Adjustment For Baseline Factors Research Articles

Abstract 14928: Coronary Artery Disease Impacts Cardiac Remodeling in Patients Treated for Severe Aortic Stenosis in the PARTNER Trials

Introduction: Coronary artery disease (CAD) is common in patients with severe aortic stenosis (AS), but the impact on cardiac remodeling and outcomes after AS treatment is unknown. Hypothesis: We hypothesize that greater CAD burden will be associated with less beneficial remodeling and increased adverse events. Methods: Patients with severe AS in the PARTNER (Placement of Aortic Transcatheter Valves) 1, 2 or 3 trials, with baseline and 1 year echoes, were categorized as: 1. Obstructive CAD (coronary stenosis ≥50% on invasive angiography, prior myocardial infarction (MI) or previous revascularization); or 2. Non-obstructive or no CAD (all stenosis <50% and no prior MI or revasc). Clinical and imaging characteristics were compared and changes in cardiac structure and function were assessed at 1 year. Associations between CAD, cardiac remodeling and cardiovascular (CV) events at 2 years were examined. Results: Among 5552 patients with severe AS, 1598 (28.8%) had non-obstructive or no CAD and were more likely to be female (67.1%), have fewer CAD risk factors, and receive SAVR (28% vs. 19%) compared to those with obstructive CAD (all p<0.0001). Despite lower LV mass index (LVMi), patients with non-obstructive or no CAD had higher aortic valve velocities, gradients, ejection fraction (EF) and stroke volume index compared to those with obstructive CAD. After 1 year, the decrease in LVMi was similar between groups (p=0.91), but patients with obstructive CAD were more likely to increase EF by ≥5% (p=0.006), reduce LV dimensions (p=0.04), or decrease mitral regurgitation (p=0.01). After adjustment for baseline factors and AS treatment, CV death or heart failure (HF) hospitalization was higher among patients with obstructive CAD (HR 1.16, 95% CI: 1.03-1.30, p=0.01). When LV remodeling at 1 year was also adjusted for, the point estimate was similar but there was no significant difference in the landmarked rate of CV death or HF hospitalization between year 1 and 2 (HR 1.22, 95% CI: 0.95-1.56, p=0.12). Conclusions: Nearly a third of patients with severe AS did not have obstructive CAD and had a better prognosis after treatment for AS. However, patients with obstructive CAD and LV remodeling were not at greater risk for CV events compared to those with non-obstructive or no CAD.

Do baseline characteristics and treatments account for geographical disparities in the outcomes of patients with newly diagnosed atrial fibrillation? The prospective GARFIELD-AF registry

ObjectiveIn patients with newly diagnosed atrial fibrillation (AF), do baseline risk factors and stroke prevention strategies account for the geographically diverse outcomes.DesignGlobal Anticoagulant Registry in the FIELD-Atrial Fibrillation is a...

Age-Specific and Sex-Specific Trends in Life-Sustaining Care After Acute Stroke.

BackgroundTemporal trends in life‐sustaining care after acute stroke are not well characterized. We sought to determine contemporary trends by age and sex in the use of life‐sustaining care after acute ischemic stroke and intracerebral hemorrhage in a large, population‐based cohort.Methods and ResultsWe used linked administrative data to identify all hospitalizations for acute ischemic stroke or intracerebral hemorrhage in the province of Ontario, Canada, from 2003 to 2017. We calculated yearly proportions of intensive care unit admission, mechanical ventilation, percutaneous feeding tube placement, craniotomy/craniectomy, and tracheostomy. We used logistic regression models to evaluate the association of age and sex with life‐sustaining care and determined whether trends persisted after adjustment for baseline factors and estimated stroke severity. There were 137 358 people with acute ischemic stroke or intracerebral hemorrhage hospitalized during the study period. Between 2003 and 2017, there was an increase in the proportion receiving care in the intensive care unit (12.4% to 17.7%) and mechanical ventilation (4.4% to 6.6%). There was a small increase in craniotomy/craniectomy, a decrease in percutaneous feeding tube use, and no change in tracheostomy. Trends were generally consistent across stroke types and persisted after adjustment for comorbid conditions, stroke‐center type, and estimated stroke severity. After adjustment, women and those aged ≥80 years had lower odds of all life‐sustaining care, although the disparities in intensive care unit admission narrowed over time.ConclusionsUse of life‐sustaining care after acute stroke increased between 2003 and 2017. Women and those at older ages had lower odds of intensive care, although the differences narrowed over time. Further research is needed to determine the reasons for these findings.

