Manejo de Hipertensión Arterial en Pacientes con Enfermedad Coronaria

Dogma Disputed: Can Aggressively Lowering Blood Pressure in Hypertensive Patients with Coronary Artery Disease Be Dangerous?
Franz H. Messerli, MD; Giuseppe Mancia, MD; C. Richard Conti, MD; Ann C. Hewkin, MSc; Stuart Kupfer, MD; Annette Champion, MBA; Rainer Kolloch, MD; Athanase Benetos, MD; and Carl J. Pepine, MD
Annals of Internal Medicine 20 June 2006 Volume 144 Issue 12 Pages 884-893

Background: Because coronary perfusion occurs mainly during diastole, patients with coronary artery disease (CAD) could be at increased risk for coronary events if diastolic pressure falls below critical levels.

Objective: To determine whether low blood pressure could be associated with excess mortality and morbidity in this population.

Design: A secondary analysis of data from the International Verapamil-Trandolapril Study (INVEST), which was conducted from September 1997 to February 2003.

Setting: 862 sites in 14 countries.

Patients: 22 576 patients with hypertension and CAD.

Interventions: Patients from INVEST were randomly assigned to a verapamil sustained-release– or atenolol-based strategy; blood pressure control and outcomes were equivalent.

Measurements: An unadjusted quadratic proportional hazards model was used to evaluate the relationship between average on-treatment blood pressure and risk for the primary outcome (all-cause death, nonfatal stroke, and nonfatal myocardial infarction [MI]), all-cause death, total MI, and total stroke. A second model adjusted for differences in baseline covariates.
Results: The relationship between blood pressure and the primary outcome, all-cause death, and total MI was J-shaped, particularly for diastolic pressure, with a nadir at 119/84 mm Hg. After adjustment, the J-shaped relationship persisted between diastolic pressure and primary outcome. The MI–stroke ratio remained constant over a wide blood pressure range, but at a lower diastolic blood pressure, there were substantially more MIs than strokes. An interaction between decreased diastolic pressure and history of revascularization was observed; low diastolic pressure was associated with a relatively lower risk for the primary outcome in patients with revascularization than in those without revascularization.

Limitations: This is a post hoc analysis of hypertensive patients with CAD.

Conclusions: The risk for the primary outcome, all-cause death, and MI, but not stroke, progressively increased with low diastolic blood pressure. Excessive reduction in diastolic pressure should be avoided in patients with CAD who are being treated for hypertension.

Metaanálisis de Antibióticos Profilácticos en Hernioplastía con Malla Inguinal

Prophylactic Antibiotics for Mesh Inguinal Hernioplasty: A Meta-analysis.
Annals of Surgery. 245(3):392-396, March 2007.
Sanabria, Alvaro MD, MSc; Dominguez, Luis Carlos MD, MSc; Valdivieso, Eduardo MD, MSc; Gomez, Gabriel MD, MPH

Objective: To assess the effectiveness of antibiotic prophylaxis in mesh hernioplasty.

Background: Antibiotic prophylaxis use in mesh inguinal hernioplasty is controversial. Available evidence is nonconclusive because of the low number of clinical trials assessing its effectiveness. Some trials have a small sample size that could overestimate or underestimate the real effectiveness of this intervention. Meta-analysis is a good method to improve these methodological flaws.

Methods: Meta-analysis intended to measure the benefits of antibiotic prophylaxis on surgical site infection rate in adult patients scheduled for mesh inguinal hernioplasty. Six randomized clinical trials were found. Quality was assessed using Cochrane Collaboration criteria.

Results: A total of 2507 patients were analyzed. Surgical site infection frequency was 1.38% in the antibiotic group versus 2.89% in the control group (odds ratio = 0.48; 95% confidence interval, 0.27-0.85). There was no statistical heterogeneity. Sensitivity analysis by quality did not show differences in overall results.

Conclusion: Antibiotic prophylaxis use in patients submitted to mesh inguinal hernioplasty decreased the rate of surgical site infection by almost 50%.

Cirugía Laparoscopica sin Trocares ¿Es Posible?

