Informe Jurídico sobre Resolución 1618-2017-OS/DSHL de fecha 02 de octubre de 2017, procedimiento administrativo sancionador iniciado por Osinergmin contra la empresa Frontera Energy del Perú S.A.

jurídicos utilizados por Osinergmin en el procedimiento administrativo sancionador iniciado contra la empresa Frontera Energy del Perú S.A. (en adelante, Frontera), a través del expediente 201600140515. En ese sentido, se tiene como objetivo determinar si el órgano sancionador vulneró el Principio de Causalidad cuando decidió sancionar a la empresa operadora por no cumplir con la obligación de retirar instalaciones inactivas que se encontraban en el Lote 192. La particularidad del caso radica en que la instalación inactiva objeto de imputación ya se encontraba en ese lugar desde antes del inicio de las actividades de la empresa operadora. Asimismo, se pretende demostrar que la instalación inactiva imputada es pasible de ser subsumida dentro del concepto jurídico de pasivos ambientales; por lo tanto, la determinación de responsabilidad respecto de la instalación inactiva debe regirse por las normas jurídicas contenidas en la Ley N° 29134, Ley que Regula los Pasivos Ambientales en el Subsector Hidrocarburos (en adelante, LPAH). Finalmente, se analiza si el órgano sancionador tiene la facultad de calificar la naturaleza jurídica de un recurso impugnativo; dado que, en el presente caso el órgano sancionador decide calificar el recurso de apelación presentado por la empresa operadora como si fuera un recurso de reconsideración. De modo que, de conformidad con el marco jurídico vigente se evidenciará las razones por las cuales no es posible que el órgano sancionador realice la recalificación del recurso impugnativo presentado por la empresa operadoraThe purpose of this legal report is to analyze the legal grounds used by Osinergmin in the disciplinary administrative procedure initiated against the company Frontera Energy del Perú S.A., through file 201600140515. In this sense, the objective is to determine if the sanctioning body violated the principle of causality when it decides to sanction the operating company for not complying with the obligation to remove inactive facilities that were in Block 192. The particularity of the case lies in the fact that the inactive installation subject to imputation was already in that place since before the operating company started its activities. Likewise, it is intended to demonstrate that the imputed inactive facility is liable to be subsumed within the legal concept of environmental liabilities; therefore, the determination of responsibility of the imputed inactive facility must be governed by the legal norms contained in Law No. 29134, Law Regulating Environmental Liabilities in the Hydrocarbons Subsector and its Regulations. Finally, it is analyzed whether the sanctioning body has the power to qualify the legal nature of a challenge; given that, in the present case, the sanctioning body decides to classify the appeal of the operating company as if it were a reconsideration resource. So, in accordance with the current legal framework, the reasons why it is not possible for the sanctioning body to reclassify the appeal filed by the operating company will be evidence

Anti-carbamylated protein antibodies as a reproducible independent type of rheumatoid arthritis autoantibodies

A large fraction of the patients with rheumatoid arthritis (RA) develop specific autoantibodies, which until recently were only of two types, rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA). We aimed to replicate important findings about a recently described third type of specific autoantibodies, anti-carbamylated protein (anti-CarP) antibodies, because they have been described based only in the homemade ELISA from a single laboratory. Our study included 520 patients with established RA and 278 healthy controls of Spanish ancestry and it was done with an independently performed ELISA. The prevalence and pattern of environmental, clinical and genetic associations of the anti-CarP antibodies were similar to the previously described. Notably, the presence and titers of anti-CarP correlated with the presence and titers of ACPA, but the anti-CarP antibodies did not share the known genetic and exposure risk factors of the ACPA. In addition, anti-CarP antibodies were independently associated with a higher (10.5%) prevalence of bone erosions. The reproducibility of these characteristics across laboratories and European subpopulations, indicates the wide validity of the results and suggests that determination of anti-CarP antibodies could contribute to explain RA pathogenesis and identify clinically relevant patient subgroups.Funding was provided by the Instituto de Salud Carlos III, PI14/01651; and Instituto de Salud Carlos III, RD12/0009/0008. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.S

Particular association of clinical and genetic features with autoimmunity to citrullinated α-enolase in rheumatoid arthritis.