Temporal Trends in Case Fatality, Discharge Destination, and Admission to Long-term Care After Acute Stroke.

To determine contemporary trends in case fatality, discharge destination, and admission to long-term care after acute ischemic stroke and intracerebral hemorrhage (ICH) using a large, population-based cohort. We used linked administrative data to identify all emergency department visits and hospital admissions for first-ever ischemic stroke or ICH in Ontario, Canada, from 2003 to 2017. We calculated crude and age-/sex-standardized risk of death at 30 days and 1 year from stroke onset. We stratified crude trends by stroke type, age, and sex and used the Kendall τ-b correlation coefficient to evaluate the significance of trends. We determined trends in discharge home and to rehabilitation and admission to long-term care at 1 year. We used Cox proportional hazard and logistic regression models to assess whether trends in outcomes persisted after adjustment for baseline factors, estimated stroke severity, and use of life-sustaining care. There were 163,574 people with acute ischemic stroke or ICH across the study period. Between 2003 and 2017, age-/sex-standardized 30-day stroke case fatality decreased from 20.5% to 13.2% (7.3% absolute and 36% relative reduction) while that at 1 year decreased from 32.2% to 22.8% (9.3% absolute and 29% relative reduction). Findings were consistent across age, sex, and stroke type, and after adjustment for comorbid conditions, stroke severity, and use of life-sustaining care. There was a reduction in long-term care admission after ischemic stroke and an increase in discharge home or to rehabilitation for both stroke types. We observed substantial reductions in acute stroke case fatality from 2003 to 2017 with a concurrent increase in discharge to home or rehabilitation and a decrease in long-term care admissions, suggesting continuous improvements in stroke systems of care.

Abstract P381: Pre-Treatment Perfusion Mismatch Volumes in Ischemic Stroke Patients Treated With Tenecteplase or Alteplase

Introduction: The overall goal of this study is to evaluate the relationship of pretreatment perfusion mismatch volumes to outcomes in patients receiving alteplase (ALT) to those receiving tenecteplase (TNK). Methods: This study included patients receiving treatment with ALT (0.9 mg/kg; max, 90 mg) or TNK (0.25 mg/kg; max, 25 mg) between 09/01/2017 - 06/30/2020 identified through our local stroke registry stroke registry. Of the 505 patients meeting these criteria, 280 have been screened, including patients receiving EVT (n=94) and a sampling of n=111 from the ALT group and 75 from the TNK group. Final eligibility will be patients with a pretreatment perfusion deficit, mismatch > 15 mL, and mismatch (MM) ratio ≥ 1.2. Volumes are based on RAPID software (iSchemiaView). Using univariate (chi-squared with continuity correction or Mann-Whitney U) and adjusted logistic models, the effect of lysis type and pre-treatment imaging were assessed on the primary outcome of discharge disposition. Results: A total of 93 patients were included in our analysis, 40 receiving ALT and 53 patients receiving TNK, demographics found in Table 1. Discharge to home occurred in 48.8% (20/40) of patients treated with ALT and 30.7% (16/53) treated with TNK, odds ratio (OR), 0.47; 95% CI [0.20, 1.09], (P-value for OR=0.0766). Upon adjustment for EVT, age, sex, NIHSS on admission, imaging modality, cohort imbalances (marked by *), and MM, the relation of lysis type to discharge to home gave an OR of 0.25; 95% CI [0.06, 0.90], P= 0.0383) with age (P<0.0001) and imaging modality (P=0.0020) significantly contributing to the model. Lysis type did not significantly influence discharge to hospice or death (OR, 0.62; 95% CI [0.05, 6.86], P=0.6945) upon adjustment for baseline factors. Conclusion: In this preliminary analysis, MM volumes did not contribute to the outcome of discharged to home. Analysis of the full cohort is ongoing and final analyses will relate lytic type to infarct volume growth and clinical outcomes.