Trocar-less Instrumentation for Laparoscopy: Magnetic Positioning of Intra-abdominal Camera and Retractor.
Annals of Surgery. 245(3):379-384, March 2007.
Park, Sangtae MD, MPH; Bergs, Richard A. MS; Eberhart, Robert PhD; Baker, Linda MD; Fernandez, Raul PhD; Cadeddu, Jeffrey A. MD

Objective: To develop a novel laparoscopic system of moveable instruments that are positioned intra-abdominally and "locked" into place by external permanent magnets placed on the abdomen.

Summary Background Data: In conventional laparoscopy, multiple trocars are required because of the limited degrees of freedom of conventional instrumentation, and the limited working envelope (an inverted cone) created by the fulcrum motion around each port. While robotic systems can improve the number of degrees of freedom, they are restricted by even smaller working envelopes.

Methods: A collaborative research group from the Department of Urology and the Automation & Robotics Research Institute of the University of Texas, Arlington built a prototype system of magnetically anchored instruments for trocar-less laparoscopy. The only design mandate was that the developed technology be able to pass into the abdomen through one existing 12-mm diameter trocar.

Results: A transabdominal "magnetic anchoring and guidance system" (MAGS) platform was developed to incorporate instruments, retractors, and a controllable intra-abdominal camera. In vitro, the platform was able to anchor 375 and 147 g across porcine tissue 1.8 and 2.5 cm thick, respectively. The permanent magnet platforms were sufficiently strong to retract the porcine liver and securely anchor the camera. Its versatility was demonstrated by moving the camera to virtually any location in the peritoneum with no working envelope restrictions and the subsequent completion of porcine laparoscopic procedures with 2 trocars only.

Conclusions: Trocar-less laparoscopy using magnetically anchored instruments is feasible and may expand intracorporeal instrument manipulation substantially beyond current-day capability. The ability to reduce the number of trocars necessary for laparoscopic surgery has the potential to revolutionize surgical practice.

Alvimopan para Prevenir el Ileo Postoperatorio tras Resecciones Intestinales

Alvimopan, for Postoperative Ileus Following Bowel Resection: A Pooled Analysis of Phase III Studies.
Annals of Surgery. 245(3):355-363, March 2007.
Delaney, Conor P. MD, PhD; Wolff, Bruce G. MD; Viscusi, Eugene R. MD; Senagore, Anthony J. MD, MS, MBA; Fort, John G. MD; Du, Wei PhD ; Techner, Lee DPM; Wallin, Bruce MD

Objective: To obtain further analysis regarding specific outcomes and alvimopan doses in bowel resection (BR) patients.

Summary Background Data: Although postoperative ileus (POI) is common after BR, there is currently no recognized treatment or prevention available. Alvimopan, a novel, peripherally active mu-opioid receptor antagonist, accelerated GI recovery after BR or hysterectomy in 3 phase III trials.

Methods: A pooled retrospective subset analysis of BR patients in alvimopan phase III trials was performed. Randomized BR patients received alvimopan 6 mg (n = 397), 12 mg (n = 413), or placebo (n = 402) >=2 hours before surgery and twice daily until hospital discharge for <=7 days. The primary endpoint of each trial was time to recovery of GI function. Hospital discharge order (DCO) written, readmission, and morbidities were also assessed. Cox proportional hazard models were used to analyze treatment effects on time-to-event endpoints.

Results: Alvimopan (6 or 12 mg) significantly accelerated GI recovery (GI-3; hazard ratio = 1.28 and 1.38, respectively; P <= 0.001 for both). Alvimopan significantly accelerated time to DCO written by 16 hours for 6 mg and 18 hours for 12 mg (P < 0.001 for both) from a mean of 147 hours for placebo. Alvimopan-treated patients had reduced postoperative morbidity compared with placebo, and incidence of prolonged hospital stay or readmission was significantly reduced (P < 0.001). Tolerability profiles were similar among groups.

Conclusions: Alvimopan significantly accelerated GI recovery in BR patients. A 12-mg dose provided more consistent benefits across both sexes and all ages. Postoperative morbidity rates, prolonged hospital stay, and rates of hospital readmission were significantly reduced. Alvimopan reduces the consequences of POI after BR.

