leading to some inconsistencies in the results of the studies. Furthermore, the different methodologic approaches of the studies used has made it difficult to derive generic conclusions. We provide here a quantitative summary of the short-term effects of photochemical air pollutants on mortality in seven Spanish cities involved in the EMECAM project, using generalized additive models from analyses of single and multiple pollutants. Nitrogen dioxide and ozone data were provided by seven EMECAM cities (Barcelona, Gijón, Huelva, Madrid, Oviedo, Seville, and Valencia). Mortality indicators included daily total mortality from all causes excluding external causes, daily cardiovascular mortality, and daily respiratory mortality. Individual estimates, obtained from city-specific generalized additive Poisson autoregressive models, were combined by means of fixed effects models and, if significant heterogeneity among local estimates was found, also by random effects models. Significant positive associations were found between daily mortality (all causes and cardiovascular) and NO(2), once the rest of air pollutants were taken into account. A 10 microg/m(3) increase in the 24-hr average 1-day NO(2)level was associated with an increase in the daily number of deaths of 0.43% [95% confidence interval (CI), -0.003-0.86%] for all causes excluding external. In the case of significant relationships, relative risks for cause-specific mortality were nearly twice as much as that for total mortality for all the photochemical pollutants. Ozone was independently related only to cardiovascular daily mortality. No independent statistically significant relationship between photochemical air pollutants and respiratory mortality was found. The results in this study suggest that, given the present levels of photochemical pollutants, people living in Spanish cities are exposed to health risks derived from air pollution.

Colorectal Cancer Classification and Cell Heterogeneity: A Systems Oncology Approach.

Colorectal cancer is a heterogeneous disease that manifests through diverse clinical scenarios. During many years, our knowledge about the variability of colorectal tumors was limited to the histopathological analysis from which generic classifications associated with different clinical expectations are derived. However, currently we are beginning to understand that under the intense pathological and clinical variability of these tumors there underlies strong genetic and biological heterogeneity. Thus, with the increasing available information of inter-tumor and intra-tumor heterogeneity, the classical pathological approach is being displaced in favor of novel molecular classifications. In the present article, we summarize the most relevant proposals of molecular classifications obtained from the analysis of colorectal tumors using powerful high throughput techniques and devices. We also discuss the role that cancer systems biology may play in the integration and interpretation of the high amount of data generated and the challenges to be addressed in the future development of precision oncology. In addition, we review the current state of implementation of these novel tools in the pathological laboratory and in clinical practice.

Disentangling the attention network test: behavioral, event related potentials, and neural source analyses.

BACKGROUND The study of the attentional system remains a challenge for current neuroscience. The "Attention Network Test" (ANT) was designed to study simultaneously three different attentional networks (alerting, orienting, and executive) based in subtraction of different experimental conditions. However, some studies recommend caution with these calculations due to the interactions between the attentional networks. In particular, it is highly relevant that several interpretations about attentional impairment have arisen from these calculations in diverse pathologies. Event related potentials (ERPs) and neural source analysis can be applied to disentangle the relationships between these attentional networks not specifically shown by behavioral measures. RESULTS This study shows that there is a basic level of alerting (tonic alerting) in the no cue (NC) condition, represented by a slow negative trend in the ERP trace prior to the onset of the target stimuli. A progressive increase in the CNV amplitude related to the amount of information provided by the cue conditions is also shown. Neural source analysis reveals specific modulations of the CNV related to a task-related expectancy presented in the NC condition; a late modulation triggered by the central cue (CC) condition and probably representing a generic motor preparation; and an early and late modulation for spatial cue (SC) condition suggesting specific motor and sensory preactivation. Finally, the first component in the information processing of the target stimuli modulated by the interaction between orienting network and the executive system can be represented by N1. CONCLUSIONS The ANT is useful as a paradigm to study specific attentional mechanisms and their interactions. However, calculation of network effects is based in subtractions with non-comparable experimental conditions, as evidenced by the present data, which can induce misinterpretations in the study of the attentional capacity in human subjects.

Cuestiones controvertidas en evaluación económica (II): medidas de resultado en salud de las intervenciones sanitarias

In this second article of a series of three, we will discuss using the Metaplan technique on controversial issues of health outcomes in economic evaluation of health care interventions. The four-discussion areas focus on: choice of health outcomes measures, where any outcome measure is superior to another; extrapolation and transferability of health outcomes measures, which should not be assumed the results of an EEIS of one country to another without making certain adjustments; appropriate instruments to measure quality of life in Spain, where the EQ-5D was indicated as convenient due to its widespread international use; and, indirect comparisons, where the combination of both comparisons, direct and indirect, it would be advisable if the test for indirect estimates is consistent and has been validated. Finally, research lines to try to overcome the identified discrepancies were identified in each of these areas, some of those are: doing studies of correlation between scores of specific and generic instruments measuring quality of life; update or create a database of economic evaluations in Spain; estimating utilities for the Spanish population by existing generic and specific instruments; or, establish a common way to show the results of a meta-analysis network.