Survival implications of prescription opioid and benzodiazepine use in lung transplant recipients: Analysis of linked transplant registry and pharmacy fill records

Prescription opioid and benzodiazepine use have been associated with morbidity and mortality among some groups of solid organ transplant recipients, but implications for outcomes among lung transplant patients are not well described. We conducted a retrospective cohort study using linked national transplant registry and pharmaceutical records to characterize the associations between benzodiazepine and opioid prescription fills in the years before and after lung transplant (2006-2017), with risk-adjusted posttransplant survival (adjusted hazard ratio, LCLaHRUCL). Among 11,568 recipients, 33.7% filled an opioid prescription, and 25.8% filled a benzodiazepine prescription before transplant. Compared to patients without prescriptions, those who filled both short- and long-acting benzodiazepine prescriptions before transplant had 2-fold higher mortality in the first year posttransplant (aHR, 1.392.123.21), after adjustment for baseline factors and opioid fills, while pretransplant opioid fills were not associated with posttransplant mortality after adjustment for benzodiazepine fills. Pretransplant opioid and benzodiazepine use strongly predicted more use after transplant. Fills of both short- and long-acting benzodiazepines in the first year posttransplant were associated with 77% increased mortality >1-to-2 years posttransplant (aHR, 1.061.772.96). Compared with no posttransplant opioid fills, there was a dose-dependent association between first-year opioid fills and subsequent adjusted mortality risk (level 2: aHR, 1.171.501.92 to level 4: aHR, 1.562.012.59). These effects were independent, and interactions were not detected. Benzodiazepine prescription fills before and after lung transplant, and opioid fills after transplant, are independently associated with posttransplant mortality. Review of benzodiazepine and opioid use history is relevant to risk-stratifying patients before and after lung transplant.

Factors associated with participation over time in the Avon Longitudinal Study of Parents and Children: a study using linked education and primary care data.

BackgroundIn observational research, choosing an optimal analysis strategy when variables are incomplete requires an understanding of the factors associated with ongoing participation and non-response, but this cannot be fully examined with incomplete data. Linkage to external datasets provides additional information on those with incomplete data, allowing examination of factors related to missingness.MethodsWe examined the association between baseline sociodemographic factors and ongoing participation in the Avon Longitudinal Study of Parents and Children. We investigated whether child and adolescent outcomes measured in linked education and primary care data were associated with participation, after accounting for baseline factors. To demonstrate the potential for bias, we examined whether the association between maternal smoking and these outcomes differed in the subsample who completed the 19-year questionnaire.ResultsLower levels of school attainment, lower general practitioner (GP) consultation and prescription rates, higher body mass index (BMI), special educational needs (SEN) status, not having an asthma diagnosis, depression and being a smoker were associated with lower participation after adjustment for baseline factors. For example, the adjusted odds ratio (OR) for participation comparing ever smokers (by 18 years) with non-smokers was: 0.65, 95% CI (0.56, 0.75). The associations with maternal smoking differed between the subsample of participants at 19 years and the entire sample, although differences were small and confidence intervals overlapped. For example: for SEN status, OR = 1.19 (1.06, 1.33) (all participants); OR = 1.03 (0.79, 1.45) (subsample).ConclusionsA range of health-related and educational factors are associated with ongoing participation in ALSPAC; this is likely to be the case in other cohort studies. Researchers need to be aware of this when planning their analysis. Cohort studies can use linkage to routine data to explore predictors of ongoing participation and conduct sensitivity analyses to assess potential bias.