Colesterol y Albúmina Como Marcadores de Riesgo en Cirugía

Cholesterol and serum albumin as risk factors for death in patients undergoing general surgery
British Journal of Surgery march 2007 p.369-375
S. Palma, A. Cosano, M. Mariscal, G. Martínez-Gallego, M. Medina-Cuadros, M. Delgado-Rodríguez
Abstract
Serum levels of total cholesterol, its fractions (high-density lipoprotein-cholesterol (HDL-C) and low-density lipoprotein-cholesterol) and albumin are related to a poor outcome during hospital stay. It has been not assessed whether they are related to death in the long term after general surgery.
This prospective cohort study included 2848 general surgical patients with a median follow-up of 6 years after discharge from hospital. Sampling for biochemical measurements was done at the time of admission.
The outcome investigated was all-cause mortality and multivariable Cox regression was used for statistical analysis.
Three hundred and seventy-eight patients (13·3 per cent) died during follow-up. Serum albumin (adjusted hazard ratio (HR) 2·2 (95 per cent confidence interval (c.i.) 1·5 to 3·4) for lowest versus highest quintile), total cholesterol (HR 1·6 (95 per cent c.i. 1·1 to 2·3) for lowest versus highest quintile) and HDL-C (HR 1·6 (95 per cent c.i. 1·1 to 2·4) for lowest versus highest quintile) showed a significant inverse relationship with all-cause mortality in both crude and multivariable analyses.
Serum albumin and HDL-C were associated with death for up to 2 years after surgery, whereas total cholesterol had the strongest association more than 2 years after discharge.Low levels of serum albumin, total cholesterol and HDL-C are associated with death after discharge from hospital in patients having general surgery

Analgesia con Opiacios en Dolor Abdominal

Utilización de analgésicos opiáceos en el proceso diagnóstico y de toma de decisiones sobre pacientes con dolor abdominal agudo no traumático. Revisión sistemática de la literatura

Carlos Manterola, Viviana Pineda, Manuel Vial, Paula Astudillo.
Departamento de Cirugía. Facultad de Medicina. Universidad de La Frontera. Temuco. Chile.

Introducción. Hay controversia acerca del uso de analgesia durante el proceso diagnóstico y la toma de decisiones sobre pacientes con dolor abdominal agudo no traumático (DAA). El objetivo de este estudio es determinar si el uso de analgésicos opiáceos (AO) en pacientes con DAA puede incrementar el riesgo de error diagnóstico.

Método. Revisión sistemática de la literatura. Se incluyeron ensayos clínicos aleatorizados (ECA), sin restricción idiomática, que comparasen el uso de AO o placebo en pacientes con DAA, administrados antes de cualquier intervención. Fueron excluidos los ECA con temática no atingente. Las variables consideradas fueron la edad, el sexo, los porcentajes de efectos adversos, apendicitis, cambios al examen físico y error diagnóstico, la modificación de la intensidad del dolor medido por escala visual analógica y la calidad metodológica de los estudios. Se realizó una búsqueda en las bases de datos MEDLINE y Cochrane, utilizando términos MeSH. El análisis de cada artículo fue realizado aplicando una puntuación de calidad metodológica mediante la que se calcularon promedios ponderados para cada variable. Se aplicaron las pruebas estadísticas de la χ² y de la t de Student para comparación de grupos.

Resultados. Se encontraron 6 artículos que cumplían los criterios de selección cuya puntuación de calidad metodológica promedio fue de 21,6. Los estudios incluyen a una población de 363 pacientes tratados con opiáceos y 336 con placebo, sin diferencias en promedio de edad (39,4 y 39,6 años), distribución por sexos, prevalencia de apendicitis aguda (el 23,3 y el 24%) ni error diagnóstico (el 15,6 y el 21,1%; p = 0,0637). Se verificó que había diferencias en la variable reducción del dolor (27,2 y 7,2 mm, respectivamente; p = 0,0167).

Conclusiones. El uso de AO en pacientes con DAA no incrementa el riesgo de error diagnóstico y reduce el dolor durante el proceso de toma de decisiones.

Acceso directo al trabajo completo en español formato PDF haciendo click en el título de este entry.

Pancreatitis Crónica: Drenaje del Conducto Pancreatico Quirúrgico vs Endoscópico

Endoscopic versus Surgical Drainage of the Pancreatic Duct in Chronic Pancreatitis
N Engl J Med Feb 2007; 356(7):676-84
Djuna L. Cahen, M.D., Dirk J. Gouma, M.D., Ph.D., Yung Nio, M.D., Erik A. J. Rauws, M.D., Ph.D., Marja A. Boermeester, M.D., Ph.D., Olivier R. Busch, M.D., Ph.D., Jaap Stoker, M.D., Ph.D., Johan S. Laméris, M.D., Ph.D., Marcel G.W. Dijkgraaf, Ph.D., Kees Huibregtse, M.D., Ph.D., and Marco J. Bruno, M.D., Ph.D.

