Empirical study of correlated survival times for recurrent events with proportional hazards margins and the effect of correlation and censoring.

Background: In longitudinal studies where subjects experience recurrent incidents over a period of time, such as respiratory infections, fever or diarrhea, statistical methods are required to take into account the within-subject correlation. Methods: For repeated events data with censored failure, the independent increment (AG), marginal (WLW) and conditional (PWP) models are three multiple failure models that generalize Cox"s proportional hazard model. In this paper, we revise the efficiency, accuracy and robustness of all three models under simulated scenarios with varying degrees of within-subject correlation, censoring levels, maximum number of possible recurrences and sample size. We also study the methods performance on a real dataset from a cohort study with bronchial obstruction. Results: We find substantial differences between methods and there is not an optimal method. AG and PWP seem to be preferable to WLW for low correlation levels but the situation reverts for high correlations. Conclusions: All methods are stable in front of censoring, worsen with increasing recurrence levels and share a bias problem which, among other consequences, makes asymptotic normal confidence intervals not fully reliable, although they are well developed theoretically.

Empirical study of correlated survival times for recurrent events with proportional hazards margins and the effect of correlation and censoring.

Background: In longitudinal studies where subjects experience recurrent incidents over a period of time, such as respiratory infections, fever or diarrhea, statistical methods are required to take into account the within-subject correlation. Methods: For repeated events data with censored failure, the independent increment (AG), marginal (WLW) and conditional (PWP) models are three multiple failure models that generalize Cox"s proportional hazard model. In this paper, we revise the efficiency, accuracy and robustness of all three models under simulated scenarios with varying degrees of within-subject correlation, censoring levels, maximum number of possible recurrences and sample size. We also study the methods performance on a real dataset from a cohort study with bronchial obstruction. Results: We find substantial differences between methods and there is not an optimal method. AG and PWP seem to be preferable to WLW for low correlation levels but the situation reverts for high correlations. Conclusions: All methods are stable in front of censoring, worsen with increasing recurrence levels and share a bias problem which, among other consequences, makes asymptotic normal confidence intervals not fully reliable, although they are well developed theoretically.

Association of early repolarization with risk of cardiac mortality in the general population

Early repolarization, which is characterized by an elevation of the J-point on 12-lead electrocardiography, is a common finding that has been considered as benign for decades. However, in the last years, it has been related with vulnerability to idiopathic ventricular fibrillation and with cardiac mortality in the general population. Recently, 4 potential ECG predictors that could differentiate the benign from the malignant form of early repolarization have been suggested. Any previous study about early repolarization has been done in Spain. Aim. To ascertain whether the presence of early repolarization pattern in a resting electrocardiogram is associated with a major risk of cardiac death in a Spanish general population and to determine whether the presence of potential predictors of malignancy in a resting electrocardiogram increases the risk of cardiac mortality in patients with early repolarization pattern. Methods. We will analyse the presence of early repolarization and the occurrence of cardiac mortality in a retrospective cohort study of 4,279 participants aged 25 to 74 years in the province of Girona. This cohort has been followed during a mean of 9.8 years. Early repolarization will be stratified according to the degree of J-point elevation (≥0.1 mV or ≥0.2 mV), the morphology of the J-wave (slurring, notching or any of these two), the ST-segment pattern (ascending or descending) and the localization (inferior leads, lateral leads, or both). Association of early repolarization with cardiac death will be assessed by adjusted Cox-proportional hazards models

Association of early repolarization with risk of cardiac mortality in the general population

