Outdoor air pollution and cancer: An overview of the current evidence and public health recommendations.

Outdoor air pollution is a major contributor to the burden of disease worldwide. Most of the global population resides in places where air pollution levels, because of emissions from industry, power generation, transportation, and domestic burning, considerably exceed the World Health Organization's health-based air-quality guidelines. Outdoor air pollution poses an urgent worldwide public health challenge because it is ubiquitous and has numerous serious adverse human health effects, including cancer. Currently, there is substantial evidence from studies of humans and experimental animals as well as mechanistic evidence to support a causal link between outdoor (ambient) air pollution, and especially particulate matter (PM) in outdoor air, with lung cancer incidence and mortality. It is estimated that hundreds of thousands of lung cancer deaths annually worldwide are attributable to PM air pollution. Epidemiological evidence on outdoor air pollution and the risk of other types of cancer, such as bladder cancer or breast cancer, is more limited. Outdoor air pollution may also be associated with poorer cancer survival, although further research is needed. This report presents an overview of outdoor air pollutants, sources, and global levels, as well as a description of epidemiological evidence linking outdoor air pollution with cancer incidence and mortality. Biological mechanisms of air pollution-derived carcinogenesis are also described. This report concludes by summarizing public health/policy recommendations, including multilevel interventions aimed at individual, community, and regional scales. Specific roles for medical and health care communities with regard to prevention and advocacy and recommendations for further research are also described.

Influence of luminal and basal subtype in prognosis of high-grade non muscle invasive urothelial carcinoma.

BACKGROUND: Recent studies have shown that the classification of high-grade urothelial carcinoma non-muscle invasive (HGBCNMI) based on molecular subtypes might be a valuable strategy to identify patients with a worse clinical prognosis. OBJECTIVE: Determine the effect of the luminal and basal molecular subtype determined by immunistochemical on prognosis in patients with HGBC in Mexican population. METHODS: Phenotypes were evaluated by immunohistochemical staining of luminal (GATA3, FOXA1) and basal (CK5/6, CK14) markers in paraffin-embedded tissue samples from 45 patients with a diagnosis of HGBCNMI treated at Instituto Nacional de Cancerología-México (INCan) between 2009 and 2019. The association with prognosis was evaluated using Kaplan-Meier curves and multivariable-adjusted Cox models. RESULTS: HGBCNMI patients showed mean age of 58.77 years (SD: ±12.08 years). We identified expression of the luminal molecular subtype in 35 cases (77.78 %), and 10 cases (22.22 %) with "combined" expression of the molecular subtype (basal and luminal expression). The combined phenotype was statistically more frequent in metastatic cases (p-value = 0.028). In Kaplan-Meier curves, combined expression of luminal and basal molecular markers was associated with disease progression (p-value = 0.002, log-rank test). Cox regression models confirmed this association, which was not influenced by age (p-value = 0.007) or gender (p-value = 0.007). No association of phenotypes with overall survival (p-value = 0.860) or relapse (p-value = 0.5) was observed. CONCLUSION: The combined expression of immunohistochemical markers of the luminal and basal subtype might be considered as predictor for disease progression in patients with HGBCNMI in Mexican population.

Mutational Landscape of Bladder Cancer in Mexican Patients: KMT2D Mutations and chr11q15.5 Amplifications Are Associated with Muscle Invasion.

Bladder cancer (BC) is the most common neoplasm of the urinary tract, which originates in the epithelium that covers the inner surface of the bladder. The molecular BC profile has led to the development of different classifications of non-muscle invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC). However, the genomic BC landscape profile of the Mexican population, including NMIBC and MIBC, is unknown. In this study, we aimed to identify somatic single nucleotide variants (SNVs) and copy number variations (CNVs) in Mexican patients with BC and their associations with clinical and pathological characteristics. We retrospectively evaluated 37 patients treated between 2012 and 2021 at the National Cancer Institute-Mexico (INCan). DNA samples were obtained from paraffin-embedded tumor tissues and exome sequenced. Strelka2 and Lancet packages were used to identify SNVs and insertions or deletions. FACETS was used to determine CNVs. We found a high frequency of mutations in TP53 and KMT2D, gains in 11q15.5 and 19p13.11-q12, and losses in 7q11.23. STAG2 mutations and 1q11.23 deletions were also associated with NMIBC and low histologic grade.

