Association of adiposity, telomere length and mortality: data from the NHANES 1999-2002.

BACKGROUND/OBJECTIVES: Telomere shortening is associated with age and risk of medical comorbidity. We assessed the relationship between measures of adiposity, leukocyte telomere length, and mortality and whether it is modified by age. SUBJECTS/METHODS: Subjects with dual-energy X-ray absorptiometry measures were identified using the National Health and Nutrition Examination Survey 1999-2002. Obesity was categorized using two body fat definitions (BF1%: men ⩾25%; females ⩾35%; BF2% ⩾28% and ⩾38%, respectively), body mass index (BMI) and waist circumference (WC; men ⩾102 cm; females ⩾88 cm). Telomere length relative to standard reference DNA (T/S ratio) was assessed using quantitative PCR. Weighted multivariable regression models evaluated the association of telomere length with adiposity, both continuously and categorically (low/normal BF%, low/high WC and standard BMI categories). Differences in telomere length by age and adiposity were ascertained and subsequent models were stratified by age. Proportional hazard models assessed the risk of mortality by adiposity status. A telomere by adiposity interaction was tested in the entire cohort and by age category (<60 vs ⩾60 years; <70 vs ⩾70 years). RESULTS: We identified 7827 subjects. Mean age was 46.1 years. Overall telomere length was 1.05±0.01 (s.e.) that differed by BF1% (low/high: 1.12±0.02 vs 1.03±0.02; P<0.001), BF2% (1.02±0.02 vs 1.11±0.02; P<0.001), BMI (underweight 1.08±0.03; normal 1.09±0.02; overweight 1.04±0.02; and obese 1.03±0.02;P<0.001) and WC (low/high 1.09±0.02 vs 1.02±0.02; P<0.001). Adjusted ß-coefficients evaluating the relationship between telomere length and adiposity (measured continuously) were as follows: BF1% (ß=-0.0033±0.0008; P<0.001), BF2% (-0.041±0.008; P<0.001), BMI (ß=-0.025±0.0008; P=0.005) and WC (ß=-0.0011±0.0004; P=0.007). High BF% (BF1%: ß=-0.035±0.011; P=0.002; BF2%: ß=-0.041±0.008; P<0.001) and WC (ß=-0.035±0.011; P=0.008) were inversely related to telomere length (TL). Stratifying by age, high BF1% (-0.061±0.013), BF2% (-0.065±0.01), BMI-obesity (-0.07±0.015) and high WC (-0.048±0.013) were significant (all P<0.001). This association diminished with increasing age. In older participants, TL was inversely related to mortality (hazard ratio 0.36 (0.27, 0.49)), as were those classified by BF1% (0.68 (0.56, 0.81)), BF2% (0.75 (0.65, 0.80)), BMI (0.50 (0.42, 0.60)) and WC (0.72 (0.63, 0.83)). No interaction was observed between adiposity status, telomere length and mortality. CONCLUSIONS: Obesity is associated with shorter telomere length in young participants, a relationship that diminishes with increasing age. It does not moderate the relationship with mortality.

Association between eating time interval and frequency with ideal cardiovascular health: Results from a random sample Czech urban population.

