Genotyping of UGT1A1*80 as an Alternative to UGT1A1*28 Genotyping in Spain.

BACKGROUND: The variant rs34983651 (UGT1A1*28) and its genotyping are used to prevent irinotecan-induced toxicity. Several variants are in close linkage disequilibrium. Our objective was to evaluate the potential correlation of genotyping UGT1A1*80 instead of UGT1A1*28 in different populations. METHODS: We studied SNPs in linkage disequilibrium with UGT1A1*28 in several populations and selected rs887829 to develop an inexpensive and rapid genotyping method and compare it with the one we currently use for UGT1A1*28 genotyping. Samples from cancer patients (n = 701) already tested using PCR and electrophoresis prior to treatment with irinotecan for rs34983651 (UGT1A1*28) in a Spanish hospital were genotyped for rs887829 (UGT1A1*80) using real-time PCR with a TaqMan probe. RESULTS: We observed a complete match for both genotypes, except in one sample. This method was 100% efficient in correctly genotyping *28/*28 patients, 99.68% efficient for *1/*28, and 100% efficient for *1/*1. Linkage disequilibrium between populations showed the Iberian population to be the most suitable for the clinical use of UGT1A1*80. This method is less expensive and the time to decision is shorter. CONCLUSION: Genotyping of rs887829 using the proposed method may be used to substitute genotyping of rs34983651 as a pharmacogenetics test in cancer patients prior to starting irinotecan-based treatments, mainly in the Iberian population. In addition, it is less expensive than other conventional methods and easy to implement, with a shorter time to decision than UGT1A1*28.

ABO blood group is involved in the quality of the specific immune response anti-SARS-CoV-2.

Since December 2019, the coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread throughout the world. To eradicate it, it is crucial to acquire a strong and long-lasting anti-SARS-CoV-2 immunity, by either natural infection or vaccination. We collected blood samples 12-305 days after positive polymerase chain reactions (PCRs) from 35 recovered individuals infected by SARS-CoV-2. Peripheral blood mononuclear cells were stimulated with SARS-CoV-2-derived peptide pools, such as the spike (S), nucleocapsid (N) and membrane (M) proteins, and we quantified anti-S immunoglobulins in plasma. After 10 months post-infection, we observed a sustained SARS-CoV-2-specific CD4+ T-cell response directed against M-protein, but responses against S- or N-proteins were lost over time. Besides, we demonstrated that O-group individuals presented significantly lower frequencies of specific CD4+ T-cell responses against Pep-M than non O-group individuals. The non O-group subjects also needed longer to clear the virus, and they lost cellular immune responses over time, compared to the O-group individuals, who showed a persistent specific immune response against SARS-CoV-2. Therefore, the S-specific immune response was lost over time, and individual factors might determine the sustainability of the body's defenses, which must be considered in the future design of vaccines to achieve continuous anti-SARS-CoV-2 immunity.

DPYD Exome, mRNA Expression and Uracil Levels in Early Severe Toxicity to Fluoropyrimidines: An Extreme Phenotype Approach.

Dihydropyrimidine dehydrogenase deficiency is a major cause of severe fluoropyrimidine-induced toxicity and could lead to interruption of chemotherapy or life-threatening adverse reactions. This study aimed to characterize the DPYD exon sequence, mRNA expression and in vivo DPD activity by plasma uracil concentration. It was carried out in two groups of patients with extreme phenotypes (toxicity versus control) newly treated with a fluoropyrimidine, during the first three cycles of treatment. A novel nonsense gene variant (c.2197insA) was most likely responsible for fluoropyrimidine-induced toxicity in one patient, while neither DPYD mRNA expression nor plasma uracil concentration was globally associated with early toxicity. Our present work may help improve pharmacogenetic testing to avoid severe and undesirable adverse reactions to fluoropyrimidine treatment and it also supports the idea of looking beyond DPYD.

Pharmacogenetics of trough serum anti-TNF levels in paediatric inflammatory bowel disease.

