One Step Ahead: Herpesviruses Light the Way to Understanding Interferon-Stimulated Genes (ISGs).

The host immune system is engaged in a constant battle with microorganisms, with the immediate detection of pathogenic invasion and subsequent signalling acting as crucial deterrents against the establishment of a successful infection. For this purpose, cells are equipped with a variety of sensors called pattern recognition receptors (PRR), which rapidly detect intruders leading to the expression of antiviral type I interferons (IFN). Type I IFN are crucial cytokines which exert their biological effects through the induction of hundreds of IFN-stimulated genes (ISGs). The expression profile of these ISGs varies depending on the virus. For a small subset of ISGs, their anti- or even proviral effects have been revealed, however, the vast majority are uncharacterised. The spotlight is now on herpesviruses, with their large coding capacity and long co-evolution with their hosts, as a key to understanding the impact of ISGs during viral infection. Studies are emerging which have identified multiple herpesviral antagonists specifically targeting ISGs, hinting at the significant role these proteins must play in host defence against viral infection, with the promise of more to come. In this review, we will discuss the current knowledge of the complex interplay between ISGs and human herpesviruses: the antiviral role of selected ISGs during herpesviral infections, how herpesviruses antagonise these ISGs and, in some cases, even exploit them to benefit viral infection.

Fractures in patients with poliomyelitis: Past or current challenge?

Fractures in poliomyelitic limbs are a challenge to surgeons, due to polio's sequelae and morphological disorders, which make conventional osteosynthesis difficult. We present a retrospective study of 62 patients and 73 non-simultaneous fractures in their lower limbs. Average age was 61,7 years and 53,2% were females. We analyzed the preinjury functional level, etiology of the fracture, fracture pattern, treatment used (be conservative or surgical), and implant used in surgical cases. We treated 85,1% of them surgically and 37,9% of them maintained the same functional situation as before the fracture. 55,4% of them experienced the need to add some mechanical aids after the lesion and 6,8% lost the ability to walk. Most of the surgical treatments employed were similar as the ones used in non-poliomyelitic patients, although some cases required atypical implants, such as a Multiloc (® DePuy Synthes) humeral nail for a tibial shaft fracture, due to narrow bone. Mortality along the 1st year was 2.7%. We found similar functional and radiological results as those described in non-poliomyelitic limbs.

LOXL2-mediated H3K4 oxidation reduces chromatin accessibility in triple-negative breast cancer cells.

Oxidation of H3 at lysine 4 (H3K4ox) by lysyl oxidase-like 2 (LOXL2) generates an H3 modification with an unknown physiological function. We find that LOXL2 and H3K4ox are higher in triple-negative breast cancer (TNBC) cell lines and patient-derived xenografts (PDXs) than those from other breast cancer subtypes. ChIP-seq revealed that H3K4ox is located primarily in heterochromatin, where it is involved in chromatin compaction. Knocking down LOXL2 reduces H3K4ox levels and causes chromatin decompaction, resulting in a sustained activation of the DNA damage response (DDR) and increased susceptibility to anticancer agents. This critical role that LOXL2 and oxidized H3 play in chromatin compaction and DDR suggests that functionally targeting LOXL2 could be a way to sensitize TNBC cells to conventional therapy.

Postoperative radiotherapy provides better local control and long-term outcome in selective cases of cutaneous squamous cell carcinoma with perineural invasion.