Early repolarization, which is characterized by an elevation of the J-point on 12-lead electrocardiography, is a common finding that has been considered as benign for decades. However, in the last years, it has been related with vulnerability to idiopathic ventricular fibrillation and with cardiac mortality in the general population. Recently, 4 potential ECG predictors that could differentiate the benign from the malignant form of early repolarization have been suggested. Any previous study about early repolarization has been done in Spain. Aim. To ascertain whether the presence of early repolarization pattern in a resting electrocardiogram is associated with a major risk of cardiac death in a Spanish general population and to determine whether the presence of potential predictors of malignancy in a resting electrocardiogram increases the risk of cardiac mortality in patients with early repolarization pattern. Methods. We will analyse the presence of early repolarization and the occurrence of cardiac mortality in a retrospective cohort study of 4,279 participants aged 25 to 74 years in the province of Girona. This cohort has been followed during a mean of 9.8 years. Early repolarization will be stratified according to the degree of J-point elevation (≥0.1 mV or ≥0.2 mV), the morphology of the J-wave (slurring, notching or any of these two), the ST-segment pattern (ascending or descending) and the localization (inferior leads, lateral leads, or both). Association of early repolarization with cardiac death will be assessed by adjusted Cox-proportional hazards models

Clinical consequences of switching from olanzapine to risperidone and vice versa in outpatients with schizophrenia: 36-month results from the worldwide schizophrenia outpatients health outcomes (W-SOHO) study

BACKGROUND: With many atypical antipsychotics now available in the market, it has become a common clinical practice to switch between atypical agents as a means of achieving the best clinical outcomes. This study aimed to examine the impact of switching from olanzapine to risperidone and vice versa on clinical status and tolerability outcomes in outpatients with schizophrenia in a naturalistic setting. METHODS: W-SOHO was a 3-year observational study that involved over 17,000 outpatients with schizophrenia from 37 countries worldwide. The present post hoc study focused on the subgroup of patients who started taking olanzapine at baseline and subsequently made the first switch to risperidone (n=162) and vice versa (n=136). Clinical status was assessed at the visit when the first switch was made (i.e. before switching) and after switching. Logistic regression models examined the impact of medication switch on tolerability outcomes, and linear regression models assessed the association between medication switch and change in the Clinical Global Impression-Schizophrenia (CGI-SCH) overall score or change in weight. In addition, Kaplan-Meier survival curves and Cox-proportional hazards models were used to analyze the time to medication switch as well as time to relapse (symptom worsening as assessed by the CGI-SCH scale or hospitalization). RESULTS: 48% and 39% of patients switching to olanzapine and risperidone, respectively, remained on the medication without further switches (p=0.019). Patients switching to olanzapine were significantly less likely to experience relapse (hazard ratio: 3.43, 95% CI: 1.43, 8.26), extrapyramidal symptoms (odds ratio [OR]: 4.02, 95% CI: 1.49, 10.89) and amenorrhea/galactorrhea (OR: 8.99, 95% CI: 2.30, 35.13). No significant difference in weight change was, however, found between the two groups. While the CGI-SCH overall score improved in both groups after switching, there was a significantly greater change in those who switched to olanzapine (difference of 0.29 points, p=0.013). CONCLUSION: Our study showed that patients who switched from risperidone to olanzapine were likely to experience a more favorable treatment course than those who switched from olanzapine to risperidone. Given the nature of observational study design and small sample size, additional studies are warranted.

Sex differences in hospital readmission among colorectal cancer patients.

Background: While several studies have analysed sex and socioeconomic differences in cancer incidence and mortality, sex differences in oncological health care have been seldom considered. Objective: To investigate sex based inequalities in hospital readmission among patients diagnosed with colorectal cancer. Design: Prospective cohort study. Setting: Hospital Universitary in L¿Hospitalet (Barcelona, Spain). Participants: Four hundred and three patients diagnosed with colorectal between January 1996 and December 1998 were actively followed up until 2002. Main outcome measurements and methods: Hospital readmission times related to colorectal cancer after surgical procedure. Cox proportional model with random effect (frailty) was used to estimate hazard rate ratios and 95% confidence intervals of readmission time for covariates analysed. Results: Crude hazard rate ratio of hospital readmission in men was 1.61 (95% CI 1.21 to 2.15). When other significant determinants of readmission were controlled for (including Dukes¿s stage, mortality, and Charlson¿s index) a significant risk of readmission was still present for men (hazard rate ratio: 1.52, 95% CI 1.17 to 1.96). Conclusions: In the case of colorectal cancer, women are less likely than men to be readmitted to the hospital, even after controlling for tumour characteristics, mortality, and comorbidity. New studies should investigate the role of other non-clinical variable such as differences in help seeking behaviours or structural or personal sex bias in the attention given to patients.