AIMS: Identifying DNA variants associated with trough serum anti-tumour necrosis factor (TNF) levels could predict response to treatment in inflammatory bowel disease (IBD). To date, no specific studies have been performed in children. The aim of this study was to identify genetic variants associated with trough serum anti-TNF levels and whether these variants are differential markers for infliximab and adalimumab. METHODS: We included 154 children (age < 18 years) from 17 hospitals who had been diagnosed with IBD and actively treated with infliximab or adalimumab. Twenty-one polymorphisms were genotyped using real-time PCR. Trough serum anti-TNF levels were measured using enzyme-linked immunosorbent assay (ELISA). The association between DNA polymorphisms and the therapeutic range or the absolute values of anti-TNF drugs was analysed by Fisher exact test, student's t-test and logistic regression. RESULTS: The variants rs5030728 (TLR4) and rs11465996 (LY96) were associated with subtherapeutic infliximab levels. rs1816702 (TLR2) was associated with supratherapeutic levels and rs3397 (TNFRSF1B) with subtherapeutic levels of adalimumab (P < .05). In addition, rs1816702 (TLR2) and rs2569190 (CD14) were associated with absolute values of trough serum adalimumab, and rs2569190 (CD14) was associated with absolute values of trough serum adalimumab and infliximab (P < .05). CONCLUSION: Genotyping of these DNA variants before starting treatment may help to select the best anti-TNF drug in paediatric patients. The SNP rs1816702 is the most promising marker for tailoring the anti-TNF regimen in children with IBD. For the first time, DNA variants are associated with trough serum anti-TNF levels.

Comprehensive Flow Cytometry Profiling of the Immune System in COVID-19 Convalescent Individuals.

SARS-CoV-2 has infected more than 200 million people worldwide, with more than 4 million associated deaths. Although more than 80% of infected people develop asymptomatic or mild COVID-19, SARS-CoV-2 can induce a profound dysregulation of the immune system. Therefore, it is important to investigate whether clinically recovered individuals present immune sequelae. The potential presence of a long-term dysregulation of the immune system could constitute a risk factor for re-infection and the development of other pathologies. Here, we performed a deep analysis of the immune system in 35 COVID-19 recovered individuals previously infected with SARS-CoV-2 compared to 16 healthy donors, by flow cytometry. Samples from COVID-19 individuals were analysed from 12 days to 305 days post-infection. We observed that, 10 months post-infection, recovered COVID-19 patients presented alterations in the values of some T-cell, B-cell, and innate cell subsets compared to healthy controls. Moreover, we found in recovered COVID-19 individuals increased levels of circulating follicular helper type 1 (cTfh1), plasmablast/plasma cells, and follicular dendritic cells (foDC), which could indicate that the Tfh-B-foDC axis might be functional to produce specific immunoglobulins 10 months post-infection. The presence of this axis and the immune system alterations could constitute prognosis markers and could play an important role in potential re-infection or the presence of long-term symptoms in some individuals.

La perspectiva de personas migrantes sobre el acceso a la atención sanitaria en el contexto de políticas de austeridad en Andalucía / The perspective of migrants on access to health care in the context of austerity policies in Andalusia (Spain)

OBJETIVO: Conocer la valoración de personas migrantes sobre su acceso al sistema sanitario tras la entrada en vigor del Real Decreto-Ley16/2012 y sobre el efecto que han podido producir los recortes económicos en dicho acceso. MÉTODO: Estudio cualitativo fenomenológico con entrevistas semiestructuradas, realizado en Andalucía, en dos fases (2009-2010 y 2012-2013), con 36 participantes. Se segmentó la muestra por tiempo de estancia, nacionalidad y ámbito de residencia. Las nacionalidades de las personas migrantes son Bolivia, Marruecos y Rumanía. RESULTADOS: Como elementos facilitadores del acceso en ambas fases se identifican la situación administrativa regular, la posesión de tarjeta sanitaria individual, el conocimiento del idioma, las redes sociales y la información. Los resultados muestran diferencias en el acceso a la atención sanitaria de las personas migrantes antes y después de la aplicación del RDL 16/2012, en el marco de las políticas de austeridad. En la segunda fase se agravan algunas barreras de acceso, como los tiempos de espera y la incompatibilidad de horarios, y empeoran las condiciones socioeconómicas y administrativas de las personas participantes. CONCLUSIONES: El diseño de políticas económicas y de regulación de la atención sanitaria debería tener en cuenta las barreras y los facilitadores de acceso como ejes fundamentales de la protección de la salud de las personas migrantes y, por ende, de la población general