BACKGROUND: Perineural invasion (PNI) is a feature of poor prognosis in cutaneous squamous cell carcinoma (CSCC). The benefit of postoperative radiotherapy (PORT) in the management of CSCC with PNI is still not well established. OBJECTIVES: We aimed to evaluate the usefulness of PORT in the treatment of CSCC with PNI so as to determine which patients would best benefit from this type of treatment. METHODS: A retrospective multicenter cohort of 110 CSCCs with PNI was evaluated. Eighteen recurrent cases were excluded for subsequent analysis. We searched for the types of PNI associated with poor outcome and analysed the effectiveness of PORT on different groups of CSCC with PNI. We also assessed for the usefulness of PORT depending on the surgical margin status (either clear or positive). RESULTS: Postoperative radiotherapy showed clear benefit over observation in CSCC with PNI and positive margins after surgery, where the management by observation increased the risk of poor outcome events 2.43 times (P = 0.025), and especially in those with positive margins and PNI ≥0.1 mm, where the risk of poor prognosis is eight times greater following a management by observation (P = 0.0065). Multivariate competing risk analysis preserved statistical significance. CONCLUSIONS: The use of PORT on patients with CSCC with PNI and positive margins after surgery, especially in PNI ≥0.1 mm, significantly improves long-term outcome. The benefit of PORT in cases with clear margins is not as evident, especially in those with PNI of small-calibre nerves. Clinical trials are imperative.

Genome Wide Meta-Analysis identifies common genetic signatures shared by heart function and Alzheimer's disease.

Echocardiography has become an indispensable tool for the study of heart performance, improving the monitoring of individuals with cardiac diseases. Diverse genetic factors associated with echocardiographic measures have been previously reported. The impact of several apoptotic genes in heart development identified in experimental models prompted us to assess their potential association with human cardiac function. This study aimed at investigating the possible association of variants of apoptotic genes with echocardiographic traits and to identify new genetic markers associated with cardiac function. Genome wide data from different studies were obtained from public repositories. After quality control and imputation, a meta-analysis of individual association study results was performed. Our results confirmed the role of caspases and other apoptosis related genes with cardiac phenotypes. Moreover, enrichment analysis showed an over-representation of genes, including some apoptotic regulators, associated with Alzheimer's disease. We further explored this unexpected observation which was confirmed by genetic correlation analyses. Our findings show the association of apoptotic gene variants with echocardiographic indicators of heart function and reveal a novel potential genetic link between echocardiographic measures in healthy populations and cognitive decline later on in life. These findings may have important implications for preventative strategies combating Alzheimer's disease.

Hematomas subcutáneos a tensión por anticoagulantes en ancianos: ¿más morbimortalidad precoz que las fracturas de cadera? / Tension subcutaneous haematomas associated with anticoagulants in the elderly: Do they have earlier morbidity and mortality than hip fractures?

Introducción: Las complicaciones del tratamiento con fármacos anticoagulantes han sido ampliamente descritas, si bien los hematomas a tensión en extremidades se consideran en muchos casos patologías banales. Material y método: Estudio descriptivo retrospectivo entre 2014 y 2017, incluyendo a pacientes con hematomas tras un mínimo traumatismo en extremidades por anticoagulantes intervenidos por Traumatología. Resultados: Se incluyó a 32 pacientes; el 81% eran mujeres, con una edad media de 83,56 años e ICCa de 5,97. La localización anatómica de los hematomas fue: el 65,6% en pierna/pie, el 15,6% en muslo/glúteo y el 18,8% en miembro superior. El 78,13% consumía acenocumarol, el 15,63% HBPM y el 3,13% NACO, siendo el 59,38% de los casos por FA, el 15,63% por valvulopatías/prótesis valvulares y el 12,5% por TEP/TVP. El tiempo medio desde el diagnóstico al drenaje quirúrgico fue de 2,66 días, principalmente por alteraciones de la coagulación. Un 46,88% fueron reintervenidos para nuevo drenaje, cura o cobertura del defecto cutáneo y 3 pacientes precisaron embolización. Fue necesaria la valoración por otras especialidades en el 78,1%. La estancia media fue de 22,34 días y la tasa de mortalidad intrahospitalaria del 9,38%. Conclusión: Los hematomas a tensión por anticoagulantes en extremidades acontecen en pacientes pluripatológicos y ancianos frágiles. Habitualmente el drenaje quirúrgico se retrasa por multitud de factores, lo que conlleva defectos cutáneos amplios que requieren reintervenciones y estancias hospitalarias prolongadas que se asocian a complicaciones médicas. En nuestro estudio, los datos de estancia media y tasa de mortalidad son superiores a los de las fracturas de cadera, por lo que no debemos subestimar esta patología