BACKGROUND AND AIMS: The frequency and timing of meals may affect cardiovascular health (CVH) outcomes, but large-scale epidemiological studies are lacking. The aim of this study was to understand the relationship between eating time interval and frequency, and measures of ideal CVH in the Kardiovize Brno cohort study, a random urban sample population in Central Europe. METHODS AND RESULTS: 1659 members of the Kardiovize Brno 2030 cohort were included in a cross-sectional study (mean age = 46.86 years; 44.6% male). Exposure variables were eating time interval and frequency, and skipping meals. Primary outcomes were indices of CVH, including body mass index, diet, physical activity, smoking, blood pressure, glucose and cholesterol, and the composite CVH score. Cluster analysis and binary logistic regression analysis were used to evaluate eating habits and the association between variables. After adjustment for well-known risk factors, subjects who skipped breakfast or the afternoon snack had a higher risk of poor CVH (OR = 1.613; 95%CI = 1.121-2.320; p = 0.010; OR = 1.409; 95%CI = 1.110-1.788; p = 0.005, respectively). Moreover, we identified three clusters of individuals based on eating habits; from cluster 1 to cluster 3, eating time interval and frequency increased and this was associated with increases in CVH score from 8.70 (SEM = 0.10) in cluster 1, and 9.06 (SEM = 0.08) in cluster 2 to 9.42 (SEM = 0.09) in cluster 3 (p-trend = 0.019). CONCLUSIONS: Our findings suggest that skipping breakfast or the afternoon snack are risk factors for poor CVH, while higher eating time interval and frequency may promote ideal CVH.

Diagnostic accuracy of body mass index to identify obesity in older adults: NHANES 1999-2004.

BACKGROUND: Body composition changes with aging lead to increased adiposity and decreased muscle mass, making the diagnosis of obesity challenging. Conventional anthropometry, including body mass index (BMI), while easy to use clinically may misrepresent adiposity. We determined the diagnostic accuracy of BMI using dual-energy X-ray absorptiometry (DEXA) in assessing the degree of obesity in older adults. METHODS: The National Health and Nutrition Examination Surveys 1999-2004 were used to identify adults aged ⩾60 years with DEXA measures. They were categorized (yes/no) as having elevated body fat by gender (men: ⩾25%; women ⩾35%) and by BMI ⩾25 and ⩾30 kg m(-)(2). The diagnostic performance of BMI was assessed. Metabolic characteristics were compared in discordant cases of BMI/body fat. Weighting and analyses were performed per NHANES (National Health and Nutrition Examination Survey) guidelines. RESULTS: We identified 4984 subjects (men: 2453; women: 2531). Mean BMI and % body fat was 28.0 kg m(-2) and 30.8% in men, and 28.5 kg m(-)(2) and 42.1% in women. A BMI ⩾30 kg m(-)(2) had a low sensitivity and moderately high specificity (men: 32.9 and 80.8%, concordance index 0.66; women: 38.5 and 78.5%, concordance 0.69) correctly classifying 41.0 and 45.1% of obese subjects. A BMI ⩾25 kg m(-2) had a moderately high sensitivity and specificity (men: 80.7 and 99.6%, concordance 0.81; women: 76.9 and 98.8%, concordance 0.84) correctly classifying 80.8 and 78.5% of obese subjects. In subjects with BMI <30 kg m(-)(2), body fat was considered elevated in 67.1% and 61.5% of men and women, respectively. For a BMI ⩾30 kg m(-)(2), sensitivity drops from 40.3% to 14.5% and 44.5% to 23.4%, whereas specificity remains elevated (>98%), in men and women, respectively, in those 60-69.9 years to subjects aged ⩾80 years. Correct classification of obesity using a cutoff of 30 kg m(-)(2) drops from 48.1 to 23.9% and 49.0 to 19.6%, in men and women in these two age groups. CONCLUSIONS: Traditional measures poorly identify obesity in the elderly. In older adults, BMI may be a suboptimal marker for adiposity.

Differential effects of leptin on adiponectin expression with weight gain versus obesity.