Background For patients with chronic pancreatitis and a dilated pancreatic duct, ductal decompression is recommended. We conducted a randomized trial to compare endoscopic and surgical drainage of the pancreatic duct.

Methods All symptomatic patients with chronic pancreatitis and a distal obstruction of the pancreatic duct but without an inflammatory mass were eligible for the study. We randomly assigned patients to undergo endoscopic transampullary drainage of the pancreatic duct or operative pancreaticojejunostomy. The primary end point was the average Izbicki pain score during 2 years of follow-up. The secondary end points were pain relief at the end of follow-up, physical and mental health, morbidity, mortality, length of hospital stay, number of procedures undergone, and changes in pancreatic function.

Results Thirty-nine patients underwent randomization: 19 to endoscopic treatment (16 of whom underwent lithotripsy) and 20 to operative pancreaticojejunostomy. During the 24 months of follow-up, patients who underwent surgery, as compared with those who were treated endoscopically, had lower Izbicki pain scores (25 vs. 51, P<0.001) and better physical health summary scores on the Medical Outcomes Study 36-Item Short-Form General Health Survey questionnaire (P=0.003). At the end of follow-up, complete or partial pain relief was achieved in 32% of patients assigned to endoscopic drainage as compared with 75% of patients assigned to surgical drainage (P=0.007). Rates of complications, length of hospital stay, and changes in pancreatic function were similar in the two treatment groups, but patients receiving endoscopic treatment required more procedures than did patients in the surgery group (a median of eight vs. three, P<0.001).

Conclusions Surgical drainage of the pancreatic duct was more effective than endoscopic treatment in patients with obstruction of the pancreatic duct due to chronic pancreatitis.

Panamerican Journal of Trauma

Aquí podran acceder al Panamerican Journal of Trauma con los trabajos presentados y publicados para el Congreso Panamericano de Trauma 2006.

Formato PDF 108 páginas

http://www.panamtrauma.org/J%20of%20Trauma%20vol13%20no.02.pdf

Reposición de Volumen y Hemorragia

The Resuscitative Fluid You Choose May Potentiate Bleeding.
Journal of Trauma-Injury Infection & Critical Care. 61(6):1350-1358, December 2006.Brummel-Ziedins, Kathleen PhD; Whelihan, Matthew F. BS; Ziedins, Eduards G. MD; Mann, Kenneth G. PhD

Background: Trauma is the leading cause of death in the younger population in the United States, frequently from the development of hemorrhagic shock. Controversy exists over the type of volume resuscitation for restoring hemodynamic stability that should be used in hemorrhagic shock. Little is known about how various resuscitative paradigms affect the coagulation cascade, which is essential to controlling hemorrhagic shock.

Methods: We studied the effect of various resuscitative formulas on blood coagulation using a new model of whole blood in a controlled setting with corn trypsin inhibitor and a 5-pM stimulus of tissue factor. We investigated thrombin generation, fibrin formation, and platelet activation with four diluents: 0.9% NaCl (NS), lactated Ringer's solution (LR), 6% hydroxyethyl starch (HES), and 3% NaCl (HS), each from 0% to 75% blood dilution. Thrombin generation was measured periodically during a time course of 20 minutes in its complex with antithrombin III. Platelet activation and fibrinopeptide A (FPA) release were monitored in serum at a 20-minute time point. Fibrin clots were collected and weighed.

Results: The coagulation markers (thrombin generation, platelet activation, and FPA release) were significantly different by dilution (p <>30% dilutions, HS produced no stable clots and HES dramatically decreased clot formation by 61% and maintained this level.

Conclusions: LR and NS had the least effect on thrombin generation, clot formation, and platelet activation at various concentrations compared with HES and HS. This observational data suggests that volume expanders such as HES and HS may be detrimental in treatment of hemorrhagic shock.