Introduction: Complications related to anticoagulant therapy have been widely described, although tension haematomas in the extremities are frequently undervalued, and commonly considered banal pathologies. Material and method: Retrospective descriptive study between 2014 and 2017, including patients with limb haematomas after minimal trauma related with anticoagulant therapy, and surgically treated by Traumatology. Results: 32 cases were eventually included, 81% were women, average age of 83.56 years, and a mean aCCI of 5.97. Anatomical location of haematomas was 65.6% in leg/foot, 15.6% in thigh/buttock, and 18.8% in the upper limb. Seventy-eight point thirteen percent received acenocoumarol, 15.63% LMWH, and 3.13% NOACs. Of the cases, 59.38% were due to AF, 15.63% to valvular heart disease/valve prosthesis, and 12.5% to PE/DVT. The mean time from diagnosis to surgical drainage was 2.66 days, mainly as a result of alterations in coagulation parameters. Forty-six point eighty-eight percent were reoperated for new drainage, cure or skin defect coverage, and 3 patients required embolisation. Of the patients, 78% needed consultation with other specialties. The average length of stay was 22.34 days, and the in-hospital mortality rate was 9.38%. Conclusion: Tension haematomas in the extremities associated with anticoagulants occur in patients with multiple comorbidities that make them vulnerable. Surgical drainage is usually delayed by numerous factors which lead to skin defects that require further surgical operations, and prolonged hospital stays that are associated with medical complications. In our study, the average length of stay and in-hospital mortality rate were higher than those for hip fractures, so we should not underestimate this pathology

Tension subcutaneous haematomas associated with anticoagulants in the elderly: Do they have earlier morbidity and mortality than hip fractures? / Hematomas subcutáneos a tensión por anticoagulantes en ancianos: ¿más morbimortalidad precoz que las fracturas de cadera?

INTRODUCTION: Complications related to anticoagulant therapy have been widely described, although tension haematomas in the extremities are frequently undervalued, and commonly considered banal pathologies. MATERIAL AND METHOD: Retrospective descriptive study between 2014 and 2017, including patients with limb haematomas after minimal trauma related with anticoagulant therapy, and surgically treated by Traumatology. RESULTS: 32 cases were eventually included, 81% were women, average age of 83.56 years, and a mean aCCI of 5.97. Anatomical location of haematomas was 65.6% in leg/foot, 15.6% in thigh/buttock, and 18.8% in the upper limb. Seventy-eight point thirteen percent received acenocoumarol, 15.63% LMWH, and 3.13% NOACs. Of the cases, 59.38% were due to AF, 15.63% to valvular heart disease/valve prosthesis, and 12.5% to PE/DVT. The mean time from diagnosis to surgical drainage was 2.66 days, mainly as a result of alterations in coagulation parameters. Forty-six point eighty-eight percent were reoperated for new drainage, cure or skin defect coverage, and 3 patients required embolisation. Of the patients, 78% needed consultation with other specialties. The average length of stay was 22.34 days, and the in-hospital mortality rate was 9.38%. CONCLUSION: Tension haematomas in the extremities associated with anticoagulants occur in patients with multiple comorbidities that make them vulnerable. Surgical drainage is usually delayed by numerous factors which lead to skin defects that require further surgical operations, and prolonged hospital stays that are associated with medical complications. In our study, the average length of stay and in-hospital mortality rate were higher than those for hip fractures, so we should not underestimate this pathology.