Dose and setting of rehabilitation received after stroke in Queensland, Australia: a prospective cohort study

Objective: The aims of this study were to describe patterns and dose of rehabilitation received following stroke and to investigate their relationship with outcomes. Design: This was a prospective observational cohort study. Setting: A total of seven public hospitals and all subsequent rehabilitation services in Queensland, Australia, participated in the study. Subjects: Participants were consecutive patients surviving acute stroke between July 2016 and January 2017. Methods: We tracked rehabilitation for six months following stroke and obtained 90- to 180-day outcomes from the Australian Stroke Clinical Registry. Measures: Dose of rehabilitation – time in therapy by physiotherapy, occupational therapy and speech pathology; modified Rankin Scale (mRS)- premorbid, acute care discharge and 90- to 180-day follow-up. Results: We recruited 504 patients, of whom 337 (median age = 73 years, 41% female) received 643 episodes of rehabilitation in 83 different services. Initial rehabilitation was predominantly inpatient (260/337, 77%) versus community-based (77/337, 21%). Therapy time was greater within inpatient services (median = 29 hours) compared to community-based (6 hours) or transition care (16 hours). Median (Quartile 1, Quartile 3) six-month cumulative therapy time was 73 hours (40, 130) when rehabilitation commenced in stroke units and continued in inpatient rehabilitation units; 43 hours (23, 78) when commenced in inpatient rehabilitation units; and 5 hours (2, 9) with only community rehabilitation. In 317 of 504 (63%) with follow-up data, improvement in mRS was most likely with inpatient rehabilitation (OR = 3.6, 95% CI = 1.7–7.7), lower with community rehabilitation (OR = 1.6, 95% CI = 0.7–3.8) compared to no rehabilitation, after adjustment for baseline factors. Conclusion: Amount of therapy varied widely between rehabilitation pathways. Amount of therapy and chance of improvement in function were highest with inpatient rehabilitation.

2307. Risk factors for Cytomegalovirus (CMV) reactivation and Association with Clinical Outcomes in Critically Ill Adults with Sepsis: A Pooled Analysis of Prospective Studies

BackgroundCMV reactivation in seropositive, non-immunosuppressed adults with sepsis has been associated with worse clinical outcomes. To inform rational design of interventional trials determining whether CMV prevention improves outcomes, it is critical to identify the independence and strength of the association of CMV reactivation measures with clinically-relevant endpoints. Identification of patient factors associated with CMV reactivation would allow for optimization of the study population.MethodsWe performed a secondary pooled analysis of two prospective cohorts with sepsis: an observational cohort of ICU patients (n = 40) and the placebo cohort from a randomized, double-blind trial of ganciclovir to prevent CMV reactivation in acute critical illness (n = 66). Personnel blinded to the PCR results assessed clinical variables; CMV DNAemia was measured by quantitative plasma PCR twice weekly. Multivariable modeling using logistic and linear methods was used to examine the associations of CMV with clinical outcomes and between baseline patient factors and measures of CMV reactivation (adjusted for age, race, gender, transfusion status, study cohort, and APACHE score).ResultsCMV reactivation occurred at any level in 38/106 (36%), at >100 IU/mL in 25/106 (24%), and at >1,000 IU/mL in 14/106 (13%). In a multivariate model, CMV reactivation at any level, >100 IU/mL, or >1,000 IU/mL was associated with fewer days alive and not requiring ventilation: mean difference of −3.5 days ([95% CI −7.0, 0], P = 0.057), −5.1 days ([−8.9, −1.2], P = 0.012), and −6.1 days ([−10.9, −1.2], P = 0.016), respectively. Multiple measures of CMV reactivation were associated with other clinically-relevant outcomes, even after adjustment for baseline factors (Table 1). The association of APACHE score with CMV reactivation measures was inconsistent and with small effect size. We did not identify other patient variables associated with subsequent CMV reactivation.ConclusionCMV reactivation in seropositive adults with sepsis is independently and quantitatively associated with clinically-important outcomes, including death or continued hospitalization by day 28, ventilator-, ICU-, and hospital-free days. These effect sizes provide key data to inform design parameters of future interventional trials. Disclosures All authors: No reported disclosures.