Role of brain extracellular vesicles in air pollution-related cognitive impairment and neurodegeneration.

A relationship between environmental exposure to air pollution and cognitive impairment and neurological disorders has been described. Previous literature has focused on the direct effects of the air pollution components on neuronal and glial cells, as well as on involvement of oxidative stress and neuroinflammation on microglia and astrocyte reactivity. However, other mechanisms involved in the air pollution effects on central nervous system (CNS) toxicity can be playing critical roles. Increasingly, extracellular vesicle's (EVs) mediated intercellular communication is being recognized as impacting the development of cognitive impairment and neurological disorders like Alzheimer's disease and others. Here we describe the available evidence about toxic air pollutants and its components on brain, an involvement of brain cells specific and EVs types (based in the origin or in the size of EVs) in the initiation, exacerbation, and propagation of the neurotoxic effects (inflammation, neurodegeneration, and accumulation of neurotoxic proteins) induced by air pollution in the CNS. Additionally, we discuss the identification and isolation of neural-derived EVs from human plasma, the most common markers for neural-derived EVs, and their potential for use as diagnostic or therapeutic molecules for air pollution-related cognitive impairment and neurodegeneration.

Acantholytic squamous cell carcinomas of the cervix: A case series.

Squamous cell carcinoma of the uterine cervix is considered the most common histologic variant of cervical cancer, with well-established treatment protocols and prognosis. An infrequent histologic variant of cervical squamous cell carcinoma is the acantholytic variant (ASCC), which is characterized by discohesive cells that result in a pseudoglandular and/or angiomatoid pattern of growth. This variant of squamous cell carcinoma has been regarded as having a poor prognosis at certain anatomic sites such as the head and neck and vulva. In the uterine cervix, the importance of this variant has not been yet established. A ten-year retrospective review of squamous cell carcinoma of the uterine cervix was performed to identify this variant and correlate it with clinical characteristics to better define its prognostic implications. During the study period 19 cases were identified containing from 10 to 80% acantholytic component. Mean age at diagnosis was 49 years. Clinical stages were 1A2 (1 case), Ib1 (16), and IIA1 (2). Median follow-up was 92 months. When compared with controls, ASCC were larger in size (1.4 vs 3.5 cm), had deeper involvement of the cervical stroma (21 vs 47%), had more lymph node metastasis (8 vs 26%), more frequent recurrences (4 vs 15%) and a shorter disease-free survival; however, no statistical differences were identified in overall survival. ASCC is an infrequent variant of cervical cancer which seems to have an impact on disease-free survival but no in overall survival.

Somatic Mutational Landscape in Mexican Patients: CDH1 Mutations and chr20q13.33 Amplifications Are Associated with Diffuse-Type Gastric Adenocarcinoma.

The Hispanic population, compared with other ethnic groups, presents a more aggressive gastric cancer phenotype with higher frequency of diffuse-type gastric adenocarcinoma (GA); this could be related to the mutational landscape of GA in these patients. Using whole-exome sequencing, we sought to present the mutational landscape of GA from 50 Mexican patients who were treated at The Instituto Nacional de Cancerología from 2019 to 2020. We performed a comprehensive statistical analysis to explore the relationship of the genomic variants and clinical data such as tumor histology and presence of signet-ring cell, H. pylori, and EBV. We describe a potentially different mutational landscape between diffuse and intestinal GA in Mexican patients. Patients with intestinal-type GA tended to present a higher frequency of NOTCH1 mutations, copy number gains in cytobands 13.14, 10q23.33, and 12q25.1, and copy number losses in cytobands 7p12, 14q24.2, and 11q13.1; whereas patients with diffuse-type GA tended to present a high frequency of CDH1 mutations and CNV gains in cytobands 20q13.33 and 22q11.21. This is the first description of a mutational landscape of GA in Mexican patients to better understand tumorigenesis in Hispanic patients and lay the groundwork for discovering potential biomarkers and therapeutic targets.

Long-term PM2.5 exposure before diagnosis is associated with worse outcome in breast cancer.