BACKGROUND/OBJECTIVE: Adiponectin exerts beneficial effects by reducing inflammation and improving lipid metabolism and insulin sensitivity. Although the adiponectin level is lower in obese individuals, whether weight gain reduces adiponectin expression in humans is controversial. We sought to investigate the role of weight gain, and consequent changes in leptin, on altering adiponectin expression in humans. METHODS/RESULTS: Forty-four normal-weight healthy subjects were recruited (mean age 29 years; 14 women) and randomized to either gain 5% of body weight by 8 weeks of overfeeding (n=34) or maintain weight (n=10). Modest weight gain of 3.8±1.2 kg resulted in increased adiponectin level (P=0.03), whereas weight maintenance resulted in no changes in adiponectin. Further, changes in adiponectin correlated positively with changes in leptin (P=0.0085). In-vitro experiments using differentiated human white preadipocytes showed that leptin increased adiponectin mRNA and protein expression, whereas a leptin antagonist had opposite effects. To understand the role of leptin in established obesity, we compared adipose tissue samples obtained from normal-weight versus obese subjects. We noted, first, that leptin activated cellular signaling pathways and increased adiponectin mRNA in the adipose tissue from normal-weight participants, but did not do so in the adipose tissue from obese participants. Second, we noted that obese subjects had increased caveolin-1 expression, which attenuates leptin-dependent increases in adiponectin. CONCLUSIONS: Modest weight gain in healthy individuals is associated with increases in adiponectin levels, which correlate positively with changes in leptin. In vitro, leptin induces adiponectin expression, which is attenuated by increased caveolin-1 expression. In addition, the adipose tissue from obese subjects shows increased caveolin-1 expression and impaired leptin signaling. This leptin signal impairment may prevent concordant increases in adiponectin levels in obese subjects despite their high levels of leptin. Therefore, impaired leptin signaling may contribute to low adiponectin expression in obesity and may provide a target for increasing adiponectin expression, hence improving insulin sensitivity and cardio-metabolic profile in obesity.

Diagnostic performance of body mass index to identify obesity as defined by body adiposity: a systematic review and meta-analysis.

OBJECTIVE: We performed a systematic review and meta-analysis of studies that assessed the performance of body mass index (BMI) to detect body adiposity. DESIGN: Data sources were MEDLINE, EMBASE, Cochrane, Database of Systematic Reviews, Cochrane CENTRAL, Web of Science, and SCOPUS. To be included, studies must have assessed the performance of BMI to measure body adiposity, provided standard values of diagnostic performance, and used a body composition technique as the reference standard for body fat percent (BF%) measurement. We obtained pooled summary statistics for sensitivity, specificity, positive and negative likelihood ratios (LRs), and diagnostic odds ratio (DOR). The inconsistency statistic (I2) assessed potential heterogeneity. RESULTS: The search strategy yielded 3341 potentially relevant abstracts, and 25 articles met our predefined inclusion criteria. These studies evaluated 32 different samples totaling 31 968 patients. Commonly used BMI cutoffs to diagnose obesity showed a pooled sensitivity to detect high adiposity of 0.50 (95% confidence interval (CI): 0.43-0.57) and a pooled specificity of 0.90 (CI: 0.86-0.94). Positive LR was 5.88 (CI: 4.24-8.15), I (2)=97.8%; the negative LR was 0.43 (CI: 0.37-0.50), I (2)=98.5%; and the DOR was 17.91 (CI: 12.56-25.53), I (2)=91.7%. Analysis of studies that used BMI cutoffs >or=30 had a pooled sensitivity of 0.42 (CI: 0.31-0.43) and a pooled specificity of 0.97 (CI: 0.96-0.97). Cutoff values and regional origin of the studies can only partially explain the heterogeneity seen in pooled DOR estimates. CONCLUSION: Commonly used BMI cutoff values to diagnose obesity have high specificity, but low sensitivity to identify adiposity, as they fail to identify half of the people with excess BF%.

Accuracy of body mass index in diagnosing obesity in the adult general population.