OBJECTIVE: To confirm that the presence of anti-citrullinated alpha-enolase peptide 1 (anti-CEP-1) antibodies identifies a subgroup of patients with rheumatoid arthritis (RA). METHODS: DNA and serum samples were obtained from 451 patients with RA and 279 healthy control subjects, all of whom were of Spanish ancestry. Antibodies to cyclic citrullinated peptide (CCP) and CEP-1 were measured by enzyme-linked immunosorbent assay. HLA-DRB1 and the R620W single-nucleotide polymorphism of PTPN22 were genotyped. RESULTS: Anti-CEP-1 and anti-CCP antibodies were observed in 26.8% and 71.2% of the patients with RA, respectively. Most of the patients (86.6%) with anti-CEP-1 antibodies also had anti-CCP antibodies. Erosive arthritis, rheumatoid factor (RF) positivity, and the presence of the HLA shared epitope (especially the DRB1*04 alleles) were disproportionately associated with the group of patients with both antibodies. In addition, evidence of a significant interaction between the shared epitope and the risk allele of PTPN22 was observed only in these patients. In contrast, the association with these clinical and genetic features was weaker in patients with anti-CCP antibodies but lacking anti-CEP-1 antibodies. These results were obtained in patients in whom the prevalence of RA risk factors differed from that in other previously studied patients. CONCLUSION: We observed that autoimmunity against citrullinated alpha-enolase may identify a subset of patients with a higher frequency of joint erosions and RF positivity. In addition, we confirmed the disproportionately large effect of the susceptibility alleles of HLA-DRB1 and their interaction with PTPN22 in this subset of patients. These results extend, confirm, and generalize the evidence supporting the specificity of the anti-CEP-1 antibody-positive subgroup of patients with RA among anti-CCP antibody-positive patients with RA

Puntos de alivio: Proyecto de comunicación para mejorar la ruta del paciente del Instituto Nacional de Enfermedades Neoplásicas (INEN)

Si bien la salud es un derecho fundamental de las personas, aún existe una gran brecha para lograr el acceso universal a salud de calidad. A nivel nacional, una de las problemáticas se vincula al cáncer. En dicho sector de atención de salud, uno de los grandes problemas son las necesidades de información de los pacientes con cáncer que asisten al Instituto Nacional de Enfermedades Neoplásicas (INEN) ubicado en Lima. En ese sentido, con el fin de plantear un proyecto comunicacional, se plantean los resultados de un diagnóstico comunicacional que presenta como objetivo principal conocer la información disponible para los pacientes, así como las vivencias y necesidades que tienen durante su ruta en el tratamiento. Entonces, la investigación se centra en analizar los recursos informativos, identificar dificultades de acceso a la información, identificar percepciones y discursos, y evidenciar las funciones de la Oficina de Comunicaciones del Instituto desde un enfoque cualitativo, basado en el uso de entrevistas a profundidad, análisis de contenido y observación no participante, principalmente. Así, desde el enfoque de Comunicación para el Desarrollo, se identifica que hay diversas necesidades de información no cubiertas en los pacientes y que pueden entenderse como ‘puntos de dolor’. Hay tres problemas específicos: desubicación de los pacientes al llegar al INEN por la falta de información completa, necesaria y oportuna; el estado de estrés de los pacientes les dificulta la comprensión de recursos comunicacionales complejos; y, el desconocimiento de las redes de apoyo, sus derechos, y los lugares y procedimientos para reclamar. Es así que, se plantea el proyecto comunicacional “Puntos de Alivio”, el cual busca Contribuir a que los pacientes del INEN gocen de mayor bienestar durante su tránsito por el instituto a través de una experiencia de comunicación empática y articulada, a través del trabajo con la Oficina de Comunicaciones del INEN.Even health is a fundamental right for people, there is still a wide gap to achieve universal health access of good quality. Nationally, one of the problems is related to cancer. In the healthcare sector, one of the big problems is the information needs of cancer patients attending the National Institute of Neoplastic Diseases (INEN, by its acronym in Spanish) located in Lima. Accordingly, in order to propose a communication project, the following text presents first the results of a communicational diagnosis, which main objective is to know the information available to patients, as well as the experiences and needs they have during their treatment route. Then, the research focuses on analyzing information resources, identifying difficulties in accessing information, gathering perceptions and speeches, and demonstrating the functions of the Institute's Office of Communications from a qualitative approach, based on the use of in-depth interviews, content analysis and non-participant observation. Thus, from the Communication for Development approach, it is identified that there are various information needs not met in patients which can be understood as ‘pain points’. There are three specific problems: patient disorientation upon arrival at INEN due to the lack of complete and adequate information given in time; the state of stress of the patients makes it difficult for them to understand complex communication resources; and, the lack of knowledge of support networks, their rights, places and procedures to claim. As a result, the “Relief Points” communication project is proposed, and seeks to help INEN cancer patients enjoy greater wellfare during their transit into and out of the institute through an experience of empathic and articulated communication, with the efforts of the INEN Communications Office.Trabajo de investigació