¿Cuál es el Mejor Marcador de Sepsis en Pacientes Quemados

Inflammatory markers in patients with severe burn injury
What is the best indicator of sepsis?
Athina Lavrentievaa, Theodore Kontakiotis, a, , Lambis Lazaridisa, Nikolaos Tsotsolisa, John Koumisa, George Kyriazisa and Militsa Bitzania aAristotle University, Pulmonary, Exochi, Thessaloniki, Greece

Objective
To estimate the diagnostic value of serum PCT, CRP, leukocyte count and temperature as markers of sepsis in critically ill ICU burn patients.

Design and setting
Prospective, observational study in a four bed Burn Intensive Care Unit.

Patients
Forty-three patients admitted in a Burn ICU were included in our study.

Measurements and results
Serum PCT, CRP concentrations, WCC (white cell count), neutrophils and temperature were measured within the first 24 h after-burn and daily thereafter. Severity of organ failure was estimated by sequential organ failure assessment (SOFA) score. Every day we classified all patients in one of the following three categories: non-systemic inflammatory condition (non-SIRS), SIRS non-infected and SIRS 2 infected or sepsis. Patients with infected SIRS differ significantly from non-infected SIRS in PCT (11.8 ± 15.8 versus 0.63 ± 0.0.43, respectively, p < 0.001). On the other hand, WCC, temperature and neurtophils did not differ significantly between patients with SIRS non-infected and infected SIRS. CRP was elevated in all three groups but didn’t differ significantly between SIRS non-infected and septic patients. Area under receiver operating curves was 0.975 and showed reasonable discriminative power (p = 0.002, 95% CI, 0.91–1.035) in predicting of sepsis only for PCT.

Conclusions
Serum procalcitonin levels can be used as an early indicator of septic complication in patients with severe burn injury

¿Predictores Clinicos Para Distinguir Entre Patología Inflamatoria Pélvica vs Apendicitis Aguda?

Clinical prediction rule to distinguish pelvic inflammatory disease from acute appendicitis in women of childbearing age
Koji Morishita MDa, , , Masanori Gushimiyagi MDb, Mikio Hashiguchi MDc, Gerald H. Stein MDd, e and Yasuharu Tokuda MD, MPHf
The American Journal of Emergency Medicine 2007; 25(2):152-7

Objective
We aimed to develop a clinical prediction rule to distinguish pelvic inflammatory disease (PID) from acute appendicitis in women of childbearing age.

Methods
We reviewed medical records over a 4-year period of female patients of childbearing age who had presented with abdominal pain at an urban emergency department and had either appendicitis (n = 109) or PID (n = 72). A prediction rule was developed by use of recursive partitioning based on significant factors for the discrimination.

Results
The significant factors to favor PID over appendicitis were (1) no migration of pain (odds ratio [OR], 4.2; 95% confidence interval [CI], 1.5-11.5), (2) bilateral abdominal tenderness (OR, 16.7; 95% CI, 5.3-50.0), and (3) absence of nausea and vomiting (OR, 8.4; 95% CI, 2.8-24.8). The prediction rule could rule out appendicitis from PID with sensitivity of 99% (95% CI, 94-100%) when classified as a low-risk group by the following factors: (1) no migration of pain, (2) bilateral abdominal tenderness, and (3) no nausea and vomiting.

Conclusion
We developed a prediction rule for childbearing-aged women presenting with acute abdominal pain to distinguish acute appendicitis from PID based on 3 simple, clinical features: migration of pain, bilateral abdominal tenderness, and nausea and vomiting. Prospective validation is needed in other settings.

Material Protésico para Reparar Hernias

Un artículo de revisión publicado en el número de febrero 2007 de Contemporary Surgery trata sobre material protésico para la reparación de hernias. El acceso al artículo completo en formato pdf es:

http://www.contemporarysurgery.com/pdf/6302/6302CS_Review.pdf

Hipertensión Intraabdominal y Sindrome Compartimental

La hipertensión intraabdominal y el síndrome compartimental abdominal: ¿qué debe saber y cómo debe tratarlos el cirujano?
Gregorio Castellanosa Antonio Piñeroa Juan Ángel Fernándeza aServicio de Cirugía General y del Aparato Digestivo I (Prof. P. Parrilla). Hospital Universitario Virgen de la Arrixaca. Murcia. España.

El seguimiento adecuado de los pacientes críticos médico-quirúrgicos facilita el diagnóstico temprano y un tratamiento adecuado de la hipertensión intraabdominal (HIA) y del síndrome compartimental abdominal (SCA).

