El relato de la historia que nadie conocía: programa de medicina familiar para la transformación social / Telling the story nobody knew: social transformation through family medicine

Objetivo: conocer el desarrollo del programa de medicina familiar de la Fundación Universitaria de Ciencias de la Salud (FUCS) de Bogotá DC, Colombia, diez años [2007- 2017] Método: mediante la sistematización de experiencias se compilaron las voces de quienes han hecho parte en la formación y evolución del programa, como egresados, docentes y personal administrativo. Resultados: se logró develar los momentos históricos más relevantes en la estructuración y organización, identificando los enfoques epistémicoclínico y comunitario que durante años han matizado la formación de residentes, los procesos administrativos, los convenios institucionales, así como los aciertos, desaciertos y tensiones. Discusión: el programa de ha estado permeado por los cambios en las tendencias teóricas dadas por el ámbito internacional. También ha demostrado su valioso aporte a la medicina familiar como disciplina dentro del contexto colombiano. Conclusión: el programa ha logrado consolidarse a nivel nacional y ha mantenido un espíritu innovador, buscando siempre ser el primero en implementar nuevas estrategias y formas de aplicar la medicina familiar.

Objective: The objective was to know the development of the Family Medicine Program of the University Foundation of Health Sciences during the last ten years [2007- 2017]. Method: Through the systematization of experiences, the voices of those who have taken part in the formation and evolution of the Program were compiled, such as: Graduates, teachers and administrative personnel. Results: It was possible to unveil the most relevant historical moments in the structuring and organization of the Program and from there, the clinical and community epistemic approaches that for years have nuanced resident training, administrative processes, institutional agreements, as well as, were known. the successes, failures and tensions. Discussion: The Family Medicine Program of the FUCS, has been strongly permeated by the changes in the theoretical tendencies given in the international context, on the other hand, its essential contribution to family medicine as a discipline has been demonstrated, within the Colombian context Conclusion: The Program has managed to consolidate itself within the national context and period after period has maintained an innovative spirit; always looking to be the first to implement new strategies, new ways of applying family medicine.

Associations between gene polymorphisms in fatty acid metabolism pathway and preterm delivery in a US urban black population.

There is increasing evidence suggesting that higher intakes of fish or n-3 polyunsaturated fatty acids supplements may decrease the risk of preterm delivery (PTD). We hypothesized that genetic variants of the enzymes critical to fatty acids biosynthesis and metabolism may be associated with PTD. We genotyped 231 potentially functional single nucleotide polymorphisms (SNPs) and tagSNPs in 9 genes (FADS1, FADS2, PTGS1, PTGS2, ALOX5, ALOX5AP, PTGES, PTGES2, and PTGES3) among 1,110 black mothers, including 542 mothers who delivered preterm (<37 weeks gestation) and 568 mothers who delivered full-term babies (≥37 weeks gestation) at Boston Medical Center. After excluding SNPs that are in complete linkage disequilibrium or have lower minor allele frequency (<1%) or call rate (<90%), we examined the association of 206 SNPs with PTD using multiple logistic regression models. We also imputed 190 HapMap SNPs via program MACH and examined their associations with PTD. Finally, we explored gene-level and pathway-level associations with PTD using the adaptive rank truncated product (ARTP) methods. A total of 21 SNPs were associated with PTD (p value ranging from 0.003 to 0.05), including 3 imputed SNPs. Gene-level ARTP statistics indicated that the gene PTGES2 was significantly associated with PTD with a gene-based p value equal to 0.01. No pathway-based association was found. In this large and comprehensive candidate gene study, we found a modest association of genes in fatty acid metabolism pathway with PTD. Further investigation of these gene polymorphisms jointly with fatty acid measures and other genetic factors would help better understand the pathogenesis of PTD.

Role of African ancestry and gene-environment interactions in predicting preterm birth.