BACKGROUND: Body mass index (BMI) is the most widely used measure to diagnose obesity. However, the accuracy of BMI in detecting excess body adiposity in the adult general population is largely unknown. METHODS: A cross-sectional design of 13 601 subjects (age 20-79.9 years; 49% men) from the Third National Health and Nutrition Examination Survey. Bioelectrical impedance analysis was used to estimate body fat percent (BF%). We assessed the diagnostic performance of BMI using the World Health Organization reference standard for obesity of BF%>25% in men and>35% in women. We tested the correlation between BMI and both BF% and lean mass by sex and age groups adjusted for race. RESULTS: BMI-defined obesity (> or =30 kg m(-2)) was present in 19.1% of men and 24.7% of women, while BF%-defined obesity was present in 43.9% of men and 52.3% of women. A BMI> or =30 had a high specificity (men=95%, 95% confidence interval (CI), 94-96 and women=99%, 95% CI, 98-100), but a poor sensitivity (men=36%, 95% CI, 35-37 and women=49%, 95% CI, 48-50) to detect BF%-defined obesity. The diagnostic performance of BMI diminished as age increased. In men, BMI had a better correlation with lean mass than with BF%, while in women BMI correlated better with BF% than with lean mass. However, in the intermediate range of BMI (25-29.9 kg m(-2)), BMI failed to discriminate between BF% and lean mass in both sexes. CONCLUSIONS: The accuracy of BMI in diagnosing obesity is limited, particularly for individuals in the intermediate BMI ranges, in men and in the elderly. A BMI cutoff of> or =30 kg m(-2) has good specificity but misses more than half of people with excess fat. These results may help to explain the unexpected better survival in overweight/mild obese patients.

Effect of pravastatin on blood pressure in people with cardiovascular disease.

Experimental evidence and several small studies in humans suggest that HMG-CoA (3-hydroxy 3-methylglutaryl coenzyme A) reductase inhibitors (statins) reduce blood pressure, perhaps through effects on endothelial function or by reducing inflammation. We tested the hypothesis that pravastatin would reduce blood pressure at 3 months and the risk of developing new hypertension over a follow-up period of 5 years. This was a post hoc subgroup analysis of a randomized double-blind placebo-controlled trial of pravastatin 40 mg daily vs placebo in 4159 participants with previous myocardial infarction and total plasma cholesterol <240 mg/dl (6.2 mmol/l). The primary outcome was the unadjusted change in mean arterial pressure (MAP) from baseline to 3 months. We also considered systolic and diastolic blood pressure (SBP and DBP) and pulse pressure. Analysis of covariance was used to calculate the adjusted effect of treatment on change in these outcomes at 3, 6, 12 and 24 months postrandomization, after controlling for potential confounders. Logistic regression was used to calculate the adjusted effect of treatment on incident hypertension (blood pressure > or =140/90 in those without known hypertension at baseline). This analysis included 4126/4159 (99.2%) participants for whom blood pressure was measured at baseline and during at least one follow-up visit. Median duration of follow-up was 57.8 months. The unadjusted and adjusted change in MAP, SBP, DBP or pulse pressure from baseline was not significantly different for pravastatin or placebo recipients at 3, 6, 12 or 24 months after randomization, or at last follow-up. Pravastatin did not reduce the adjusted risk of incident systolic hypertension (odds ratio 0.99, 95% CI 0.80-1.23), or incident diastolic hypertension (odds ratio 0.97, 95% CI 0.73-1.27). In summary, pravastatin 40 mg daily did not reduce blood pressure in survivors of myocardial infarction without overt hypercholesterolaemia.

Exposure to bisphenol A and behavior in school-age children.