La cavidad abdominal y el retroperitoneo actúan como compartimentos estancos, y cualquier cambio en el volumen de su contenido puede elevar la presión intraabdominal (PIA).

La HIA es sólo una medida elevada de la PIA, y el SCA supone el punto final de una HIA sostenida con la aparición de disfunciones orgánicas.

Para el diagnóstico de la HIA y del SCA se requiere medir la PIA, la presión de perfusión abdominal y el pH intramucoso gástrico, y correlacionar estos datos con signos de deterioro clínico en el paciente.

Las medidas terapéuticas médicas en el SCA son limitadas, y la descompresión abdominal es el tratamiento del SCA sintomático establecido.

Para acceder al texto completo en formato PDF hacer click en el título de este "entry".

Anatomía del Síndrome de Boerhaave

Anatomy of the Boerhaave syndrome
Owen Korn MD, FACSa, , , Juan C. Oñate MDb and René López MDb aDepartment of Surgery, Clinical Hospital University of Chile, Santiago, ChilebMedico-Legal Service, Santiago, Chile

Background
Spontaneous rupture of the esophagus (Boerhaave syndrome) occurs almost invariably at the same anatomic site. A weakness of the distal esophageal wall is suspected but has not been confirmed by anatomic studies. The aim of this work was to determine the existence of a structural abnormality in the esophageal wall.

Material and Methods
In six fresh human cadavers, the left lung was removed and the esophagus was insufflated in situ with air until it burst. The mucosa of the specimens was stripped off, allowing the fibers of the inner muscular coat to be seen. In addition a specimen from a patient who died from this cause was submitted to the same procedure.

Results
The site of the experimental rupture matched the clinical case. The tear was located at the margin of contact between “clasp” and oblique fibers, and extends upwards.

Conclusions
The connective tissue of the junction between clasp and oblique fibers appears to constitute a weak point in the lower esophagus.

Contaminación por Material Particulado e Incidencia de Eventos Cardiovasculares en Mujeres

Long-Term Exposure to Air Pollution and Incidence of Cardiovascular Events in Women
Kristin A. Miller, M.S., David S. Siscovick, M.D., M.P.H., Lianne Sheppard, Ph.D., Kristen Shepherd, M.S., Jeffrey H. Sullivan, M.D., M.H.S., Garnet L. Anderson, Ph.D., and Joel D. Kaufman, M.D., M.P.H.
N Engl J Med 2007; 356(5):447-58

Background
Fine particulate air pollution has been linked to cardiovascular disease, but previous studies have assessed only mortality and differences in exposure between cities. We examined the association of long-term exposure to particulate matter of less than 2.5 µm in aerodynamic diameter (PM2.5) with cardiovascular events.

Methods
We studied 65,893 postmenopausal women without previous cardiovascular disease in 36 U.S. metropolitan areas from 1994 to 1998, with a median follow-up of 6 years. We assessed the women's exposure to air pollutants using the monitor located nearest to each woman's residence. Hazard ratios were estimated for the first cardiovascular event, adjusting for age, race or ethnic group, smoking status, educational level, household income, body-mass index, and presence or absence of diabetes, hypertension, or hypercholesterolemia.

Results
A total of 1816 women had one or more fatal or nonfatal cardiovascular events, as confirmed by a review of medical records, including death from coronary heart disease or cerebrovascular disease, coronary revascularization, myocardial infarction, and stroke. In 2000, levels of PM2.5 exposure varied from 3.4 to 28.3 µg per cubic meter (mean, 13.5). Each increase of 10 µg per cubic meter was associated with a 24% increase in the risk of a cardiovascular event (hazard ratio, 1.24; 95% confidence interval [CI], 1.09 to 1.41) and a 76% increase in the risk of death from cardiovascular disease (hazard ratio, 1.76; 95% CI, 1.25 to 2.47). For cardiovascular events, the between-city effect appeared to be smaller than the within-city effect. The risk of cerebrovascular events was also associated with increased levels of PM2.5 (hazard ratio, 1.35; 95% CI, 1.08 to 1.68).

Conclusions
Long-term exposure to fine particulate air pollution is associated with the incidence of cardiovascular disease and death among postmenopausal women. Exposure differences within cities are associated with the risk of cardiovascular disease.