Liberal red blood cell transfusions impair quality of life after cardiac surgery / La transfusión liberal de concentrado de hematíes deteriora la calidad de vida después de la cirugía cardíaca

Background: The optimal blood management after cardiac surgery remains controversial. Moreover, blood transfusions may have an impact on long-term outcomes. Objective: The aim of this study is to characterize the impact of liberal red blood cell transfusions on Health-Related Quality of life (HRQoL) after cardiac surgery. Methods: We studied a cohort of 205 consecutive patients after ICU discharge. Baseline characteristics and clinical data were recorded, and HRQoL was assessed using the EuroQoL-5D instrument, applied 6 months after ICU discharge. A specific question regarding the improvement in the quality of life after the surgical intervention was added to the HRQoL questionnaire. Risk factors related to impaired quality of life were identified using univariate comparisons and multivariate regression techniques. Results: The median (interquartile range, IQR) of transfused red blood cells was 3 (1-4). Among 205 patients, 178 were studied 6 months after discharge. Impairment in at least one dimension of the EuroQoL-5D questionnaire was observed in 120 patients, with an overall score of 0.8 (IQR 0.61-1). The number of red blood cell transfusions was related to an impaired HRQoL (OR 1.17 per additional unit, 95% confidence interval 1.03-1.36, p=0.03), a trend to lower visual analog scale score (coefficient −0.75 per additional unit, 95% confidence interval −1.61 to 0.1, p=0.09) and an absence of improvement in HRQoL after surgery compared to the previous status (OR 1.13, 95% confidence interval 1.03-1.25, p=0.01). Conclusions: Liberal red blood cell transfusions increase the risk of impaired HRQoL after cardiac surgery

Antecedentes: El manejo óptimo de la sangre después de cirugía cardíaca sigue siendo controvertido. Objetivo: Analizar el impacto de la transfusión liberal de concentrado de hematíes (CdH) sobre la calidad de vida relacionada con la salud (CVRS) después de la cirugía cardíaca. Métodos: Se estudió una cohorte de 205 pacientes consecutivos. Se registraron las características basales y los datos clínicos, y se evaluó la CVRS utilizando el EuroQoL-5D, 6 meses después del alta de la UCI. Se añadió una pregunta específica sobre la mejoría de la CVRS tras la cirugía cardiaca. Los factores de riesgo relacionados con la alteración de la CVRS se identificaron mediante el uso de comparaciones univariadas y técnicas de regresión multivariante. Resultados: La mediana (rango intercuartílico [IQR]) de los CdH transfundidos fue de 3 (1-4). De 205 pacientes, 178 fueron estudiados 6 meses después del alta, 120 pacientes (67%) mostraron deficiencias en alguna dimensión del cuestionario EuroQoL-5D, con un puntaje general de 0,8 (IQR: 0,61-1). El número de transfusiones de CdH se relacionó con una CVRS deteriorada (OR: 1,17 por unidad adicional; intervalo de confianza del 95%: 1,03-1,36; p=0,03), menor escala analógica visual (coeficiente: −0,75 por unidad adicional, intervalo de confianza del 95%: −1,61-0,1; p=0,09) y una ausencia de mejoría en la CVRS después de la cirugía en comparación con el estado previo (OR: 1,13; intervalo de confianza del 95%: 1,03-1,25; p=0,01). Conclusión: La transfusión liberal de CdH aumenta el riesgo de deterioro de la CVRS después de la cirugía cardíaca

Liberal red blood cell transfusions impair quality of life after cardiac surgery.

BACKGROUND: The optimal blood management after cardiac surgery remains controversial. Moreover, blood transfusions may have an impact on long-term outcomes. OBJECTIVE: The aim of this study is to characterize the impact of liberal red blood cell transfusions on Health-Related Quality of life (HRQoL) after cardiac surgery. METHODS: We studied a cohort of 205 consecutive patients after ICU discharge. Baseline characteristics and clinical data were recorded, and HRQoL was assessed using the EuroQoL-5D instrument, applied 6 months after ICU discharge. A specific question regarding the improvement in the quality of life after the surgical intervention was added to the HRQoL questionnaire. Risk factors related to impaired quality of life were identified using univariate comparisons and multivariate regression techniques. RESULTS: The median (interquartile range, IQR) of transfused red blood cells was 3 (1-4). Among 205 patients, 178 were studied 6 months after discharge. Impairment in at least one dimension of the EuroQoL-5D questionnaire was observed in 120 patients, with an overall score of 0.8 (IQR 0.61-1). The number of red blood cell transfusions was related to an impaired HRQoL (OR 1.17 per additional unit, 95% confidence interval 1.03-1.36, p=0.03), a trend to lower visual analog scale score (coefficient -0.75 per additional unit, 95% confidence interval -1.61 to 0.1, p=0.09) and an absence of improvement in HRQoL after surgery compared to the previous status (OR 1.13, 95% confidence interval 1.03-1.25, p=0.01). CONCLUSIONS: Liberal red blood cell transfusions increase the risk of impaired HRQoL after cardiac surgery.