Predictors of psychiatric hospitalization during 6 months of maintenance treatment with olanzapine long-acting injection: post hoc analysis of a randomized, double-blind study.

BACKGROUND: Hospitalization is a costly and distressing event associated with relapse during schizophrenia treatment. No information is available on the predictors of psychiatric hospitalization during maintenance treatment with olanzapine long-acting injection (olanzapine-LAI) or how the risk of hospitalization differs between olanzapine-LAI and oral olanzapine. This study aimed to identify the predictors of psychiatric hospitalization during maintenance treatment with olanzapine-LAI and assessed four parameters: hospitalization prevalence, incidence rate, duration, and the time to first hospitalization. Olanzapine-LAI was also compared with a sub-therapeutic dose of olanzapine-LAI and with oral olanzapine. METHODS: This was a post hoc exploratory analysis of data from a randomized, double-blind study comparing the safety and efficacy of olanzapine-LAI (pooled active depot groups: 405 mg/4 weeks, 300 mg/2 weeks, and 150 mg/2 weeks) with oral olanzapine and sub-therapeutic olanzapine-LAI (45 mg/4 weeks) during 6 months' maintenance treatment of clinically stable schizophrenia outpatients (n=1064). The four psychiatric hospitalization parameters were analyzed for each treatment group. Within the olanzapine-LAI group, patients with and without hospitalization were compared on baseline characteristics. Logistic regression and Cox's proportional hazards models were used to identify the best predictors of hospitalization. Comparisons between the treatment groups employed descriptive statistics, the Kaplan-Meier estimator and Cox's proportional hazards models. RESULTS: Psychiatric hospitalization was best predicted by suicide threats in the 12 months before baseline and by prior hospitalization. Compared with sub-therapeutic olanzapine-LAI, olanzapine-LAI was associated with a significantly lower hospitalization rate (5.2% versus 11.1%, p < 0.01), a lower mean number of hospitalizations (0.1 versus 0.2, p = 0.01), a shorter mean duration of hospitalization (1.5 days versus 2.9 days, p < 0.01), and a similar median time to first hospitalization (35 versus 60 days, p = 0.48). Olanzapine-LAI did not differ significantly from oral olanzapine on the studied hospitalization parameters. CONCLUSIONS: In clinically stable schizophrenia outpatients receiving olanzapine-LAI maintenance treatment, psychiatric hospitalization was best predicted by a history of suicide threats and prior psychiatric hospitalization. Olanzapine-LAI was associated with a significantly lower incidence of psychiatric hospitalization and shorter duration of hospitalization compared with sub-therapeutic olanzapine-LAI. Olanzapine-LAI did not differ significantly from oral olanzapine on hospitalization parameters.

A note on the Malliavin differentiability of the Heston volatility

We show that the Heston volatility or equivalently the Cox-Ingersoll-Ross process is Malliavin differentiable and give an explicit expression for the derivative. This result assures the applicability of Malliavin calculus in the framework of the Heston stochastic volatility model and the Cox-Ingersoll-Ross model for interest rates.