OBJECTIVE: To estimate whether African ancestry, specific gene polymorphisms, and gene-environment interactions could account for some of the unexplained preterm birth variance within African American women. METHODS: We genotyped 1,509 African ancestry-informative markers, cytochrome P450 1A1 (CYP1A1), and glutathione S-transferases Theta 1 (GSTT1) variants in 1,030 self-reported African American mothers. We estimated the African ancestral proportion using the ancestry-informative markers for all 1,030 self-reported African American mothers. We examined the effect of African ancestry and CYP1A1- and GSTT1-smoking interactions on preterm birth cases as a whole and within its subgroups: very preterm birth (gestational age less than 34 weeks); and late preterm birth (gestational age greater than 34 and less than 37 weeks). We applied logistic regression and receiver operating characteristic curve analysis, separately, to evaluate whether African ancestry and CYP1A1- and GSTT1-smoking interactions could make additional contributions to preterm birth beyond epidemiologic factors. RESULTS: We found significant associations of African ancestry with preterm birth (22% compared with 31%, odds ratio [OR] 1.11, 95% confidence interval [CI] 1.02-1.20) and very preterm birth (23% compared with 33%, OR 1.17, 95% CI 1.03-1.33), but not with late preterm birth (22% compared with 29%, OR 1.06, 95% CI 0.97-1.16). In addition, the receiver operating characteristic curve analysis suggested that African ancestry and CYP1A1- and GSTT1-smoking interactions made substantial contributions to very preterm birth beyond epidemiologic factors. CONCLUSION: Our data underscore the importance of simultaneously considering epidemiologic factors, African ancestry, specific gene polymorphisms, and gene-environment interactions to better understand preterm birth racial disparity and to improve our ability to predict preterm birth, especially very preterm birth.

Race, ancestry, and development of food-allergen sensitization in early childhood.

OBJECTIVE: We examined whether the risk of food-allergen sensitization varied according to self-identified race or genetic ancestry. METHODS: We studied 1104 children (mean age: 2.7 years) from an urban multiethnic birth cohort. Food sensitization was defined as specific immunoglobulin E (sIgE) levels of ≥ 0.35 kilo-units of allergen (kUA)/L for any of 8 common food allergens. Multivariate logistic regression analyses were used to evaluate the associations of self-identified race and genetic ancestry with food sensitization. Analyses also examined associations with numbers of food sensitizations (0, 1 or 2, and ≥ 3 foods) and with logarithmically transformed allergen sIgE levels. RESULTS: In this predominantly minority cohort (60.9% black and 22.5% Hispanic), 35.5% of subjects exhibited food sensitizations. In multivariate models, both self-reported black race (odds ratio [OR]: 2.34 [95% confidence interval [CI]: 1.24-4.44]) and African ancestry (in 10% increments; OR: 1.07 [95% CI: 1.02-1.14]) were associated with food sensitization. Self-reported black race (OR: 3.76 [95% CI: 1.09-12.97]) and African ancestry (OR: 1.19 [95% CI: 1.07-1.32]) were associated with a high number (≥ 3) of food sensitizations. African ancestry was associated with increased odds of peanut sIgE levels of ≥ 5 kUA/L (OR: 1.25 [95% CI: 1.01-1.52]). Similar ancestry associations were seen for egg sIgE levels of ≥ 2 kUA/L (OR: 1.13 [95% CI: 1.01-1.27]) and milk sIgE levels of ≥ 5 kUA/L (OR: 1.24 [95% CI: 0.94-1.63]), although findings were not significant for milk. CONCLUSIONS: Black children were more likely to be sensitized to food allergens and were sensitized to more foods. African ancestry was associated with peanut sensitization.

Association of antenatal steroid use with cord blood immune biomarkers in preterm births.