PURPOSE: Increasingly epidemiological evidence supports that environmental factors are associated with breast cancer (BC) outcomes after a BC diagnosis. Although evidence suggests that air pollution exposure is associated with higher mortality in women with BC, studies investigating potential mechanisms have been lacking. METHODS: We evaluated women with BC (N = 151) attended at the National Cancer Institute-Mexico from 2012 to 2015. We calculated 1-year average exposures to particulate matter < 2.5 µm (PM2.5) at home address before diagnosis. We used linear and logistic regression models to determine the associations between PM2.5 exposure and BC aggressiveness (tumor size, molecular phenotype). RESULTS: Average annual PM2.5 exposure of this population was 23.0 µg/m3 [standard deviation (SD)]: 1.90 µg/m3]. PM2.5 levels were positively correlated with tumor size at diagnosis (r = 0.22; p = 0.007). Multivariable linear models had a similar inference [risk ratio (RR): 1.32; 95% confidence interval (95% CI): 1.04, 1.674]. We did not observe differences in this association by age or menopause status. Further, women with triple-negative BC (TNBC) had significantly higher PM2.5 levels compared with other phenotypes (p = 0.015). Multivariable-adjusted logistic regression models assessing the association between PM2.5 and tumor size had a similar inference (RR 1.41; 95% CI 1.05, 1.89) overall for all ages and also for women who were ≤ 50 years old at diagnosis (RR 1.63; 95% CI 1.036, 2.57). CONCLUSIONS: Our findings suggest a significant association between long-term PM2.5 exposure and BC aggressiveness based on tumor size and phenotype, as well as a worse outcome.

Nutritional Indexes as Predictors of Survival and Their Genomic Implications in Gastric Cancer Patients.

Gastric cancer is an aggressive malignancy with poor prognosis. Although obesity is a risk factor, an association between overweight and better survival has been reported. We explored the genomic implications of such association. Data from 940 patients were analyzed using Cox regression models and ROC curves to assess body mass index (BMI) and prognostic nutritional index (PNI) as predictors of survival. The exome sequencing of a random subset was analyzed to determine copy number variation (CNV) and single nucleotide variation (SNV), using Kruskal-Wallis and chi-square tests to evaluate their clinical implications. Overall survival was lower in patients with BMI ≤ 24.9 and PNI ≤ 29 (p < 0.001). BMI and survival were directly correlated (HR: 0.972, 95% CI: 0.953, 0.992; p-value < 0.007). A higher PNI correlated with improved survival (HR: 0.586, 95% CI: 0.429, 0.801; p-value <0.001). We found a PNI cutoff point of 41.00 for overall survival. Genomic analysis showed an association between lower BMI, less CNV events (p-value = 0.040) and loss of tumor suppressor genes (p-value = 0.021). BMI and PNI are independent factors for overall survival in gastric cancer, probably linked to variations in genomic intratumoral alterations.

Is your environment making you older? Molecular biomarkers and new approaches to investigate the influences of environmental chemicals through aging.

Aging is characterized by a gradual and progressive decline in system integrity that occurs with advancing chronological age. Although it is a physiological process, aging is associated with a myriad of age-related diseases (ARDs), including frailty, sarcopenia, chronic obstructive pulmonary disease, cardiovascular disease, cancer, and neurodegenerative diseases. While not exclusively ARDs, many of these diseases lead to death, a lesser quality of life, and increased healthcare costs for individuals and systems. ARDs share several underlying molecular mechanisms, such as cellular damage, inflammation, DNA methylation changes, stem cells exhaustion, and DNA mutations, which have been outlined as hallmarks of aging. Evidence suggests that environmental exposures, including but not limited to metals, air pollution, endocrine-disrupting chemicals, and noise, may accelerate biological aging. Over the past few years, aging research has identified new molecular biomarkers of the aging process. When applied to investigate environmental influences, these biomarkers can help identify individuals who are particularly susceptible to the influences of environmental exposures on aging processes and therefore guide in implementing possible preventive measures.

Time in range and HbA1C after 6 months with a multidisciplinary program for children and adolescents with diabetes mellitus, real world data from Mexico City.