OBJECTIVE: To conduct an assessment of migrant people regarding their access to the health system following entry into force of Royal Decree-Law 16/2012 along with the impact of economic cuts on such access. METHOD: Qualitative phenomenological study with semi-structured interviews, conducted in Andalusia (Spain), in two phases (2009-2010 and 2012-2013), with 36 participants. The sample was segmented by length of stay, nationality and area of residence. The nationalities of origin are Bolivia, Morocco and Romania. RESULTS: Elements facilitating access in both periods: regular administrative situation, possession of Individual Health Card, knowledge of the language, social networks and information. The results show differences in access to health care for migrants before and after the enforcement of the RDL 16/2012, within austerity policies. In the second period, access barriers such as waiting times or incompatibility of schedules are aggravated and the socio-economic and administrative conditions of participants worsen. CONCLUSIONS: The design of policies, economic and regulatory health care, should take into account barriers and facilitators of access as fundamental main points of health protection for migrants and, therefore, for the general population

[The perspective of migrants on access to health care in the context of austerity policies in Andalusia (Spain)]. / La perspectiva de personas migrantes sobre el acceso a la atención sanitaria en el contexto de políticas de austeridad en Andalucía.

OBJECTIVE: To conduct an assessment of migrant people regarding their access to the health system following entry into force of Royal Decree-Law 16/2012 along with the impact of economic cuts on such access. METHOD: Qualitative phenomenological study with semi-structured interviews, conducted in Andalusia (Spain), in two phases (2009-2010 and 2012-2013), with 36 participants. The sample was segmented by length of stay, nationality and area of residence. The nationalities of origin are Bolivia, Morocco and Romania. RESULTS: Elements facilitating access in both periods: regular administrative situation, possession of Individual Health Card, knowledge of the language, social networks and information. The results show differences in access to health care for migrants before and after the enforcement of the RDL 16/2012, within austerity policies. In the second period, access barriers such as waiting times or incompatibility of schedules are aggravated and the socio-economic and administrative conditions of participants worsen. CONCLUSIONS: The design of policies, economic and regulatory health care, should take into account barriers and facilitators of access as fundamental main points of health protection for migrants and, therefore, for the general population.

Consecuencias del efecto ingratitud: de la Gripe A al COVID-19 / Consecuences of the ingratitude effect: From Influenza A to COVID-19

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Severe toxicity to capecitabine due to a new variant at a donor splicing site in the dihydropyrimidine dehydrogenase (DPYD) gene.

Severe, life-threatening adverse reactions to capecitabine sometimes occur in the treatment of solid tumors. Screening for dihydropyrimidine dehydrogenase (DPYD) deficiency is encouraged before start of treatment, but the genetic variants that are commonly analyzed often fail to explain toxicities seen in clinical practice. Here we describe the case of a 79-year-old Caucasian female with breast cancer who presented with life-threatening, rapidly increasing toxicity after 1 week of treatment with capecitabine and for whom routine genetic DPYD test resulted negative. DPYD exon sequencing found variant c.2242+1G>T at the donor splicing site of exon 19. This variant is responsible for skipping of exon 19 and subsequent generation of a non-functional DPYD enzyme. This variant has not been described previously but was found in three other members of the patient's family. With this case, we show that exon sequencing of DPYD in patients who experience marked toxicity to fluoropyrimidines and test negative for commonly evaluated variants can prove extremely useful for identifying new genetic variants and better explain adverse reactions causality.