Non-HLA genes PTPN22, CDK6 and PADI4 are associated with specific autoantibodies in HLA-defined subgroups of rheumatoid arthritis

Introduction: Genetic susceptibility to complex diseases has been intensively studied during the last decade, yet only signals with small effect have been found leaving open the possibility that subgroups within complex traits show stronger association signals. In rheumatoid arthritis (RA), autoantibody production serves as a helpful discriminator in genetic studies and today anti-citrullinated cyclic peptide (anti-CCP) antibody positivity is employed for diagnosis of disease. The HLA-DRB1 locus is known as the most important genetic contributor for the risk of RA, but is not sufficient to drive autoimmunity and additional genetic and environmental factors are involved. Hence, we addressed the association of previously discovered RA loci with disease-specific autoantibody responses in RA patients stratified by HLA-DRB1*04. Methods: We investigated 2178 patients from three RA cohorts from Sweden and Spain for 41 genetic variants and four autoantibodies, including the generic anti-CCP as well as specific responses towards citrullinated peptides from vimentin, alpha-enolase and type II collagen. Results: Our data demonstrated different genetic associations of autoantibody-positive disease subgroups in relation to the presence of DRB1*04. Two specific subgroups of autoantibody-positive RA were identified. The SNP in PTPN22 was associated with presence of anti-citrullinated enolase peptide antibodies in carriers of HLA-DRB1*04 (Cochran-Mantel-Haenszel test P = 0.0001, P corrected <0.05), whereas SNPs in CDK6 and PADI4 were associated with anti-CCP status in DRB1*04 negative patients (Cochran-Mantel-Haenszel test P = 0.0004, P corrected <0.05 for both markers). Additionally we see allelic correlation with autoantibody titers for PTPN22 SNP rs2476601 and anti-citrullinated enolase peptide antibodies in carriers of HLA-DRB1*04 (Mann Whitney test P = 0.02) and between CDK6 SNP rs42041 and anti-CCP in non-carriers of HLA-DRB1*04 (Mann Whitney test P = 0.02). Conclusion: These data point to alternative pathways for disease development in clinically similar RA subgroups and suggest an approach for study of genetic complexity of disease with strong contribution of HLA

Evaluation of 12 GWAS-drawn SNPs as biomarkers of rheumatoid arthritis response to TNF inhibitors. A potential SNP association with response to etanercept

Research in rheumatoid arthritis (RA) is increasingly focused on the discovery of biomarkers that could enable personalized treatments. The genetic biomarkers associated with the response to TNF inhibitors (TNFi) are among the most studied. They include 12 SNPs exhibiting promising results in the three largest genome-wide association studies (GWAS). However, they still require further validation. With this aim, we assessed their association with response to TNFi in a replication study, and a meta-analysis summarizing all nonredundant data. The replication involved 755 patients with RA that were treated for the first time with a biologic drug, which was either infliximab (n = 397), etanercept (n = 155) or adalimumab (n = 203). Their DNA samples were successfully genotyped with a single-base extension multiplex method. Lamentably, none of the 12 SNPs was associated with response to the TNFi in the replication study (p > 0.05). However, a drug-stratified exploratory analysis revealed a significant association of the NUBPL rs2378945 SNP with a poor response to etanercept (B = -0.50, 95% CI = -0.82, -0.17, p = 0.003). In addition, the metaanalysis reinforced the previous association of three SNPs: rs2378945, rs12142623, and rs4651370. In contrast, five of the remaining SNPs were less associated than before, and the other four SNPs were no longer associated with the response to treatment. In summary, our results highlight the complexity of the pharmacogenetics of TNFi in RA showing that it could involve a drug-specific component and clarifying the status of the 12 GWAS-drawn SNPsThis work was supported by the Instituto de Salud Carlos III (ISCIII, Spain) through grants PI14/01651, PI17/01606 and RD16/0012/0014 to AG and PI12/01909 to JJG-R. These grants are partially financed by the European Regional Development Fund of the EU (FEDER

Evaluation of 12 GWAS-drawn SNPs as biomarkers of rheumatoid arthritis response to TNF inhibitors. A potential SNP association with response to etanercept

