Skeletal muscle mitochondrial energetics are associated with maximal aerobic capacity and walking speed in older adults.

BACKGROUND: Lower ambulatory performance with aging may be related to a reduced oxidative capacity within skeletal muscle. This study examined the associations between skeletal muscle mitochondrial capacity and efficiency with walking performance in a group of older adults. METHODS: Thirty-seven older adults (mean age 78 years; 21 men and 16 women) completed an aerobic capacity (VO peak) test and measurement of preferred walking speed over 400 m. Maximal coupled (State 3; St3) mitochondrial respiration was determined by high-resolution respirometry in saponin-permeabilized myofibers obtained from percutanous biopsies of vastus lateralis (n = 22). Maximal phosphorylation capacity (ATP) of vastus lateralis was determined in vivo by P magnetic resonance spectroscopy (n = 30). Quadriceps contractile volume was determined by magnetic resonance imaging. Mitochondrial efficiency (max ATP production/max O consumption) was characterized using ATP per St3 respiration (ATP/St3). RESULTS: In vitro St3 respiration was significantly correlated with in vivo ATP (r = .47, p = .004). Total oxidative capacity of the quadriceps (St3*quadriceps contractile volume) was a determinant of VO peak (r = .33, p = .006). ATP (r = .158, p = .03) and VO peak (r = .475, p < .0001) were correlated with preferred walking speed. Inclusion of both ATP/St3 and VO peak in a multiple linear regression model improved the prediction of preferred walking speed (r = .647, p < .0001), suggesting that mitochondrial efficiency is an important determinant for preferred walking speed. CONCLUSIONS: Lower mitochondrial capacity and efficiency were both associated with slower walking speed within a group of older participants with a wide range of function. In addition to aerobic capacity, lower mitochondrial capacity and efficiency likely play roles in slowing gait speed with age.

Long-term outcome of idiopathic steroid-resistant nephrotic syndrome: a multicenter study.

Long-term outcome of idiopathic steroid-resistant nephrotic syndrome was retrospectively studied in 78 children in eight centers for the past 20 years. Median age at onset was 4.4 years (1.1-15.0 years) and the gender ratio was 1.4. Median follow-up period was 7.7 years (1.0-19.7 years). The disease in 45 patients (58%) was initially not steroid-responsive and in 33 (42%) it was later non-responsive. The main therapeutic strategies included administration of ciclosporine (CsA) alone (n = 29; 37%) and CsA + mycophenolate mofetil (n = 18; 23%). Actuarial patient survival rate after 15 years was 97%. Renal survival rate after 5 years, 10 years and 15 years was 75%, 58% and 53%, respectively. An age at onset of nephrotic syndrome (NS) > 10 years was the only independent predictor of end-stage renal disease (ESRD) in a multivariate analysis using a Cox regression model (P < 0.001). Twenty patients (26%) received transplants; ten showed recurrence of the NS: seven within 2 days, one within 2 weeks, and two within 3-5 months. Seven patients lost their grafts, four from recurrence. Owing to better management, kidney survival in idiopathic steroid-resistant nephrotic syndrome (SRNS) has improved during the past 20 years. Further prospective controlled trials will delineate the potential benefit of new immunosuppressive treatment.

J-shaped association between serum glucose and functional outcome in acute ischemic stroke.