OBJECTIVES: To evaluate the effect of maternal administration of antenatal steroids (ANS) on cord blood cytokine levels at birth in preterm infants. METHODS: Cord blood cytokine concentrations were measured for pro-inflammatory cytokines (IL-1ß, IL-6, and IL-8); anti-inflammatory cytokines (IL-4, IL-10 and TGF-ß); and neurotrophic cytokines (BDNF, NT-3, and NT-4) in two hundred preterm infants. Data were analyzed using multivariable linear regression to model the independent and joint effects of ANS and inflammation on mean log cord blood cytokine concentrations adjusted for gestational age and Apgar scores. RESULTS: Exposure to ANS had no significant effect on the cord blood concentrations of cytokines measured in this study. All three pro-inflammatory cytokine levels and levels of IL-10 were significantly increased and cord blood levels of TGF-ß and NT-3 were significantly decreased in infants with placental inflammation. CONCLUSION: Although exposure to ANS did not have any significant effect on cord blood levels of cytokines, there was a trend toward the attenuation of inflammatory response and higher levels of neurotrophic cytokines in infants born to mothers with placental inflammation and exposure to ANS compared to infants born to mothers with placental inflammation and no ANS exposure.

Placental inflammatory response is associated with poor neonatal growth: preterm birth cohort study.

OBJECTIVE: We sought to determine whether placental markers of intrauterine inflammation were associated with poor weight gain among premature infants in the neonatal period. METHODS: We reviewed 697 preterm births prospectively enrolled as part of an ongoing molecular epidemiological study. Placental markers and serial weight gain were analyzed for premature infants who were hospitalized for >/=21 days (N = 256). Placentas were examined for maternal inflammatory response (MIR), defined as subchorionitis, chorioamnionitis, deciduitis, or free membranitis, and fetal inflammatory response (FIR), defined as inflammation extending to the umbilical cord or chorionic plate. Multivariate linear regression and stratified analyses were performed. RESULTS: Decreases in weight gain at day 21 were associated with the presence of either MIR or FIR (beta coefficient = -4.63 +/- 1.41; P = .001). The association was stronger with FIR than MIR (P for trend = .0027) and persisted in the remaining hospitalized infants at day 28 (n = 223; beta coefficient = -5.53 +/- 1.85; P = .0028). Mean body weights were similar among the 3 groups by corrected age of 36 weeks or discharge, whichever came first. Associations between placental inflammation and poor growth persisted among infants with prenatal corticosteroid exposure and/or neonatal complications and remained marginally significant in the nonexposed groups. Among infants without intrauterine growth restriction, significant association persisted (n = 186; beta coefficient = -5.68 +/- 1.56; P = .0003). CONCLUSIONS: Placental inflammation is associated with poor neonatal growth. MIR and FIR may be useful markers for identifying infants at risk for postnatal growth failure.

Maternal obesity, diabetes mellitus and cord blood biomarkers in large-for-gestational age infants.

Infants born large-for-gestational age (LGA) are at risk for early childhood obesity. The aims of this study were to investigate factors associated with LGA status and their relationship to inflammatory biomarkers that have been implicated in the LGA infant at birth. Included were 364 mother-infant pairs enrolled as part of an ongoing longitudinal cohort study of infant birth weight being conducted at Boston Medical Center (BMC). LGA was defined as birth weight (BW) ≥90(th) percentile of the reference population at BMC (N=45). Appropriate-for-gestational age (AGA) was defined as BW<90(th) and >10(th) percentile (N=319). Cord blood IL-6, IL-8, TNF-alpha and RANTES levels were analyzed from a larger panel of immune biomarkers measured using multiplex immunoassay. Multivariate regression models were used to determine the associations between LGA status, maternal BMI and diabetes (DM), which included either gestational or type 2 diabetes (T2DM), and cord blood biomarkers, with adjustment for important demographic and clinical variables. Maternal pre-pregnancy BMI within the obesity range (≥30 kg/m(2)), as well as DM, were each associated with increased risk of LGA (OR=2.64, 95%CI 1.31-6.20; OR=5.58, 95%CI 2.06-15.13, respectively). Among the 4 biomarkers, only RANTES (regulated on activation, normal T cell express and secreted upon uptake), which is a chemokine secreted by white adipose tissue, was significantly increased in LGA infants (beta-coefficient=0.37; 95% CI: 0.09, 0.65; P<0.01). This association remained essentially unchanged after adjustment for maternal DM and BMI (beta-coefficient=0.37; 95% CI: 0.08, 0.65; P=0.01). Ponderal index (PI=BW×100/length(3)) was also positively correlated with RANTES. Cord blood RANTES is selectively elevated with fetal macrosomia, independent of maternal factors. Further investigation of RANTES as a marker of LGA and future childhood health is warranted.