INTRODUCTION: Bisphenol A (BPA) exposure has been shown to affect human brain neurodevelopment and behavior. OBJECTIVE: We aimed to investigate whether environmental exposure to BPA in children was associated with their childhood behavior. METHODS: Urinary BPA concentrations and behavioral characteristics were assessed in 300 children belonging to the INMA "Environment and Childhood" Granada birth cohort in their follow-up at 9-11 years of age. BPA concentrations were quantified in urine using liquid chromatography-tandem mass spectrometry (LC-MS-MS), and child behavior reported by parents using the Child Behavior Checklist (CBCL/6-18) under supervision of a psychologist. The association between BPA concentrations and CBCL standardized scores was analyzed using linear regression models, adjusted for important covariates. RESULTS: Median (P25, P75) BPA concentration was 4.76 (2.77, 9.03)µg/L. Mean (±SD) CBCL externalizing and internalizing scores were 56.35 (±8.06) and 51.36 (±9.22), respectively. In multivariate regression analyses, adjusted for maternal and child characteristics, higher BPA concentrations were associated with worse behavioral scores on all scales. Children with BPA concentrations in the 4th quartile had more somatic complaints (ß=2.35; 95% CI: 0.25, 4.46) and social (ß=1.71; 95% CI: 0.19, 3.22) and thought problems (ß=2.58; 95% CI: 0.66, 4.51) in comparison to those in the 1st quartile. Children with values in the 3rd quartile of BPA concentrations also showed greater social problems (ß=1.94; 95% CI: 0.43, 3.45). CONCLUSIONS: Our results suggest that exposure to BPA in childhood may affect children's behavior. Although further investigations are required, preventive measures should be undertaken to reduce inadvertent exposure to BPA.

Prognostic value of cardiac troponin T after noncardiac surgery: 6-month follow-up data.

OBJECTIVES: We sought to evaluate the prognostic significance of cardiac troponin T (TnT) serum levels after noncardiac surgery. BACKGROUND: Cardiac TnT has been found to be marker for myocardial injury, but elevations of TnT are common in patients undergoing noncardiac surgery without clinical evidence of severe ischemia. METHODS: We studied 772 patients who underwent major noncardiac procedures and did not have major cardiovascular complications during their inpatient course. Total serum creatine kinase (CK) and cardiac TnT were measured according to a protocol that included sampling in the recovery room and during the next 2 days. A 6-month follow-up interview was performed for 722 (94%) of the patients. RESULTS: Elevated cardiac TnT and CK-MB results were detected for 92 (12%) and 211 (27%) patients, respectively. During the follow-up period, there were 19 (2.5%) major cardiac complications, including 14 cardiac deaths, 3 nonfatal myocardial infarctions and 2 admissions for unstable angina. Compared with patients with cardiac TnT values < 0.1 ng/ml, patients with elevated TnT had a relative risk for cardiac events of 5.4 (95% confidence interval: 2.2 to 13, p = 0.001), whereas CK-MB was not correlated with postdischarge cardiac events. In multivariate logistic regression analysis adjusting for preoperative clinical and CK-MB data, a cardiac TnT value > 0.1 ng/ml was in independent correlate of cardiac events (adjusted odds ratio 4.6, p < 0.05). This correlation was a function of the relation of elevated TnT levels with postoperative in-hospital congestive heart failure and new sustained arrhythmias, suggesting that elevated postoperative TnT levels detected myocardial ischemia during these clinical events. CONCLUSIONS: We conclude that an abnormal TnT level in patients undergoing noncardiac surgery may be a useful marker of ischemic disease and a predictor of 6-month prognosis.

Diagnostic performance of body mass index to identify obesity as defined by body adiposity in children and adolescents: a systematic review and meta-analysis.

BACKGROUND: The ideal means of identifying obesity in children and adolescents has not been determined although body mass index (BMI) is the most widely used screening tool. OBJECTIVE: We performed a systematic review and meta-analysis of studies assessing the diagnostic performance of BMI to detect adiposity in children up to 18 years. METHODS: Data sources were EMBASE, MEDLINE, Cochrane, Database of Systematic Reviews Cochrane CENTRAL, Web of Science and SCOPUS up to March 2013. Studies providing measures of diagnostic performance of BMI and using body composition technique for body fat percentage measurement were included. RESULTS: Thirty-seven eligible studies that evaluated 53 521 patients, with mean age ranging from 4 to 18 years were included in the meta-analysis. Commonly used BMI cut-offs for obesity showed pooled sensitivity to detect high adiposity of 0.73 (confidence interval [CI] 0.67-0.79), specificity of 0.93 (CI 0.88-0.96) and diagnostic odds ratio of 36.93 (CI 20.75-65.71). Males had lower sensitivity. Moderate heterogeneity was observed (I(2) = 48%) explained in meta-regression by differences across studies in race, BMI cut-off, BMI reference criteria (Center for Disease Control vs. International Obesity Task Force) and reference standard method assessing adiposity. CONCLUSION: BMI has high specificity but low sensitivity to detect excess adiposity and fails to identify over a quarter of children with excess body fat percentage.