BACKGROUND: Multidisciplinary interventions may be useful for children and adolescents with diabetes mellitus (DM), especially in areas where new blood glucose monitoring and control technologies are difficult to access. METHODS: PAANDA, a care program for adolescents and children with diabetes, was implemented in patients aged 0 to 18 years and 11 months. The effect of the intervention was determined by self-blood glucose monitoring (SBGM) and glycosylated hemoglobin (HbA1C ) levels at start and after 6 months. RESULTS: A total of 121 patients with DM were evaluated, mean age of 14.27 years (SD: 4.60 years). Blood glucose measurements in range (70-120 mg/dL pre-prandial or 70-180 mg/dL post-prandial) increased by 20.67% before breakfast, 8.14% after breakfast (both P-value <.001), 5.02% before lunch (P-value = .02), 8.66% after lunch (P-value <.001), 11.50% before dinner (P-value <.001), 11.87% after dinner (P-value <.001), and 8.00% at dawn (P-value = .001). This change was accompanied by fewer values in the hyperglycemic category (-19.49% before breakfast, -7.73% after breakfast, both P-value <.001) and hypoglycemia (-1.18%). HbA1C levels decreased significantly 1.8% (P-value = .018). Multivariate logistic regression analysis showed an increase in glycemic control associated with each month after the intervention time in the PAANDA program (P-value <.001 for all the time points evaluated) and a significant decrease in glycemic variability. CONCLUSIONS: The multidisciplinary PAANDA intervention had a beneficial effect on glycemic control, with an improved time in range in a population of children and adolescents with DM.

Role of social and other determinants of health in the effect of a multicomponent integrated care strategy on type 2 diabetes mellitus.

BACKGROUND: Although important advances in treatment strategies have been developed in type 2 diabetes mellitus (T2DM), large gaps exist in achieving glycemic control and preventing complications, particularly in low-and middle-income countries, which suggests a potential effect of social determinants of health (SDH, i.e., education level and socioeconomic status). However, few studies have determined the role of SDH and other determinants of health (ODH, i.e., diabetes knowledge and self-care scores) in achieving T2DM goals during effective multidisciplinary interventions. We aimed to examine a multicomponent integrated care (MIC) program on diabetes care goals and determine the effect of SDH and ODH on T2DM patients. METHODS: A before-and-after design (a pretest, a 5-month intervention, and a follow-up) was used in a T2DM population from Mexico City. The SDH included education level and socioeconomic status; the ODH included diabetes knowledge, self-care scores, and deltas (i.e., differences between baseline and follow-up scores). The triple-target goal (glycated hemoglobin, blood pressure, and LDL-cholesterol) was established as a measurement of T2DM goals. RESULTS: The DIABEMPIC (DIABetes EMPowerment and Improvement of Care) intervention (n = 498) reduced the glycated hemoglobin levels (mean reduction 2.65%, standard deviation [SD]: 2.02%) and cardiometabolic parameters; it also improved health-related quality of life. From 1.81% at baseline, 25.9% of participants (p-value< 0.001) achieved the triple-target goal. We found a significant association between education level (p-value = 0.010), diabetes knowledge at baseline (p-value = 0.004), and self-care scores at baseline (p-value = 0.033) in the delta (change between baseline and follow-up assessments) of HbA1c levels. Improvements (increase) in diabetes knowledge (p-value = 0.006) and self-care scores (p-value = 0.002) were also associated with greater reductions in HbA1c. CONCLUSIONS: MIC strategies in urban primary care settings contribute to control of T2DM. SDH, such as education level, and ODH (diabetes knowledge and self-care scores at baseline) play a key role in improving glycemic control in these settings.

Influence of social determinants, diabetes knowledge, health behaviors, and glycemic control in type 2 diabetes: an analysis from real-world evidence.