BACKGROUND AND PURPOSE: Hyperglycemia after stroke is associated with larger infarct volume and poorer functional outcome. In an animal stroke model, the association between serum glucose and infarct volume is described by a U-shaped curve with a nadir ≈7 mmol/L. However, a similar curve in human studies was never reported. The objective of the present study is to investigate the association between serum glucose levels and functional outcome in patients with acute ischemic stroke. METHODS: We analyzed 1446 consecutive patients with acute ischemic stroke. Serum glucose was measured on admission at the emergency department together with multiple other metabolic, clinical, and radiological parameters. National Institutes of Health Stroke Scale (NIHSS) score was recorded at 24 hours, and Rankin score was recorded at 3 and 12 months. The association between serum glucose and favorable outcome (Rankin score ≤2) was explored in univariate and multivariate analysis. The model was further analyzed in a robust regression model based on fractional polynomial (-2-2) functions. RESULTS: Serum glucose is independently correlated with functional outcome at 12 months (OR, 1.15; P=0.01). Other predictors of outcome include admission NIHSS score (OR, 1.18; P<0001), age (OR, 1.06; P<0.001), prestroke Rankin score (OR, 20.8; P=0.004), and leukoaraiosis (OR, 2.21; P=0.016). Using these factors in multiple logistic regression analysis, the area under the receiver-operator characteristic curve is 0.869. The association between serum glucose and Rankin score at 12 months is described by a J-shaped curve with a nadir of 5 mmol/L. Glucose values between 3.7 and 7.3 mmol/L are associated with favorable outcome. A similar curve was generated for the association of glucose and 24-hour NIHSS score, for which glucose values between 4.0 and 7.2 mmol/L are associated with a NIHSS score <7. Discussion-Both hypoglycemia and hyperglycemia are dangerous in acute ischemic stroke as shown by a J-shaped association between serum glucose and 24-hour and 12-month outcome. Initial serum glucose values between 3.7 and 7.3 mmol/L are associated with favorable outcome.

Incidence and risk factors for chronic elevation of alanine aminotransferase levels in HIV-infected persons without hepatitis b or c virus co-infection.

BACKGROUND: Chronic liver disease in human immunodeficiency virus (HIV)-infected patients is mostly caused by hepatitis virus co-infection. Other reasons for chronic alanine aminotransferase (ALT) elevation are more difficult to diagnose. METHODS: We studied the incidence of and risk factors for chronic elevation of ALT levels (greater than the upper limit of normal at 2 consecutive semi-annual visits) in participants of the Swiss HIV Cohort Study without hepatitis B virus (HBV) or hepatitis C virus (HCV) infection who were seen during the period 2002-2008. Poisson regression analysis was used. RESULTS: A total of 2365 participants were followed up for 9972 person-years (median age, 38 years; male sex, 66%; median CD4+ cell count, 426/microL; receipt of antiretroviral therapy [ART], 56%). A total of 385 participants (16%) developed chronic elevated ALT levels, with an incidence of 3.9 cases per 100 person-years (95% confidence interval [CI], 3.5-4.3 cases per 100 person-years). In multivariable analysis, chronic elevated ALT levels were associated with HIV RNA level >100,000 copies/mL (incidence rate ratio [IRR], 2.23; 95% CI, 1.45-3.43), increased body mass index (BMI, defined as weight in kilograms divided by the square of height in meters) (BMI of 25-29.9 was associated with an IRR of 1.56 [95% CI, 1.24-1.96]; a BMI 30 was associated with an IRR of 1.70 [95% CI, 1.16-2.51]), severe alcohol use (1.83 [1.19-2.80]), exposure to stavudine (IRR per year exposure, 1.12 [95% CI, 1.07-1.17]) and zidovudine (IRR per years of exposure, 1.04 [95% CI, 1.00-1.08]). Associations with cumulative exposure to combination ART, nucleoside reverse-transcriptase inhibitors, and unboosted protease inhibitors did not remain statistically significant after adjustment for exposure to stavudine. Black ethnicity was inversely correlated (IRR, 0.52 [95% CI, 0.33-0.82]). Treatment outcome and mortality did not differ between groups with and groups without elevated ALT levels. CONCLUSIONS: Among patients without hepatitis virus co-infection, the incidence of chronic elevated ALT levels was 3.9 cases per 100 person-years, which was associated with high HIV RNA levels, increased BMI, severe alcohol use, and prolonged stavudine and zidovudine exposure. Long-term follow-up is needed to assess whether chronic elevation of ALT levels will result in increased morbidity or mortality.

Fungal infection as a risk factor for HIV disease progression among patients with a CD4 count above 200/microl in the era of cART.