Research in rheumatoid arthritis (RA) is increasingly focused on the discovery of biomarkers that could enable personalized treatments. The genetic biomarkers associated with the response to TNF inhibitors (TNFi) are among the most studied. They include 12 SNPs exhibiting promising results in the three largest genome-wide association studies (GWAS). However, they still require further validation. With this aim, we assessed their association with response to TNFi in a replication study, and a meta-analysis summarizing all non-redundant data. The replication involved 755 patients with RA that were treated for the first time with a biologic drug, which was either infliximab (n = 397), etanercept (n = 155) or adalimumab (n = 203). Their DNA samples were successfully genotyped with a single-base extension multiplex method. Lamentably, none of the 12 SNPs was associated with response to the TNFi in the replication study (p > 0.05). However, a drug-stratified exploratory analysis revealed a significant association of the NUBPL rs2378945 SNP with a poor response to etanercept (B = -0.50, 95% CI = -0.82, -0.17, p = 0.003). In addition, the meta-analysis reinforced the previous association of three SNPs: rs2378945, rs12142623, and rs4651370. In contrast, five of the remaining SNPs were less associated than before, and the other four SNPs were no longer associated with the response to treatment. In summary, our results highlight the complexity of the pharmacogenetics of TNFi in RA showing that it could involve a drug-specific component and clarifying the status of the 12 GWAS-drawn SNP

Lack of validation of genetic variants associated with anti-tumor necrosis factor therapy response in rheumatoid arthritis: a genome-wide association study replication and meta-analysis

Introduction: In this study, our aim was to elucidate the role of four polymorphisms identified in a prior large genome-wide association study (GWAS) in which the investigators analyzed the responses of patients with rheumatoid arthritis (RA) to treatment with tumor necrosis factor inhibitors (TNFi). The authors of that study reported that the four genetic variants were significantly associated. However, none of the associations reached GWAS significance, and two subsequent studies failed to replicate these associations. Methods: The four polymorphisms (rs12081765, rs1532269, rs17301249 and rs7305646) were genotyped in a total of 634 TNFi-treated RA patients of Spanish Caucasian origin. Four outcomes were evaluated: changes in the Disease Activity Score in 28 joints (DAS28) after 6 and 12 months of treatment and classification according to the European League Against Rheumatism (EULAR) response criteria at the same time points. Association with DAS28 changes was assessed by linear regression using an additive genetic model. Contingency tables of genotype and allele frequencies between EULAR responder and nonresponder patients were compared. In addition, we combined our data with those of previously reported studies in a meta-analysis including 2,998 RA patients. Results: None of the four genetic variants showed an association with response to TNFi in any of the four outcomes analyzed in our Spanish patients. In addition, only rs1532269 yielded a suggestive association (P = 0.0033) with the response to TNFi when available data from previous studies were combined in the meta-analysis. Conclusion: Our data suggest that the rs12081765, rs1532269, rs17301249 and rs7305646 genetic variants do not have a role as genetic predictors of TNFi treatment outcomes

Rheumatoid arthritis response to treatment across IgG1 allotype - anti-TNF incompatibility: a case-only study.

INTRODUCTION: We have hypothesized that incompatibility between the G1m genotype of the patient and the G1m1 and G1m17 allotypes carried by infliximab (INX) and adalimumab (ADM) could decrease the efficacy of these anti-tumor necrosis factor (anti-TNF) antibodies in the treatment of rheumatoid arthritis (RA). METHODS: The G1m genotypes were analyzed in three collections of patients with RA totaling 1037 subjects. The first, used for discovery, comprised 215 Spanish patients. The second and third were successively used for replication. They included 429 British and Greek patients and 393 Spanish and British patients, respectively. Two outcomes were considered: change in the Disease Activity Score in 28 joint (ΔDAS28) and the European League Against Rheumatism (EULAR) response criteria. RESULTS: An association between less response to INX and incompatibility of the G1m1,17 allotype was found in the discovery collection at 6 months of treatment (P = 0.03). This association was confirmed in the replications (P = 0.02 and 0.08, respectively) leading to a global association (P = 0.001) that involved a mean difference in ΔDAS28 of 0.4 units between compatible and incompatible patients (2.3 ± 1.5 in compatible patients vs. 1.9 ± 1.5 in incompatible patients) and an increase in responders and decrease in non-responders according to the EULAR criteria (P = 0.03). A similar association was suggested for patients treated with ADM in the discovery collection, but it was not supported by replication. CONCLUSIONS: Our results suggest that G1m1,17 allotypes are associated with response to INX and could aid improved therapeutic targeting in RA