BACKGROUND: Although important achievements have been done in type 2 diabetes mellitus (T2D) treatment and glycemic control, new strategies may take advantage of non-pharmacological approaches and of other potential determinants of health (e.g., socioeconomic status, education, diabetes knowledge, physical activity, and self-care behavior). However, the relationships between these factors are not totally clear and have not been studied in the context of large urban settings. This study aimed to explore the relationship between these determinants of glycemic control (GC) in a low-income urban population from Mexico City, focused in exploring potential the mediation of self-care behaviors in the association between diabetes knowledge and GC. METHODS: A multicenter cross-sectional study was conducted in patients with type 2 diabetes (T2D) from 28 primary care outpatient centers located in Mexico City. Using multivariable-adjusted models, we determined the associations between diabetes knowledge, self-care behaviors, and GC. The mediation analyses to determine the pathways on glycemic control were done using linear regression models, where the significance of indirect effects was calculated with bootstrapping. RESULTS: The population (N = 513) had a mean age of 53.8 years (standard deviation: 11.3 yrs.), and 65.9% were women. Both socioeconomic status and level of education were directly associated with diabetes knowledge. Using multivariable-adjusted linear models, we found that diabetes knowledge was associated with GC (ß: -0.102, 95% Confidence Interval [95% CI] -0.189, - 0.014). Diabetes knowledge was also independently associated with self-care behavior (for physical activity: ß: 0.181, 95% CI 0.088, 0.273), and self-care behavior was associated with GC (for physical activity: ß: -0.112, 95% CI -0.194, - 0.029). The association between diabetes knowledge and GC was not observed after adjustment for self-care behaviors, especially physical activity (ß: -0.084, 95% CI -0.182, 0.014, p-value: 0.062). Finally, the mediation models showed that the effect of diabetes knowledge on GC was 17% independently mediated by physical activity (p-value: 0.049). CONCLUSIONS: Socioeconomic and educational gradients influence diabetes knowledge among primary care patients with type 2 diabetes. Self-care activities, particularly physical activity, mediated the effect of diabetes knowledge on GC. Our results indicate that diabetes knowledge should be reinforced in low-income T2D patients, with an emphasis on the benefits physical activity has on improving GC.

Molecular and cellular mechanisms linking air pollution and bone damage.

Air pollution is the second most important risk factor associated with noncommunicable diseases after smoking. The effects of pollution on health are commonly attributable to particulate matter (PM), a complex mixture of particles suspended in the air. PM can penetrate the lower respiratory tract and has harmful direct and indirect effects on different organs and tissues. Direct effects are caused by the ability of PM components to cross the respiratory membrane and enter the bloodstream; indirect effects are systemic consequences of the local airway response. Recent work suggests that PM is an independent risk factor for low bone mineral density and osteoporosis-related fractures. Osteoporosis is a common age-related disease closely linked to bone fractures, with severe clinical consequences affecting quality of life, morbidity, and mortality. In this review, we discuss potential mechanisms behind the association between outdoor air pollution, especially PM, and bone damage. The discussion features four main mechanisms: 1) several different atmospheric pollutants can induce low-grade systemic inflammation, which affects bone metabolism through a specific effect of cytokines such as TNFα, IL-1ß, IL-6, and IL-17 on osteoblast and osteoclast differentiation and function; 2) some pollutants, particularly certain gas and metal compounds, can cause oxidative damage in the airway and bone cells; 3) different groups of pollutants can act as endocrine disruptors when binding to the receptors in bone cells, changing their functioning; and 4) air pollution can directly and indirectly cause vitamin D deficiency. Characterizing these mechanisms will better define the physiopathology of bone damage, and recognizing air pollution as a modifiable risk factor for osteoporosis will inform environmental policies. Such knowledge will also guide the prevention of fractures due to fragility and help reduce health-related costs.

Diagnostic performance of intraoperative assessment in grade 2 endometrioid endometrial carcinoma.

BACKGROUND: Endometrial carcinoma is the most common gynecologic malignancy in developed countries. Grade 2 carcinoma is associated with pelvic lymph-node metastasis, depending on selected risk factors. Intraoperative assessment (IOA) can identify patients at risk for lymph node metastasis who should undergo staging surgery. Our objective was to establish the diagnostic precision of IOA in determining the need for surgical staging in grade 2 endometrioid endometrial carcinoma. METHODS: Two hundred twenty-two patients underwent IOA. Results were compared to the final pathology report. The accuracy of the IOA parameters was calculated. Variables were evaluated in patients with positive versus negative IOA. Overall and disease-free survivals were calculated according to IOA, lymphadenectomy, and nodal metastasis. RESULTS: IOA was positive in 80 patients. It showed an accuracy of 76.13% when compared with the postoperative assessment. The best individual parameter was myometrial invasion. Nodal metastasis was observed in 16 patients in the positive IOA group and 7 patients in the negative group. Patients with lymph node metastasis had a 5-year overall survival rate of 80.9%, whereas patients without metastasis had a 5-year overall survival rate of 97.9%. CONCLUSIONS: IOA is an adequate tool to identify high-risk patients in grade 2 endometrial carcinoma. Myometrial invasion is the individual parameter that yields the highest diagnostic precision.