The identification of clinical risk factors for AIDS in patients with preserved immune function is of significant interest. We examined whether patients with fungal infection (FI) and CD4 cell count >or=200/microl were at higher risk of disease progression in the era of cART. 11,009 EuroSIDA patients were followed from their first CD4 cell count >or=200/microl after 1 January 1997 until progression to any non-azoles/amphotericin B susceptible (AAS) AIDS disease, last visit or death. Initiation of antimycotic therapy (AMT) was used as a marker of FI and was modelled as a time-updated covariate using Poisson regression. After adjustment for current CD4 cell count, HIV-RNA, starting cART and diagnosis of AAS-AIDS, AMT was significantly associated with an increased incidence of non-AAS-AIDS (IRR=1.55, 95% CI 1.17-2.06, p=0.0024). Despite low incidence of AIDS in the cART era, FI in patients with a CD4 cell count >or=200/microl is associated with a 55% higher risk of non-AAS-AIDS (95% confidence interval 1.17-2.06, p=0.0024). These data suggest that patients with FI are more immune compromized than would be expected from their CD4 cell count alone. FI can be used as a clinical marker for disease progression and indirect indicator for initiation/changing cART in settings where laboratory facilities are limited.

Surgical safety and hospital volume across a wide range of interventions

OBJECTIVES:: For certain major operations, inpatient mortality risk is lower in high-volume hospitals than those in low-volume hospitals. Extending the analysis to a broader range of interventions and outcomes is necessary before adopting policies based on minimum volume thresholds. METHODS:: Using the United States 2004 Nationwide Inpatient Sample, we assessed the effect of intervention-specific and overall hospital volume on surgical complications, potentially avoidable reoperations, and deaths across 1.4 million interventions in 353 hospitals. Outcome variations across hospitals were analyzed through a 3-level hierarchical logistic regression model (patients, surgical interventions, and hospitals), which took into account interventions on multiple organs, 144 intervention categories, and structural hospital characteristics. Discriminative performance and calibration were good. RESULTS:: Hospitals with more experience in a given intervention had similar reoperation rates but lower mortality and complication rates: odds ratio per volume deciles 0.93 and 0.97. However, the benefit was limited to heart surgery and a small number of other operations. Risks were higher for hospitals that performed more interventions overall: odds ratio per 1000 for each event was approximately 1.02. Even after adjustment for specific volume, mortality varied substantially across both high- and low-volume hospitals. CONCLUSION:: Although the link between specific volume and certain inpatient outcomes suggests that specialization might help improve surgical safety, the variable magnitude of this link and the heterogeneity of hospital effect do not support the systematic use of volume-based referrals. It may be more efficient to monitor risk-adjusted postoperative outcomes and to investigate facilities with worse than expected outcomes.

Social and medical vulnerability factors of frequent users at the emergency department: a case-control study