Cord blood biomarkers of the fetal inflammatory response.

OBJECTIVE: In current, neonatal practice, clinical signs of intrauterine infection (IUI) are often non-specific. From a large panel of immune biomarkers, we seek to identify cord blood markers that are most strongly associated with the fetal inflammatory response (FIR), a specific placental lesion associated with serious neonatal complications. METHODS: We used multiplex immunoassay to measure 27 biomarkers, selected as part of an NIH-funded study of preterm birth, according to gestational age (GA) and extent of placental inflammation: involvement of chorion, amnion, decidua (maternal inflammatory response, MIR); extension to umbilical cord or chorionic plate (FIR). We used false-discovery rate (FDR < 5%, P < 0.001) to account for multiple comparisons. RESULTS: Among 506 births (GA 23-42 weeks), IL-1 beta increased with FIR among preterm subgroups (P = 0.0001 for <32 weeks; P = 0.0009 for 33-36 weeks). IL-6 and IL-8 increased with FIR among preterm and full-term infants (P < 0.0001). P-trend for IL-6 and IL-8 with MIR versus FIR was <0.0001. Comparison with respect to clinical IUI yielded persistent elevation with FIR even when clinical signs were absent. The remaining 24 markers were not significantly associated. CONCLUSION: We conclude that among 27 cord blood biomarkers, IL-1 beta, IL-6 and IL-8 are selectively associated with FIR. These markers may be clinically useful indicators of extensive IUI associated with poor neonatal outcome.

Differential patterns of 27 cord blood immune biomarkers across gestational age.

OBJECTIVES: Inflammation has been associated with preterm delivery and adverse neonatal outcomes such as cerebral palsy and chronic lung disease. However, no study to date has simultaneously examined a wide range of inflammatory mediators and their relationship to gestational age. We sought to describe the distribution of immune biomarkers in cord blood across gestational age and to investigate the association between biomarker level patterns and preterm birth. PATIENTS AND METHODS: As part of a large-scale molecular epidemiological study of preterm birth conducted at Boston Medical Center, this study analyzed both clinical and biomarker data from 927 births. Twenty-seven biomarkers were simultaneously quantified by immunoassay. The associations between the quartiles of 27 biomarkers and 3 gestational groups (< or =32, 33-36, and > or =37 weeks) were analyzed. Biomarkers found to be significant were further analyzed for dose-response correlation with preterm birth by logistic regression, adjusted for pertinent demographic and clinical factors. RESULTS: The 27 biomarkers could be classified into 1 of 3 groups: (1) biomarkers increased in preterm birth (interleukin [IL]-2, IL-4, IL-5, IL-8, IL-10, monocyte chemoattractant protein 1, macrophage inflammatory protein [MIP]-1alpha, MIP-1beta, soluble IL-6 receptor alpha, tumor necrosis factor alpha, soluble tumor necrosis factor receptor I, and TREM-1 [triggering receptor expressed on myeloid cells 1]); (2) biomarkers decreased in preterm birth (brain-derived neurotrophic factor, IL-1beta, IL-18, matrix metalloproteinase 9, and neurotrophin 3); and (3) biomarkers not associated with preterm birth (IL-6, IL-12, IL-17, granulocyte/macrophage colony-stimulating factor, interferon gamma, macrophage migration inhibitory factor, neurotrophin 4, RANTES [regulated on activation, normal T-cell expressed and secreted], transforming growth factor beta, and tumor necrosis factor beta). CONCLUSIONS: Biomarkers have different directions of association with prematurity; for significant biomarkers, the strength of association increases with biomarker concentration. Our results provide important information that could be used to guide additional studies aimed at determining mechanisms that contribute to preterm birth.

Association of genetic ancestry with preterm delivery and related traits among African American mothers.