Cervical cancer: incidence and survival in migrants within Spain

This study examined the incidence of cervical cancer and survival rates according to migrant experience of women from different regions of Spain to Girona, Catalonia (Spain). DESIGN--Using data from the population based cancer registry of Girona for the period 1980-89, crude and age adjusted incidence rates were calculated for local-born and first generation migrants from other Spanish regions. The age standardised rate ratio (SRR) was calculated and Cox's regression model was used to adjust survival according to migrant status for age and stage at diagnosis. MAIN RESULTS--The incidence of cervical cancer was significantly higher in first generation Spanish migrants compared with locally born women (SRR: 2.02; 95% CI 1.40:2.92). The stage at diagnosis was more advanced among migrants. Survival probability was significantly associated with stage at diagnosis, but age and region of birth were not. CONCLUSIONS--Migrants from the southern Spanish regions show a twofold excess in the incidence of cervical cancer compared with the Girona-born female population. Cases of cervical cancer in migrants are diagnosed at a more advanced stage and as a consequence have a poorer prognosis.

Polyphenol intake and mortality risk: a re-analysis of the PREDIMED trial

Background: Polyphenols may lower the risk of cardiovascular disease (CVD) and other chronic diseases due to their antioxidant and anti-inflammatory properties, as well as their beneficial effects on blood pressure, lipids and insulin resistance. However, no previous epidemiological studies have evaluated the relationship between the intake of total polyphenols intake and polyphenol subclasses with overall mortality. Our aim was to evaluate whether polyphenol intake is associated with all-cause mortality in subjects at high cardiovascular risk. Methods: We used data from the PREDIMED study, a 7,447-participant, parallel-group, randomized, multicenter, controlled five-year feeding trial aimed at assessing the effects of the Mediterranean Diet in primary prevention of cardiovascular disease. Polyphenol intake was calculated by matching food consumption data from repeated food frequency questionnaires (FFQ) with the Phenol-Explorer database on the polyphenol content of each reported food. Hazard ratios (HR) and 95% confidence intervals (CI) between polyphenol intake and mortality were estimated using time-dependent Cox proportional hazard models. Results: Over an average of 4.8 years of follow-up, we observed 327 deaths. After multivariate adjustment, we found a 37% relative reduction in all-cause mortality comparing the highest versus the lowest quintiles of total polyphenol intake (hazard ratio (HR) = 0.63; 95% CI 0.41 to 0.97; P for trend = 0.12). Among the polyphenol subclasses, stilbenes and lignans were significantly associated with reduced all-cause mortality (HR =0.48; 95% CI 0.25 to 0.91; P for trend = 0.04 and HR = 0.60; 95% CI 0.37 to 0.97; P for trend = 0.03, respectively), with no significant associations apparent in the rest (flavonoids or phenolic acids). Conclusions: Among high-risk subjects, those who reported a high polyphenol intake, especially of stilbenes and lignans, showed a reduced risk of overall mortality compared to those with lower intakes. These results may be useful to determine optimal polyphenol intake or specific food sources of polyphenols that may reduce the risk of all-cause mortality.

Effects of cobalt-chromium everolimus eluting stents or bare metal stent on fatal and non-fatal cardiovascular events: patient level meta-analysis