BACKGROUND: Up to 5% of patients presenting to the emergency department (ED) four or more times within a 12 month period represent 21% of total ED visits. In this study we sought to characterize social and medical vulnerability factors of ED frequent users (FUs) and to explore if these factors hold simultaneously. METHODS: We performed a case-control study at Lausanne University Hospital, Switzerland. Patients over 18 years presenting to the ED at least once within the study period (April 2008 toMarch 2009) were included. FUs were defined as patients with four or more ED visits within the previous 12 months. Outcome data were extracted from medical records of the first ED attendance within the study period. Outcomes included basic demographics and social variables, ED admission diagnosis, somatic and psychiatric days hospitalized over 12 months, and having a primary care physician.We calculated the percentage of FUs and non-FUs having at least one social and one medical vulnerability factor. The four chosen social factors included: unemployed and/or dependence on government welfare, institutionalized and/or without fixed residence, either separated, divorced or widowed, and under guardianship. The fourmedical vulnerability factors were: ≥6 somatic days hospitalized, ≥1 psychiatric days hospitalized, ≥5 clinical departments used (all three factors measured over 12 months), and ED admission diagnosis of alcohol and/or drug abuse. Univariate and multivariate logistical regression analyses allowed comparison of two JGIM ABSTRACTS S391 random samples of 354 FUs and 354 non-FUs (statistical power 0.9, alpha 0.05 for all outcomes except gender, country of birth, and insurance type). RESULTS: FUs accounted for 7.7% of ED patients and 24.9% of ED visits. Univariate logistic regression showed that FUs were older (mean age 49.8 vs. 45.2 yrs, p=0.003),more often separated and/or divorced (17.5%vs. 13.9%, p=0.029) or widowed (13.8% vs. 8.8%, p=0.029), and either unemployed or dependent on government welfare (31.3% vs. 13.3%, p<0.001), compared to non-FUs. FUs cumulated more days hospitalized over 12 months (mean number of somatic days per patient 1.0 vs. 0.3, p<0.001; mean number of psychiatric days per patient 0.12 vs. 0.03, p<0.001). The two groups were similar regarding gender distribution (females 51.7% vs. 48.3%). The multivariate linear regression model was based on the six most significant factors identified by univariate analysis The model showed that FUs had more social problems, as they were more likely to be institutionalized or not have a fixed residence (OR 4.62; 95% CI, 1.65 to 12.93), and to be unemployed or dependent on government welfare (OR 2.03; 95% CI, 1.31 to 3.14) compared to non-FUs. FUs were more likely to need medical care, as indicated by involvement of≥5 clinical departments over 12 months (OR 6.2; 95%CI, 3.74 to 10.15), having an ED admission diagnosis of substance abuse (OR 3.23; 95% CI, 1.23 to 8.46) and having a primary care physician (OR 1.70;95%CI, 1.13 to 2.56); however, they were less likely to present with an admission diagnosis of injury (OR 0.64; 95% CI, 0.40 to 1.00) compared to non-FUs. FUs were more likely to combine at least one social with one medical vulnerability factor (38.4% vs. 12.1%, OR 7.74; 95% CI 5.03 to 11.93). CONCLUSIONS: FUs were more likely than non-FUs to have social and medical vulnerability factors and to have multiple factors in combination.

A comparison of Bayesian and frequentist approaches to incorporating external information for the prediction of prostate cancer risk.

We present the most comprehensive comparison to date of the predictive benefit of genetics in addition to currently used clinical variables, using genotype data for 33 single-nucleotide polymorphisms (SNPs) in 1,547 Caucasian men from the placebo arm of the REduction by DUtasteride of prostate Cancer Events (REDUCE®) trial. Moreover, we conducted a detailed comparison of three techniques for incorporating genetics into clinical risk prediction. The first method was a standard logistic regression model, which included separate terms for the clinical covariates and for each of the genetic markers. This approach ignores a substantial amount of external information concerning effect sizes for these Genome Wide Association Study (GWAS)-replicated SNPs. The second and third methods investigated two possible approaches to incorporating meta-analysed external SNP effect estimates - one via a weighted PCa 'risk' score based solely on the meta analysis estimates, and the other incorporating both the current and prior data via informative priors in a Bayesian logistic regression model. All methods demonstrated a slight improvement in predictive performance upon incorporation of genetics. The two methods that incorporated external information showed the greatest receiver-operating-characteristic AUCs increase from 0.61 to 0.64. The value of our methods comparison is likely to lie in observations of performance similarities, rather than difference, between three approaches of very different resource requirements. The two methods that included external information performed best, but only marginally despite substantial differences in complexity.

¿Favorece la publicación en abierto el impacto de los artículos científicos? Un estudio empírico en el ámbito de la medicina intensiva

Peer-reviewed

A random linear functional approach to efficiency bounds

This paper suggests a method for obtaining efficiency bounds in models containing either only infinite-dimensional parameters or both finite- and infinite-dimensional parameters (semiparametric models). The method is based on a theory of random linear functionals applied to the gradient of the log-likelihood functional and is illustrated by computing the lower bound for Cox's regression model

Childhood cancer and nuclear power plants in Switzerland: a census-based cohort study.