Effect of diabetes mellitus on the presentation and triage of patients with acute chest pain without known coronary artery disease.

PURPOSE: Patients with diabetes and acute chest pain may be admitted to hospitals more frequently than patients without diabetes because physicians suspect atypical presentations for ischemic heart disease. This study aimed to determine whether the presentation of acute myocardial infarction and risk for major cardiac complications differs among patients without known coronary artery disease who do or do not have diabetes. PATIENTS AND METHODS: Data from an emergency department of an urban teaching hospital on the medical histories, physical examinations, and electrocardiograms of 2,694 subjects with acute chest pain and without known coronary artery disease were prospectively recorded. RESULTS: Diabetes was present in 301 (11%) patients. Compared with patients without diabetes, patients with diabetes were more likely to be < or = 60 years old (51% versus 20%) and to have a history of hypertension (70% versus 35%) or high blood cholesterol (35% versus 19%). A discharge diagnosis of acute myocardial infarction was made in 25 diabetic (8%) and in 148 nondiabetic (6%; P = 0.16) patients. A major cardiac complication occurred in two patients with diabetes (0.7%) and in 20 patients without diabetes (0.8%; P = 1.0). Patients with and without diabetes who had atypical chest pain complaints had similar rates of myocardial infarction (3% and 4%, respectively; P = 0.6). Patients with diabetes were more likely to be hospitalized (67% versus 47%; P = 0.001) both before and after adjusting for clinical and electrocardiographic data. CONCLUSIONS: For patients with acute chest pain without a prior history of coronary artery disease, diabetes was not associated with a higher rate of acute myocardial infarction or complications. However, diabetes was associated with a higher rate of hospitalization in this population, suggesting that physicians have a lower threshold for admission to the hospital of patients with diabetes.

Predictive value of creatine kinase (CK)-MB for diagnosis of acute myocardial infarction after major noncardiac surgery.

BACKGROUND: The aim of this study was to provide insight into the interpretation of CK-MB data after major noncardiac surgery. METHODS: Some 3,321 patients who underwent major non-emergent noncardiac procedures (orthopedic 31%, intrathoracic 12%, vascular 22%, other 35%) were studied. All patients had at least two CK samples measured postoperatively. RESULTS: Acute myocardial infarction was diagnosed in 43 (1.3%) patients using study criteria including CK-MB and electrocardiographic data. All of the various threshold values of peak CK-MB values and peak CK-MB as a percentage of total CK had poor positive predictive values because of high false positive rates and the low rate of acute myocardial infarction. CONCLUSION: These data demonstrate the need for markers of myocardial injury with greater cardiac specificity after noncardiac surgery.

Frontiers in Internal Medicine.

Clinical research in Internal Medicine has provided many scientific advances during the past few years. However, the newly generated information overrides the time available to read all of the medical literature regarding advances in Internal Medicine. The goal of this review is to summarize some of the most relevant improvements in clinical practice published over the last few years. From Cardiology to Pulmonology, the authors of this review expose in a succinct way what they and many of their peers consider to be the most transcendental information gathered from thousands of publications. The authors of this review article have attempted to avoid sensationalism by including facts instead of just simply optimistic preliminary findings that can mislead clinicians' decision making. The review is focused on information obtained through well-designed, prospective clinical trials and cohorts where the effectiveness of medical interventions and diagnostic procedures were tested.