OBJECTIVE: In the United States, the rate of preterm delivery (PTD) is higher in African Americans (17.8%) than non-Hispanic whites (11.5%). Such disparity cannot be fully explained by differences in socioenvironmental factors. STUDY DESIGN: We genotyped 812 mothers in a case-control PTD study at Boston Medical Center who self-reported their ethnicity as "black." Regression analysis and Wilcoxon rank-sum test were applied to evaluate ancestral distribution and the association between genetic ancestry and PTD-related traits, as well as the potential confounding effect of population stratification. RESULTS: The estimated African ancestral proportion was 0.90 +/- 0.13. We found significant associations of ancestral proportion with PTD as a whole and PTD subgrouped by the presence of maternal hypertensive disorders. We did not observe significant confounding as a result of population stratification in this case-control PTD study. CONCLUSION: Our data underline the need for more intensive investigation of genetic admixture in African Americans to identify novel susceptibility genes of PTD.

The joint association between F5 gene polymorphisms and maternal smoking during pregnancy on preterm delivery.

Factor V (F5) genetic variants and maternal smoking during pregnancy individually has been associated with increased risk of preterm delivery (PTD). We hypothesize that F5 gene and maternal smoking may synergistically increase the risk of PTD. Three single nucleotide polymorphisms (SNPs) in F5 gene (rs6019, rs2213869 and rs6022) were genotyped in 542 mothers with PTD and 1,141 mothers with term deliveries at the Boston Medical Center. The individual and interactive effects of F5 SNPs and maternal smoking on PTD and gestational age were examined, respectively. The results suggested that maternal smoking, three F5 SNPs and F5 haplotype were individually associated with PTD and gestational age. More importantly, we found significant interactions between the two F5 SNPs (rs6019 and rs6022) and maternal smoking on PTD and gestational age. Compared with non-smoking mothers carrying rs6019 GG genotype, persistently smoking mothers carrying genotypes GC or CC were associated with significantly increased risk of PTD (OR(95% CI): 2.1(1.2-3.6) for GC; 5.7(2.1-15.0) for CC; p-interaction = 0.02). A significant interaction was also observed for gestational age. Similar pattern of interactions was found between rs6022 and maternal smoking on PTD. In summary, our data indicated that F5 gene variants and maternal smoking may synergistically increase the risk of PTD.

Maternal cigarette smoking, metabolic gene polymorphisms, and preterm delivery: new insights on GxE interactions and pathogenic pathways.

Preterm delivery (PTD, <37 weeks of gestation) is a significant clinical and public health problem. Previously, we reported that maternal smoking and metabolic gene polymorphisms of CYP1A1 MspI and GSTT1 synergistically increase the risk of low birth weight. This study investigates the relationship between maternal smoking and metabolic gene polymorphisms of CYP1A1 MspI and GSTT1 with preterm delivery (PTD) as a whole and preterm subgroups. This case-control study included 1,749 multi-ethnic mothers (571 with PTD and 1,178 controls) enrolled at Boston Medical Center. After adjusting covariates, regression analyses were performed to identify individual and joint associations of maternal smoking, two functional variants of CYP1A1 and GSTT1 with PTD. We observed a moderate effect of maternal smoking on PTD (OR = 1.6; 95% CI: 1.1-2.2). We found that compared to non-smoking mothers with low-risk genotypes, there was a significant joint association of maternal smoking, CYP1A1 (Aa/aa) and GSTT1 (absent) genotypes with gestational age (beta = -3.37; SE = 0.86; P = 9 x 10(-5)) and with PTD (OR = 5.8; 95% CI: 2.0-21.1), respectively. Such joint association was particularly strong in certain preterm subgroups, including spontaneous PTD (OR = 8.3; 95% CI: 2.7-30.6), PTD < 32 weeks (OR = 11.1; 95% CI: 2.9-47.7), and PTD accompanied by histologic chorioamnionitis (OR = 15.6; 95% CI: 4.1-76.7). Similar patterns were observed across ethnic groups. Taken together, maternal smoking significantly increased the risk of PTD among women with high-risk CYP1A1 and GSTT1 genotypes. Such joint associations were strongest among PTD accompanied by histologic chorioamnionitis.