What is the impact of radical hysterectomy on endometrial cancer with cervical involvement?

BACKGROUND: When endometrial carcinoma invades the cervical stroma, overall survival and disease-free survival decrease. However, it is still controversial whether patients in suspected stage II should be treated with radical hysterectomy. The goal of this study is to describe the role of radical hysterectomy in patients with endometrial carcinoma and cervical involvement. METHODS: This was a retrospective cohort study were a total of 239 patients with endometrial carcinoma with cervical involvement from Mexico City's National Cancer Institute were divided according to the type of hysterectomy, and the outcomes were compared using statistical analysis. RESULTS: The 5-year overall survival was 75.76% for the simple hysterectomy group and 89.19% for the radical hysterectomy group, without achieving statistical significance. The 5-year disease-free survival was 72.95% for the simple hysterectomy group and 64.31% for the radical hysterectomy group, without achieving statistical significance. Radicality was associated with longer surgical times, intraoperative complications, and bleeding over 500 ml. CONCLUSIONS: In patients with endometrial carcinoma with cervical involvement, radical hysterectomy does not improve prognosis or alter adjuvant therapy.

Meta-analysis of epigenome-wide association studies of cognitive abilities.

Cognitive functions are important correlates of health outcomes across the life-course. Individual differences in cognitive functions are partly heritable. Epigenetic modifications, such as DNA methylation, are susceptible to both genetic and environmental factors and may provide insights into individual differences in cognitive functions. Epigenome-wide meta-analyses for blood-based DNA methylation levels at ~420,000 CpG sites were performed for seven measures of cognitive functioning using data from 11 cohorts. CpGs that passed a Bonferroni correction, adjusting for the number of CpGs and cognitive tests, were assessed for: longitudinal change; being under genetic control (methylation QTLs); and associations with brain health (structural MRI), brain methylation and Alzheimer's disease pathology. Across the seven measures of cognitive functioning (meta-analysis n range: 2557-6809), there were epigenome-wide significant (P < 1.7 × 10-8) associations for global cognitive function (cg21450381, P = 1.6 × 10-8), and phonemic verbal fluency (cg12507869, P = 2.5 × 10-9). The CpGs are located in an intergenic region on chromosome 12 and the INPP5A gene on chromosome 10, respectively. Both probes have moderate correlations (~0.4) with brain methylation in Brodmann area 20 (ventral temporal cortex). Neither probe showed evidence of longitudinal change in late-life or associations with white matter brain MRI measures in one cohort with these data. A methylation QTL analysis suggested that rs113565688 was a cis methylation QTL for cg12507869 (P = 5 × 10-5 and 4 × 10-13 in two lookup cohorts). We demonstrate a link between blood-based DNA methylation and measures of phonemic verbal fluency and global cognitive ability. Further research is warranted to understand the mechanisms linking genomic regulatory changes with cognitive function to health and disease.

Role of optimal cytoreduction in patients with dysgerminoma.