Update in internal medicine.

More than 500,000 new medical articles are published every year and available time to keep updated is scarcer every day. Nowadays, the task of selecting useful, consistent, and relevant information for clinicians is a priority in many major medical journals. This review has the aim of gathering the results of the most important findings in clinical medicine in the last few years. It is focused on results from randomized clinical trials and well-designed observational research. Findings were included preferentially if they showed solid results, and we avoided as much as possible including only preliminary data, or results that included only non-clinical outcomes. Some of the most relevant findings reported here include the significant benefit of statins in patients with coronary artery disease even with mean cholesterol level. It also provides a substantial review of the most significant trials assessing the effectiveness of IIb/IIIa receptor blockers. In gastroenterology many advances have been made in the H. pylori eradication, and the finding that the cure of H. pylori infection may be followed by gastroesophageal reflux disease. Some new antivirals have shown encouraging results in patients with chronic hepatitis. In the infectious disease arena, the late breaking trials in anti-retroviral disease are discussed, as well as the new trends regarding antibiotic resistance. This review approaches also the role of leukotriene modifiers in the treatment of asthma and discusses the benefit of using methylprednisolone in patients with adult respiratory distress syndrome, among many other advances in internal medicine.

[Clinical interpretation of statistical significance]. / Interpretación clínica de la significancia estadística.

In any clinical study which compares versus an established therapy, the results will be expressed in terms of statistical significance. For this reason, it is important that every clinician interested in a judicious interpretation of the scientific literature, understands the origin and interpretation of statistical significance. The present paper addresses physicians attempting to give practical meaning to research results by discriminative and critical reading. The main aim is to explain in a simple way the meaning of the P-value, confidence intervals, and the required number to treat. Using practical examples, the most common mistakes in the interpretation of statistical significance are analyzed. The difference between statistical and clinical significance is emphasized and a new way to express and compare the practical utility of clinical trial results and the required number to treat is given.

[Methodologies of publications in the Revista de Investigación Clínica during the last 20 years]. / Metodologías de las publicaciones en la Revista de Investigación Clínica en los últimos 20 años.

OBJECTIVE: To characterize the clinical research methods published in the Revista de Investigación Clínica for the past 20 years. DESIGN: Comparative study of methods used in the RIC articles published in 3-years periods representing three decades (1972-74, 1982-84, 1992-94). RESULTS: Out of 273 original papers, 218 (80%) were of clinical research. There was an increased percentage of longitudinal vs cross-sectional studies, with cohort and randomized clinical trials showing the largest increase. The total number of research manuscripts also increased. CONCLUSION: The clinical research methods of the papers in the RIC have shown an increased rate of designs with a higher scientific value.

[First-line treatment. What is lost by not giving it]. / Tratamiento óptimo. Lo que se pierde al no efectuarse.

It is highly desirable to give always the best therapeutic alternative. However, the accomplishment of this goal is not always possible, leaving the physician with second, third or no therapeutic choice at all. The reasons for this may be economic, logistic, medical and cultural. In order to know what the patients are losing, we need to test how strong the scientific evidence is for the first choice option, and second, we have to consider the magnitude of improvement on clinical outcomes, comparing the best therapy and the next best available therapy. In many instances, the difference in clinical benefit is small and even negligible.

[When should a disease be diagnosed early and whose disease?]. / Cuándo y en quién hacer diagnóstico temprano de enfermedad.

Screening programs may seem useful and effective. However, in many cases the benefit is not clear and may actually do more harm than good. Each time a clinician asks for an early diagnostic test, the scientific evidence and the attributed risks need to be defined. The effectiveness of any early diagnosis test relies on the characteristics of the test itself, the disease to be ruled-out, and the side effects of the test. Such effects may be physical and emotional and the outcomes may be against the well being of the patient. In general, if an early diagnostic test does not lead to improvement in the survival and/or morbidity of patients, its utilization is not justified.