A framework to rank genomic alterations as targets for cancer precision medicine: the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT).

Background: In order to facilitate implementation of precision medicine in clinical management of cancer, there is a need to harmonise and standardise the reporting and interpretation of clinically relevant genomics data. Methods: The European Society for Medical Oncology (ESMO) Translational Research and Precision Medicine Working Group (TR and PM WG) launched a collaborative project to propose a classification system for molecular aberrations based on the evidence available supporting their value as clinical targets. A group of experts from several institutions was assembled to review available evidence, reach a consensus on grading criteria and present a classification system. This was then reviewed, amended and finally approved by the ESMO TR and PM WG and the ESMO leadership. Results: This first version of the ESMO Scale of Clinical Actionability for molecular Targets (ESCAT) defines six levels of clinical evidence for molecular targets according to the implications for patient management: tier I, targets ready for implementation in routine clinical decisions; tier II, investigational targets that likely define a patient population that benefits from a targeted drug but additional data are needed; tier III, clinical benefit previously demonstrated in other tumour types or for similar molecular targets; tier IV, preclinical evidence of actionability; tier V, evidence supporting co-targeting approaches; and tier X, lack of evidence for actionability. Conclusions: The ESCAT defines clinical evidence-based criteria to prioritise genomic alterations as markers to select patients for targeted therapies. This classification system aims to offer a common language for all the relevant stakeholders in cancer medicine and drug development.

Frequency and clinical impact of CDKN2A/ARF/CDKN2B gene deletions as assessed by in-depth genetic analyses in adult T cell acute lymphoblastic leukemia.

Recurrent deletions of the CDKN2A/ARF/CDKN2B genes encoded at chromosome 9p21 have been described in both pediatric and adult acute lymphoblastic leukemia (ALL), but their prognostic value remains controversial, with limited data on adult T-ALL. Here, we investigated the presence of homozygous and heterozygous deletions of the CDKN2A/ARF and CDKN2B genes in 64 adult T-ALL patients enrolled in two consecutive trials from the Spanish PETHEMA group. Alterations in CDKN2A/ARF/CDKN2B were detected in 35/64 patients (55%). Most of them consisted of 9p21 losses involving homozygous deletions of the CDKNA/ARF gene (26/64), as confirmed by single nucleotide polymorphism (SNP) arrays and interphase fluorescence in situ hybridization (iFISH). Deletions involving the CDKN2A/ARF/CDKN2B locus correlated with a higher frequency of cortical T cell phenotype and a better clearance of minimal residual disease (MRD) after induction therapy. Moreover, the combination of an altered copy-number-value (CNV) involving the CDKN2A/ARF/CDKN2B gene locus and undetectable MRD (≤ 0.01%) values allowed the identification of a subset of T-ALL with better overall survival in the absence of hematopoietic stem cell transplantation.

[Surgical treatment of malignant primary tumors of the pelvis on Ennekings zone II]. / Tratamiento quirúrgico de los tumores primarios malignos de pelvis de la zona II de Enneking.