BACKGROUND: Dysgerminomas are malignant ovarian germ-cell tumors that typically affect young women. Although these tumors have an excellent response to chemotherapy, surgery is an integral part of primary treatment. OBJECTIVE: To evaluate outcomes of initial cytoreduction in patients diagnosed with dysgerminomas. METHODS: Patients who underwent primary cytoreductive surgery for ovarian dysgerminoma between January 1985 and December 2013 were identified and included in the study. A comparison was made between patients who underwent optimal versus sub-optimal cytoreduction. Descriptive, comparative statistics and odds ratios were used to establish an association. Survival curves were performed with the Kaplan-Meier method and compared using a log-rank test. A value of p<0.05 was used to establish a statistical difference. RESULTS: A total of 180 patients with a histologically confirmed dysgerminoma were included in the analysis. A subsection of 37 patients in stages III/IV were analyzed. The median age at diagnosis was 21 years (IQR 18-26). Histologically, 166 (92.2%) patients had pure dysgerminomas, whereas the rest had mixed histologies. The median tumor size was 18 (IQR 12-22) cm. In all stages, factors associated with optimal cytoreduction, were higher lactate dehydrogenase levels (OR=1.01; p=0.03), higher CA125 levels (OR=1.01; p=0.04), receiving adjuvant chemotherapy (OR=0.22; p<0.01), or undergoing treatment in a specialized institution (OR=12.68; p<0.01). Patients in stages III/IV, initially managed outside our institution were less likely to be taken for cytoreduction (OR=16.88; p=0.013). Other factors, including age (OR=1.02; p=0.39), pelvic lymph-node positivity (OR=2.24; p=0.36), pregnancy during follow-up (OR=0.91: p=0.80), or recurrence of disease (OR=1.93; p=0.23) were found to be similar in both groups. Overall survival was higher in optimally cytoreducted patients (100% vs 95.7%; p=0.032) including all stages, but not if considering only stages III/IV (100% vs 90%, p=0.186); disease-free survival was the same for both groups regardless of stage (94.3% vs 91.1%; p=0.36). CONCLUSION: Patients with optimal surgeries were most likely to be treated in referral centers. Initial residual disease did not significantly alter recurrence, progression, disease-free survival, or overall survival.

Impacto económico de los inhibidores en hemofilia tipo A pediátrica.

INTRODUCTION: Few studies have assessed the economic impact of inhibitors in hemophilia A in Mexico, especially in the pediatric population. OBJECTIVE: To determine the economic impact entailed by the development of inhibitors in pediatric patients with hemophilia A. METHOD: Patients with hemophilia A under the care of a pediatric hematology department between December 2015 and November 2017 were retrospectively assessed. Direct and indirect costs were determined based on the presence or absence of inhibitors. RESULTS: The cost analysis of the study population (n = 24) showed that diagnosis, follow-up, prophylaxis, treatment and hospitalization of these patients had an annual cost of $ 6 883 187.4 per patient, out of which more than 95 % depended on the use of hemostatic factors. Annual cost per patient in the group with inhibitors was $ 5 548 765.0 in comparison with $ 1 334 422.4 in the group without inhibitors, 4.2 times higher. CONCLUSIONS: This is the first national study to show that the presence of inhibitors in pediatric patients with hemophilia A increases the cost of the disease more than four times.

INTRODUCCIÓN: Pocos estudios han evaluado el impacto económico de los inhibidores en hemofilia tipo A en México, especialmente en población pediátrica. OBJETIVO: Determinar el impacto económico que conlleva el desarrollo de inhibidores en pacientes pediátricos con hemofilia tipo A. MÉTODO: Se evaluaron de forma retrospectiva los pacientes con hemofilia tipo A atendidos en un servicio de hematología pediátrica entre diciembre de 2015 y noviembre de 2017, y se determinaron los costos directos e indirectos a partir de la presencia o ausencia de inhibidores. RESULTADOS: El análisis de costos de la población estudiada (n = 24) mostró que el diagnóstico, seguimiento, profilaxis, tratamiento y hospitalización de estos pacientes tuvo un costo de $6 883 187.4 anuales por paciente, de los cuales más de 95 % dependió del uso de factores hemostáticos. El costo anual por paciente en el grupo con inhibidores tuvo un costo de $5 548 765.0, en comparación con $1 334 422.4 del grupo sin inhibidores, 4.2 veces superior. CONCLUSIONES: Se trata del primer estudio nacional que muestra que el desarrollo de inhibidores en pacientes pediátricos con hemofilia tipo A eleva más de cuatro veces la erogación económica derivada de esta enfermedad.

Extracellular vesicle-enriched microRNAs interact in the association between long-term particulate matter and blood pressure in elderly men.