BACKGROUND: Previous studies on childhood cancer and nuclear power plants (NPPs) produced conflicting results. We used a cohort approach to examine whether residence near NPPs was associated with leukaemia or any childhood cancer in Switzerland. METHODS: We computed person-years at risk for children aged 0-15 years born in Switzerland from 1985 to 2009, based on the Swiss censuses 1990 and 2000 and identified cancer cases from the Swiss Childhood Cancer Registry. We geo-coded place of residence at birth and calculated incidence rate ratios (IRRs) with 95% confidence intervals (CIs) comparing the risk of cancer in children born <5 km, 5-10 km and 10-15 km from the nearest NPP with children born >15 km away, using Poisson regression models. RESULTS: We included 2925 children diagnosed with cancer during 21 117 524 person-years of follow-up; 953 (32.6%) had leukaemia. Eight and 12 children diagnosed with leukaemia at ages 0-4 and 0-15 years, and 18 and 31 children diagnosed with any cancer were born <5 km from a NPP. Compared with children born >15 km away, the IRRs (95% CI) for leukaemia in 0-4 and 0-15 year olds were 1.20 (0.60-2.41) and 1.05 (0.60-1.86), respectively. For any cancer, corresponding IRRs were 0.97 (0.61-1.54) and 0.89 (0.63-1.27). There was no evidence of a dose-response relationship with distance (P > 0.30). Results were similar for residence at diagnosis and at birth, and when adjusted for potential confounders. Results from sensitivity analyses were consistent with main results. CONCLUSIONS: This nationwide cohort study found little evidence of an association between residence near NPPs and the risk of leukaemia or any childhood cancer.

La decisión de endeudamiento y los factores de mayor relevancia. Una aplicación empírica en la empresa industrial española

El presente trabajo aborda el estudio de los factores determinantes del endeudamiento empresarial para contrastar empíricamente la hipótesis del Pecking Order. El endeudamiento empresarial se mide junto a su madurez y para los diferentes tamaños empresariales dada la importancia de diferenciar sus posibles efectos contrapuestos o compensados. Los modelos utilizados para el contraste de hipótesis se han estimado con una muestra de 1.320 empresas manufactureras españolas proporcionada por la Encuesta sobre Estrategias Empresariales (ESEE), para el período 1993-2001. El análisis empírico aplica un modelo multivariante de regresión logística que permite concluir que la teoría del Pecking Order es la de mejor cumplimiento, además de constatarse que las empresas de menor tamaño tienen mayores dificultades de acceso a la financiación con deuda a largo plazo.

Prevalencia de la discapacidad en España por comunidades autónomas: el papel de los factores individuales y del entorno geográfico en su variabilidad

Fundamento: La prevalencia de discapacidad en la población general presenta una gran variabilidad geográfica, de manera que identificar aquellos factores que pudieran explicarla será importante para la planificación de políticas sociales. En este trabajo se analiza la variabilidad de la discapacidad por comunidades autónomas desde una doble vertiente, los factores individuales y del entorno. Métodos: Los datos proceden principalmente de la Encuesta de Discapacidad, Deficiencias y Estado de Salud de 1999 y del Inebase, ambas del Instituto Nacional de Estadística (INE). Se calculó la prevalencia de discapacidad simple y ajustada por edad de las CCAA. Se analizan los factores individuales asociados a la discapacidad mediante una regresión logística y los factores individuales y de la comunidad autónoma conjuntamente con una regresión logística de dos niveles. Resultados: La prevalencia de discapacidad muestra una diferencia máxima de 5,75 puntos entre las comunidades autónomas. En la regresión logística la comunidad de residencia fue estadísticamente significativa (OR: 3,35 en la de mayor prevalencia respecto a la de menor) junto con otras variables individuales: edad (OR de 40-64= 1,78 OR de 65-79= 1,87 y OR de >79= 3,34), sexo (OR mujer= 0,66), situación laboral (OR sin trabajo=2,25 OR amas casa/estudiante=1,39 y OR otros=2,03), estado de salud (OR regular= 1,69 OR malo/muy malo= 2,05) y enfermedades crónicas (OR 1-3=1,56 OR4-6=1,82 OR>6=2,59). En la regresión de dos niveles las variables individuales explican poca varianza (s=0,261) y ninguna de las variables relativas a las CCAA mejora el modelo. Conclusiones: Las características individuales no explican suficientemente la variabilidad de la discapacidad entre CCAA y no se han identificado variables del entorno que sean significativas.