INTRODUCTION: Surgical treatment of malignant bone tumors of the pelvis with periacetabular involvement is constantly evolving. Even though acetabular reconstructions improve quality of life without impairing cancer control, they are not complication free. Our purpose is to describe the functional outcomes and surgical complications of different reconstructive techniques for Enneking zone II tumors. MATERIAL AND METHODS: Fifteen patients underwent surgery for malignant pelvic bone tumors between 2002 and 2012. Seven patients were retrospectively evaluated according to the Enneking and Dunham classification and were found to have periacetabular involvement, as follows: 3 were type II; 1 types I + II; 2 types II + III, and one types I + II + III. Five patients had a standard chondrosarcoma and 2 osteosarcoma. Patients included 4 males and 3 females; mean age was 43 years. The minimum follow-up period was 12 months (mean 6.14 years). All of them underwent cancer resection with periacetabular reconstruction: massive osteochondral allograft in 3 patients, structural allograft and hip arthroplasty in 2 patients, and prosthesis with iliac anchoring in 2. They were clinically, radiologically and functionally evaluated with the MSTS scale (1993). RESULTS: The mean MSTS score 6 months after surgery was 20.71 (69%). Five patients (71.4%) had surgical complications: 2 dislocations of the native femoral head on the allograft; one aseptic prosthetic dislodgement, and 2 deep infections. All patients had free intraoperative borders. CONCLUSIONS: Acetabular reconstructions after oncologic resection for malignant bone tumors seem to provide good functional outcomes. However, only selected cases should undergo surgeries associated with a high complication rate.

El tratamiento quirúrgico de los tumores óseos malignos de pelvis con afectación periacetabular está en continua evolución. Las reconstrucciones acetabulares mejoran la calidad de vida sin perjudicar el control oncológico; sin embargo, no están exentas de complicaciones. Nuestro objetivo es describir los resultados funcionales y las complicaciones quirúrgicas de diferentes técnicas reconstructivas de la zona II de Enneking.

Solitary electromechanical pulses in lobster neurons.

Investigations of nerve activity have focused predominantly on electrical phenomena. Nerves, however, are thermodynamic systems, and changes in temperature and in the dimensions of the nerve can also be observed during the action potential. Measurements of heat changes during the action potential suggest that the nerve pulse shares many characteristics with an adiabatic pulse. First experiments in the 1980s suggested small changes in nerve thickness and length during the action potential. Such findings have led to the suggestion that the action potential may be related to electromechanical solitons traveling without dissipation. However, there have been no modern attempts to study mechanical phenomena in nerves. Here, we present ultrasensitive AFM recordings of mechanical changes on the order of 2-12Å in the giant axons of the lobster. We show that the nerve thickness changes in phase with voltage changes. When stimulated at opposite ends of the same axon, colliding action potentials pass through one another and do not annihilate. These observations are consistent with a mechanical interpretation of the nervous impulse.

ATP5H/KCTD2 locus is associated with Alzheimer's disease risk.

To identify loci associated with Alzheimer disease, we conducted a three-stage analysis using existing genome-wide association studies (GWAS) and genotyping in a new sample. In Stage I, all suggestive single-nucleotide polymorphisms (at P<0.001) in a previously reported GWAS of seven independent studies (8082 Alzheimer's disease (AD) cases; 12 040 controls) were selected, and in Stage II these were examined in an in silico analysis within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium GWAS (1367 cases and 12904 controls). Six novel signals reaching P<5 × 10(-6) were genotyped in an independent Stage III sample (the Fundació ACE data set) of 2200 sporadic AD patients and 2301 controls. We identified a novel association with AD in the adenosine triphosphate (ATP) synthase, H+ transporting, mitochondrial F0 (ATP5H)/Potassium channel tetramerization domain-containing protein 2 (KCTD2) locus, which reached genome-wide significance in the combined discovery and genotyping sample (rs11870474, odds ratio (OR)=1.58, P=2.6 × 10(-7) in discovery and OR=1.43, P=0.004 in Fundació ACE data set; combined OR=1.53, P=4.7 × 10(-9)). This ATP5H/KCTD2 locus has an important function in mitochondrial energy production and neuronal hyperpolarization during cellular stress conditions, such as hypoxia or glucose deprivation.

[Fractures of the mid third of the clavicle. Results after osteosynthesis]. / Fracturas de tercio medio de clavícula. Resultados tras osteosíntesis.