BACKGROUND: Several studies have shown that exposure to particulate matter (PM) may lead to increased systemic blood pressure, but the underlying biological mechanisms remain unknown. Emerging evidence shows that extracellular vesicle-enriched miRNAs (evmiRNAs) are associated with PM exposure and cardiovascular risk. In this study, we investigated the role of evmiRNAs in the association between PM and blood pressure, as well as their epigenetic regulation by DNA methylation. METHODS: Participants (n = 22, men) were randomly selected from the Veterans Affairs Normative Aging Study (NAS). Long-term (1-year and 6-month average) PM2.5 exposure was estimated at 1 × 1-km resolution using spatio-temporal prediction models and BC was estimated using validated time varying land use regression models. We analyzed 31 evmiRNAs detected in ≥ 90% of all individuals and for statistical analysis, we used mixed effects models with random intercept adjusted for age, body mass index, smoking, C-reactive protein, platelets, and white blood cells. RESULTS: We found that per each 2-standard deviations increase in 6-month PM2.5 ambient levels, there was an increase in 0.19 mm Hg (95% Confidence Interval [95%CI]: 0.11, 0.28 mmHg; p < 0.001) in systolic blood pressure (SBP). Per each 2-standard deviations increase in 1-year PM2.5 levels, there was an increase in 0.11 mm Hg (95% Confidence Interval [95% CI]: 0.03, 0.19 mmHg; p = 0.012) in SBP in older male individuals. We also found that both miR-199a/b (ß = 6.13 mmHg; 95% CI: 0.87, 11.39; pinteraction = 0.07) and miR-223-3p (ß = 30.17 mmHg; 95% CI: 11.96, 48.39 mmHg; pinteraction = 0.01) modified the association between 1-year PM2.5 and SBP. When exploring DNA methylation as a potential mechanism that could epigenetically regulate expression of evmiRNAs, we found that PM2.5 ambient levels were negatively associated with DNA methylation levels at CpG (cg23972892) near the enhancer region of miR-199a/b (ß = -13.11; 95% CI: -17.70, -8.52; pBonferroni< 0.01), but not miR-223-3p. CONCLUSIONS: Our findings suggest that expression of evmiRNAs may be regulated by DNA methylation in response to long-term PM2.5 ambient levels and modify the magnitude of association between PM2.5 and systolic blood pressure in older individuals.

Traffic-Related Air Pollution, Blood Pressure, and Adaptive Response of Mitochondrial Abundance.

BACKGROUND: Exposure to black carbon (BC), a tracer of vehicular-traffic pollution, is associated with increased blood pressure (BP). Identifying biological factors that attenuate BC effects on BP can inform prevention. We evaluated the role of mitochondrial abundance, an adaptive mechanism compensating for cellular-redox imbalance, in the BC-BP relationship. METHODS AND RESULTS: At ≥ 1 visits among 675 older men from the Normative Aging Study (observations=1252), we assessed daily BP and ambient BC levels from a stationary monitor. To determine blood mitochondrial abundance, we used whole blood to analyze mitochondrial-to-nuclear DNA ratio (mtDNA/nDNA) using quantitative polymerase chain reaction. Every standard deviation increase in the 28-day BC moving average was associated with 1.97 mm Hg (95% confidence interval [CI], 1.23-2.72; P<0.0001) and 3.46 mm Hg (95% CI, 2.06-4.87; P<0.0001) higher diastolic and systolic BP, respectively. Positive BC-BP associations existed throughout all time windows. BC moving averages (5-day to 28-day) were associated with increased mtDNA/nDNA; every standard deviation increase in 28-day BC moving average was associated with 0.12 standard deviation (95% CI, 0.03-0.20; P=0.007) higher mtDNA/nDNA. High mtDNA/nDNA significantly attenuated the BC-systolic BP association throughout all time windows. The estimated effect of 28-day BC moving average on systolic BP was 1.95-fold larger for individuals at the lowest mtDNA/nDNA quartile midpoint (4.68 mm Hg; 95% CI, 3.03-6.33; P<0.0001), in comparison with the top quartile midpoint (2.40 mm Hg; 95% CI, 0.81-3.99; P=0.003). CONCLUSIONS: In older adults, short-term to moderate-term ambient BC levels were associated with increased BP and blood mitochondrial abundance. Our findings indicate that increased blood mitochondrial abundance is a compensatory response and attenuates the cardiac effects of BC.