Objectives: To examine the safety and effectiveness of cobalt-chromium everolimus eluting stents compared with bare metal stents. Design: Individual patient data meta-analysis of randomised controlled trials. Cox proportional regression models stratified by trial, containing random effects, were used to assess the impact of stent type on outcomes. Hazard ratios with 95% confidence interval for outcomes were reported. Data sources and study selection: Medline, Embase, the Cochrane Central Register of Controlled Trials. Randomised controlled trials that compared cobalt-chromium everolimus eluting stents with bare metal stents were selected. The principal investigators whose trials met the inclusion criteria provided data for individual patients. Primary outcomes: The primary outcome was cardiac mortality. Secondary endpoints were myocardial infarction, definite stent thrombosis, definite or probable stent thrombosis, target vessel revascularisation, and all cause death. Results: The search yielded five randomised controlled trials, comprising 4896 participants. Compared with patients receiving bare metal stents, participants receiving cobalt-chromium everolimus eluting stents had a significant reduction of cardiac mortality (hazard ratio 0.67, 95% confidence interval 0.49 to 0.91; P=0.01), myocardial infarction (0.71, 0.55 to 0.92; P=0.01), definite stent thrombosis (0.41, 0.22 to 0.76; P=0.005), definite or probable stent thrombosis (0.48, 0.31 to 0.73; P<0.001), and target vessel revascularisation (0.29, 0.20 to 0.41; P<0.001) at a median follow-up of 720 days. There was no significant difference in all cause death between groups (0.83, 0.65 to 1.06; P=0.14). Findings remained unchanged at multivariable regression after adjustment for the acuity of clinical syndrome (for instance, acute coronary syndrome v stable coronary artery disease), diabetes mellitus, female sex, use of glycoprotein IIb/IIIa inhibitors, and up to one year v longer duration treatment with dual antiplatelets. Conclusions: This meta-analysis offers evidence that compared with bare metal stents the use of cobalt-chromium everolimus eluting stents improves global cardiovascular outcomes including cardiac survival, myocardial infarction, and overall stent thrombosis.

Effects of cobalt-chromium everolimus eluting stents or bare metal stent on fatal and non-fatal cardiovascular events: patient level meta-analysis

Objectives: To examine the safety and effectiveness of cobalt-chromium everolimus eluting stents compared with bare metal stents. Design: Individual patient data meta-analysis of randomised controlled trials. Cox proportional regression models stratified by trial, containing random effects, were used to assess the impact of stent type on outcomes. Hazard ratios with 95% confidence interval for outcomes were reported. Data sources and study selection: Medline, Embase, the Cochrane Central Register of Controlled Trials. Randomised controlled trials that compared cobalt-chromium everolimus eluting stents with bare metal stents were selected. The principal investigators whose trials met the inclusion criteria provided data for individual patients. Primary outcomes: The primary outcome was cardiac mortality. Secondary endpoints were myocardial infarction, definite stent thrombosis, definite or probable stent thrombosis, target vessel revascularisation, and all cause death. Results: The search yielded five randomised controlled trials, comprising 4896 participants. Compared with patients receiving bare metal stents, participants receiving cobalt-chromium everolimus eluting stents had a significant reduction of cardiac mortality (hazard ratio 0.67, 95% confidence interval 0.49 to 0.91; P=0.01), myocardial infarction (0.71, 0.55 to 0.92; P=0.01), definite stent thrombosis (0.41, 0.22 to 0.76; P=0.005), definite or probable stent thrombosis (0.48, 0.31 to 0.73; P<0.001), and target vessel revascularisation (0.29, 0.20 to 0.41; P<0.001) at a median follow-up of 720 days. There was no significant difference in all cause death between groups (0.83, 0.65 to 1.06; P=0.14). Findings remained unchanged at multivariable regression after adjustment for the acuity of clinical syndrome (for instance, acute coronary syndrome v stable coronary artery disease), diabetes mellitus, female sex, use of glycoprotein IIb/IIIa inhibitors, and up to one year v longer duration treatment with dual antiplatelets. Conclusions: This meta-analysis offers evidence that compared with bare metal stents the use of cobalt-chromium everolimus eluting stents improves global cardiovascular outcomes including cardiac survival, myocardial infarction, and overall stent thrombosis.