Hacia una salud pública orientada desde los determinantes sociales de la salud: informe de un taller / Towards a social determinants-oriented approach to public health: workshop report

Este artículo es el producto de los resultados de un taller con expertos y expertas en salud pública realizado en Granada en octubre de 2015, que tuvo por objetivo reflexionar sobre qué elementos clave deberían caracterizar una salud pública orientada desde los determinantes sociales de la salud. La labor de abogacía y la formación de profesionales críticos en defensa de la salud pública fueron señalados como elementos centrales. Hubo acuerdo en que el enfoque de género, la mirada salutogénica, el trabajo con otros sectores y una particular atención a colectivos más desfavorecidos son también elementos indispensables. Se subrayó la importancia de trabajar desde un marco de derechos humanos y de promover cambios legislativos. Además, el grupo señaló como reto la necesidad de generar conocimiento sobre cómo intervenir para reducir las brechas de desigualdad en salud, porque hasta ahora solo se ha avanzado identificando determinantes sociales de la salud y generando marcos conceptuales

This article is the result of a workshop with public health experts held in Granada (Spain) in October 2015 in order to reflect upon the components of the framework that should be part of a public health approach based on the social determinants of health. Advocacy and training professionals in health advocacy were identified as key elements where this was needed. During the workshop, it was agreed that the gender perspective, the salutogenic approach, interdisciplinary work and particular attention to disadvantaged groups are crucial. The importance of working from a human rights’ framework and promoting legislative changes were also mentioned. Moreover, the group mentioned that even though much progress has been made identifying social determinants of health and creating conceptual frameworks, there is limited knowledge about how to intervene to reduce health inequality gaps in our societies

Repensar la Carta de Ottawa 30 años después / Rethinking the Ottawa Charter 30 years later

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Gender inequalities in COPD decision-making in primary care.

BACKGROUND: COPD is a frequent severe illness that increasingly affects females. Gender inequalities have been reported in COPD care. OBJECTIVE: To analyze decision-making in primary care for men and women with identical COPD as a function of the gender of the family physician (FP). METHODS: Cross-sectional, multicenter study in 457 Andalusian FPs, using a self-administered vignette-based questionnaire on COPD featuring a male or female patient, with four variables on clinical reasoning: "tobacco as most important risk factor (RF)", "ordering of spirometry", "COPD as most likely diagnosis", and "referral". Multilevel logistic regression analysis. RESULTS: Response rate was 67.4% (308/457). In analysis of the four FP gender-patient gender dyads, tobacco was more frequently considered as priority RF for the man than for the woman in the vignette by female (95.6%vs.67.1%) and male (79.8%vs.62.5%) FPs. COPD was more frequently the most likely diagnosis for the man versus woman by female (84.4%vs.49.9%) and male (78.5%vs.57.8%) FPs. Male FPs more frequently ordered spirometry for the man versus woman (68.1%vs.46.8%). There were no differences in referral between male and female patients. Male FPs were more likely than female FPs to consider tobacco as priority RF for the man (p = 002). Female FPs were more likely than male FPs to refer the man (22.5%vs.8%). CONCLUSIONS: There may be gender inequalities in primary care for COPD in our setting. Diagnostic and therapeutic efforts appear lower in female patients. Male and female FPs only differed in care of the male patient, indicating FP gender-patient gender interaction.

Was access to health care easy for immigrants in Spain? The perspectives of health personnel in Catalonia and Andalusia.