Emergency hospital services utilization in Lleida (Spain): a cross-sectional study of immigrant and Spanish-born populations

Background: The use of emergency hospital services (EHS) has increased steadily in Spain in the last decade while the number of immigrants has increased dramatically. Studies show that immigrants use EHS differently than native-born individuals, and this work investigates demographics, diagnoses and utilization rates of EHS in Lleida (Spain). Methods: Cross-sectional study of all the 96,916 EHS visits by patients 15 to 64 years old, attended during the years 2004 and 2005 in a public teaching hospital. Demographic data, diagnoses of the EHS visits, frequency of hospital admissions, mortality and diagnoses at hospital discharge were obtained. Utilization rates were estimated by group of origin. Poisson regression was used to estimate the rate ratios of being visited in the EHS with respect to the Spanish-born population. Results: Immigrants from low-income countries use EHS services more than the Spanish-born population. Differences in utilization patterns are particularly marked for Maghrebi men and women and sub-Saharan women. Immigrant males are at lower risk of being admitted to the hospital, as compared with Spanish-born males. On the other hand, immigrant women are at higher risk of being admitted. After excluding the visits with gynecologic and obstetric diagnoses, women from sub-Saharan Africa and the Maghreb are still at a higher risk of being admitted than their Spanish-born counterparts. Conclusion: In Lleida (Spain), immigrants use more EHS than the Spanish born population. Future research should indicate whether the same pattern is found in other areas of Spain and whether EHS use is attributable to health needs, barriers to access to the primary care services or similarities in the way immigrants access health care in their countries of origin.

Prevalence and management of cardiovascular risk factors in Portuguese living in Portugal and Portuguese who migrated to Switzerland.

BACKGROUND: Information regarding the health status of migrants compared to subjects who remain in the country of origin is scarce. We compared the levels and management of the main cardiovascular risk factors between Portuguese living in Porto (Portugal) and Portuguese migrants living in Lausanne (Switzerland). METHODS: Cross-sectional studies conducted in Porto (EPIPorto, 1999 to 2003, n = 1150) and Lausanne (CoLaus, 2003 to 2006, n = 388) among subjects aged 35-65 years. Educational level, medical history and time since migration were collected using structured questionnaires. Body mass index, blood pressure, cholesterol and glucose levels were measured using standardized procedures. RESULTS: Portuguese living in Lausanne were younger, more frequently male and had lower education than Portuguese living in Porto. After multivariate adjustment using Poisson regression, no differences were found between Portuguese living in Porto or in Lausanne: prevalence rate ratio (PRR) and (95% confidence interval) for Portuguese living in Lausanne relative to Portuguese living in Porto: 0.92 (0.71 - 1.18) for current smoking; 0.78 (0.59 - 1.04) for obesity; 0.81 (0.62 - 1.05) for abdominal obesity; 0.82 (0.64 - 1.06) for hypertension; 0.88 (0.75 - 1.04) for hypercholesterolemia and 0.92 (0.49 - 1.73) for diabetes. Treatment and control rates for hypercholesterolemia were higher among Portuguese living in Lausanne: PRR = 1.91 (1.15 - 3.19) and 3.98 (1.59 - 9.99) for treatment and control, respectively. Conversely, no differences were found regarding hypertension treatment and control rates: PRR = 0.98 (0.66 - 1.46) and 0.97 (0.49 - 1.91), respectively, and for treatment rates of diabetes: PRR = 1.51 (0.70 - 3.25). CONCLUSIONS: Portuguese living in Lausanne, Switzerland, present a similar cardiovascular risk profile but tend to be better managed regarding hypercholesterolemia than Portuguese living in Porto, Portugal.