The proportional distribution in a cooperative model with external opportunities

[cat] En aquest article es considera un problema de cooperació entre agents on cada agent realitza una contribució (diners, capital, treball, esforç) per tal d'obtenir un benefici comú a repartir. El repartiment proporcional respecte a les contribucions és una distribució que pertany al nucli del joc cooperatiu associat. A partir d'aquest model bàsic s'introdueix un agent extern que pot realitzar una determinada aportació que serveix per avaluar el potencial benefici de cada subcoalició d'agents si aquest nou agent finalment entrés. Aquesta anàlisi pot produir que el poder relatiu dels agents hagi variat. en concret s'avalua si la distribució proporcional és encara robusta des del punt de vista de la seva pertinença al conjunt de negociació. Amb aquest objectiu, analitzem el problema utilitzant el model de joc cooperatius amb estructura de coalició. Donat que, en general, la distribució proporcional, no pertany al conjunt de negociació, s'estudia una condició suficient per a que així sigui. També enunciem una condició necessària, i finalment es proposa una condició suficient que garanteix que el repartiment proporcional és la única distribució existent dins del conjunt de negociació.

The proportional distribution in a cooperative model with external opportunities

[cat] En aquest article es considera un problema de cooperació entre agents on cada agent realitza una contribució (diners, capital, treball, esforç) per tal d'obtenir un benefici comú a repartir. El repartiment proporcional respecte a les contribucions és una distribució que pertany al nucli del joc cooperatiu associat. A partir d'aquest model bàsic s'introdueix un agent extern que pot realitzar una determinada aportació que serveix per avaluar el potencial benefici de cada subcoalició d'agents si aquest nou agent finalment entrés. Aquesta anàlisi pot produir que el poder relatiu dels agents hagi variat. en concret s'avalua si la distribució proporcional és encara robusta des del punt de vista de la seva pertinença al conjunt de negociació. Amb aquest objectiu, analitzem el problema utilitzant el model de joc cooperatius amb estructura de coalició. Donat que, en general, la distribució proporcional, no pertany al conjunt de negociació, s'estudia una condició suficient per a que així sigui. També enunciem una condició necessària, i finalment es proposa una condició suficient que garanteix que el repartiment proporcional és la única distribució existent dins del conjunt de negociació.

Oral administration of the KATP channel opener diazoxide ameliorates disease progression in a murine model of multiple sclerosis

Background Multiple Sclerosis (MS) is an acquired inflammatory demyelinating disorder of the central nervous system (CNS) and is the leading cause of nontraumatic disability among young adults. Activated microglial cells are important effectors of demyelination and neurodegeneration, by secreting cytokines and others neurotoxic agents. Previous studies have demonstrated that microglia expresses ATP-sensitive potassium (KATP) channels and its pharmacological activation can provide neuroprotective and anti-inflammatory effects. In this study, we have examined the effect of oral administration of KATP channel opener diazoxide on induced experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Methods Anti-inflammatory effects of diazoxide were studied on lipopolysaccharide (LPS) and interferon gamma (IFNy)-activated microglial cells. EAE was induced in C57BL/6J mice by immunization with myelin oligodendrocyte glycoprotein peptide (MOG35-55). Mice were orally treated daily with diazoxide or vehicle for 15 days from the day of EAE symptom onset. Treatment starting at the same time as immunization was also assayed. Clinical signs of EAE were monitored and histological studies were performed to analyze tissue damage, demyelination, glial reactivity, axonal loss, neuronal preservation and lymphocyte infiltration. Results Diazoxide inhibited in vitro nitric oxide (NO), tumor necrosis factor alpha (TNF-¿) and interleukin-6 (IL-6) production and inducible nitric oxide synthase (iNOS) expression by activated microglia without affecting cyclooxygenase-2 (COX-2) expression and phagocytosis. Oral treatment of mice with diazoxide ameliorated EAE clinical signs but did not prevent disease. Histological analysis demonstrated that diazoxide elicited a significant reduction in myelin and axonal loss accompanied by a decrease in glial activation and neuronal damage. Diazoxide did not affect the number of infiltrating lymphocytes positive for CD3 and CD20 in the spinal cord. Conclusion Taken together, these results demonstrate novel actions of diazoxide as an anti-inflammatory agent, which might contribute to its beneficial effects on EAE through neuroprotection. Treatment with this widely used and well-tolerated drug may be a useful therapeutic intervention in ameliorating MS disease.