BACKGROUND: The traditional idea that most fractures of the mid third of the clavicle heal with a good functional outcome after orthopedic treatment is increasingly controversial due to the publication of studies reporting high pseudoarthrosis rates and functional limitations in certain subpopulations. Our objective is to analyze the results obtained with open reduction and internal fixation with low profile plates for the treatment of these fractures. METHODS: We conducted an observational, retrospective, cohort study of the patients who underwent surgery for displaced fracture of the mid third between January 2006 and December 2009. They all were radiologically and functionally assessed using the Constant and disabilities of the arm, shoulder and hand scales. RESULTS: Surgical treatment of displaced fractures of the mid third of the clavicle with low profile plates using a meticulous technique results in low intra- and postoperative complication rates, with a mean healing rate of 4 months. The Constant score in the affected arm compared with the healthy one was 93.41% in the subjective assessment and 96% in the objective one. CONCLUSIONS: The good functional results obtained lead us to recommend this type of treatment, mainly in certain subpopulations (young and active patients).

Characteristics and drug utilization patterns of new users of rosuvastatin and other statins in four countries.

AIM: This study was undertaken to increase understanding of the utilization of a newly introduced statin through evaluation of characteristics of 'real-life' patients in a pharmacoepidemiology program in the USA, the Netherlands, the UK and Canada. METHODS: This was an observational analysis of prospectively collected data from primary care patients classified as new users of rosuvastatin or any other statin. New users (naïve or switched initiators) of rosuvastatin were compared with initiators of other statins, as identified from automated healthcare databases in the first 1 to 2 years of rosuvastatin availability. Demographics, statin doses, previous statin use and other lipid-lowering therapies, and relevant comorbidities were recorded. The main outcome measure was proportion of naïve and non-naïve statin users in patients prescribed rosuvastatin or 'other statins'. RESULTS: Among 346.547 new statin users identified in the cohorts, 46.838 (13.5%) were new users of rosuvastatin and most (84.1%) were statin-naïve. Patients receiving rosuvastatin were more likely to have been previously treated with another statin or non-statin lipid-lowering therapy and tended to be younger, compared with first users of other statins. CONCLUSION: These findings suggest that rosuvastatin is preferentially prescribed to patients who have not responded satisfactorily to established treatment.

GAB2 gene does not modify the risk of Alzheimer's disease in Spanish APOE 4 carriers.

OBJECTIVES: The genetic basis of Alzheimer's disease (AD) is being analyzed in multiple whole genome association studies (WGAS). The GAB2 gene has been proposed as a modifying factor of APOE epsilon 4 allele in a recent case-control WGAS conducted in the US. Given the potential application of these novel results in AD diagnostics, we decided to make an independent replication to examine the GAB2 gene effect in our series. DESIGN: We are conducting a multicenter population-based study of AD in Spain. PARTICIPANTS: We analyzed a total of 1116 Spanish individuals. Specifically, 521 AD patients, 475 controls from the general population and 120 neurologically-normal elderly controls (NNE controls). METHODS: We have genotyped GAB2 (rs2373115 G/T) and APOE rs429358 (SNP112)/rs7412 (SNP158) polymorphisms using real time-PCR technologies. RESULTS: As previously reported in Spain, APOE epsilon 4 allele was strongly associated with AD in our series (OR=2.88 [95% C.I. 2.16- 3.84], p=7.38E-11). Moreover, a large effect for epsilone 4/epsilone 4 genotype was also observed (OR=14.45 [95% C.I., 3.34-125.2], p=1.8E-6). No difference between the general population and the NNE controls series were observed for APOE genotypes (P > 0.61). Next, we explored GAB2 rs2373115 SNP singlelocus association using different genetic models and comparing AD versus controls or NNE controls. No evidence of association with AD was observed for this GAB2 marker (p > 0.17). To evaluate GAB2-APOE genegene interactions, we stratified our series according to APOE genotype and case-control status, in accordance with the original studies. Again, no evidence of genetic association with AD was observed in any strata of GAB2-APOE loci pair (p > 0.34). CONCLUSION: GAB2 rs2373115 marker does not modify the risk of Alzheimer's disease in Spanish APOE epsilon 4 carriers.