Until April 2012, all Spanish citizens were entitled to health care and policies had been developed at national and regional level to remove potential barriers of access, however, evidence suggested problems of access for immigrants. In order to identify factors affecting immigrants' access to health care, we conducted a qualitative study based on individual interviews with healthcare managers (n=27) and professionals (n=65) in Catalonia and Andalusia, before the policy change that restricted access for some groups. A thematic analysis was carried out. Health professionals considered access to health care "easy" for immigrants and similar to access for autochthons in both regions. Clear barriers were identified to enter the health system (in obtaining the health card) and in using services, indicating a mismatch between the characteristics of services and those of immigrants. Results did not differ among regions, except for in Catalonia, where access to care was considered harder for users without a health card, due to the fees charged, and in general, because of the distance to primary health care in rural areas. In conclusion, despite the universal coverage granted by the Spanish healthcare system and developed health policies, a number of barriers in access emerged that would require implementing the existing policies. However, the measures taken in the context of the economic crisis are pointing in the opposite direction, towards maintaining or increasing barriers.

Professional Success and Gender in Family Medicine: Design of Scales and Examination of Gender Differences in Subjective and Objective Success Among Family Physicians.

Two components of professional success have been defined: objective career success (OCS) and subjective career success (SCS). Despite the increasing number of women practicing medicine, gender inequalities persist. The objectives of this descriptive, cross-sectional, and multicenter study were (a) to construct and validate OCS and SCS scales, (b) to determine the relationships between OCS and SCS and between each scale and professional/family characteristics, and (c) to compare these associations between male and female family physicians (FPs). The study sample comprised 250 female and 250 male FPs from urban health centers in Andalusia (Spain). Data were gathered over 6 months on gender, age, care load, professional/family variables, and family-work balance, using a self-administered questionnaire. OSC and SCS scales were examined by using exploratory factorial analysis and Cronbach's α, and scores were compared by gender-stratified bivariate and multiple regression analyses. Intraclass correlation coefficients were calculated using a multilevel analysis. The response rate was 73.6%. We identified three OCS factors and two SCS factors. Lower scores were obtained by female versus male FPs in the OCS dimensions, but there were no gender differences in either SCS dimension.

Ammonia Affects Astroglial Proliferation in Culture.

Primary cultures of rat astroglial cells were exposed to 1, 3 and 5 mM NH4Cl for up to 10 days. Dose- and time-dependent reductions in cell numbers were seen, plus an increase in the proportion of cells in the S phase. The DNA content was reduced in the treated cells, and BrdU incorporation diminished. However, neither ammonia nor ammonia plus glutamine had any effect on DNA polymerase activity. iTRAQ analysis showed that exposure to ammonia induced a significant reduction in histone and heterochromatin protein 1 expression. A reduction in cell viability was also noted. The ammonia-induced reduction of proliferative activity in these cultured astroglial cells seems to be due to a delay in the completion of the S phase provoked by the inhibition of chromatin protein synthesis.

[Gender differences in the perception of professional achievement in family medicine, Spain]. / Diferencias de género en la percepción del logro profesional en especialistas de medicina familiar y comunitaria.

BACKGROUND: The concept of achievement is important to study the professional development. In medicine there are gender inequalities in career. The purpose was to know and compare the professional achievement's perceptions and attributions of female and male primary care physicians in Andalusia. METHOD: Qualitative study with 12 focus groups (October 2009 to November 2010). POPULATION: primary care physicians. SAMPLE: intentionally segmented by age, sex and health care management. Were conducted by sex: two groups with young physicians, two groups with middle aged and two with health care management. TOTAL: 32 female physician and 33 male physicians. Qualitative content analysis with Nuddist Vivo. RESULTS: Female and male physicians agree to perceive internal achievements and to consider aspects inherent to the profession as external achievements. The most important difference is that female physician related professional achievement with affective bond and male physician with institutional merit. Internal attributions are more important for female physician who also highlight the importance of family, the organization of working time and work-family balance. Patients, continuing education, institutional resources and computer system are the most important attributions for male physician. CONCLUSIONS: There are similarities and differences between female and male physicians both in the understanding and the attributions of achievement. The differences are explained by the gender system. The perception of achievement of the female physicians questions the dominant professional culture and incorporates new values in defining achievement. The attributions reflect the unequal impact of family and organizational variables and suggest that the female physicians would be changing gender socialization.