Effect of MyTeen SMS-Based Mobile Intervention for Parents of Adolescents

There is global pressure to respond to the burden posed by adolescent mental health problems. The National Mental Health Commission has made a call for investment in mobile health services directed at prevention and early intervention to relieve the demand on targeted mental health services that are costly to provide. Parents and primary caregivers play a significant role in the lives of adolescents and are important targets for such efforts. Currently, there is no evidence for the effectiveness of programs delivered solely via text message for parents of adolescents. To evaluate the effects of a text-messaging program (MyTeen) on promoting parental competence and mental health literacy for parents of adolescents. A parallel 2-group randomized clinical trial was conducted in New Zealand. A total of 221 parents and primary caregivers of adolescents aged 10 to 15 years were recruited from March 19 to August 17, 2018, via community outreach and social media and were randomly allocated 1:1 into the control or the intervention group. Statistical analysis was performed on the principle of intention to treat with adjustment for baseline factors and ethnicity. A text-messaging program for parents of adolescents (age 10-15 years) to promote parental competence and mental health literacy. Participants received 1 daily text message over 4 weeks. Parental competence, assessed at 1 month after randomization by the Parenting Sense of Competence Scale. In total, 221 participants (214 [96.8%] female) were randomized, 109 to the intervention group and 112 to the control group; 201 participants (91%) completed the trial at 3 months. Significant group difference was observed on the primary outcome at the end of 1 month of intervention, with participants reporting a higher level of parental competence than those in the control group (estimated mean difference, 3.33 points; 95% CI, 1.37-5.29 points; P = .002). Except for knowledge about mental health, all secondary outcomes were significant, including continued improvement in parental competence at 3 months (estimated mean difference, 4.08 points; 95% CI, 1.96-6.20 points; P < .001), knowledge of help seeking (estimated mean difference, 0.99 points; 95% CI, 0.49-1.50 points; P < .001), parental distress (estimated mean difference, -2.39 points; 95% CI, -4.37 to -0.40 points; P = .02), and parent-adolescent communication (estimated mean difference, 2.21 points; 95% CI, 0.48-3.95 points; P = .01), with participants in the intervention group reporting better parenting-related outcomes than the control group at 1 and 3 months after the intervention. This text-messaging program for parents of adolescents appears to be an effective and feasible way to facilitate the implementation and delivery of evidence-based information to populations that are not easily reached with other intervention modalities. The program can be easily scaled up for delivery as an early preventive intervention and may represent a less expensive option for service delivery. anzctr.org.au Identifier: ACTRN12618000117213.

Stroke in Patients With Peripheral Artery Disease.

Background and Purpose- Predictors of stroke and transient ischemic attack (TIA) in patients with peripheral artery disease (PAD) are poorly understood. The primary aims of this analysis were to (1) determine the incidence of ischemic/hemorrhagic stroke and TIA in patients with symptomatic PAD, (2) identify predictors of stroke in patients with PAD, and (3) compare the rate of stroke in ticagrelor- and clopidogrel-treated patients. Methods- EUCLID (Examining Use of Ticagrelor in Peripheral Artery Disease) randomized 13 885 patients with symptomatic PAD to receive monotherapy with ticagrelor or clopidogrel for the prevention of major adverse cardiovascular events (cardiovascular death, myocardial infarction, or ischemic stroke). Ischemic/hemorrhagic stroke and TIA were adjudicated and measured as incidence rates postrandomization and cumulative incidence (per patient-years). Post hoc multivariable competing risk hazards analyses were performed using baseline characteristics to determine factors associated with all-cause stroke in patients with PAD. Results- A total of 458 cerebrovascular events in 424 patients (317 ischemic strokes, 39 hemorrhagic strokes, and 102 TIAs) occurred over a median follow-up of 30 months, for a cumulative incidence of 0.87, 0.11, and 0.27 per 100 patient-years, respectively. Age, prior stroke, prior atrial fibrillation/flutter, diabetes mellitus, geographic region, ankle-brachial index <0.60, prior amputation, and systolic blood pressure were independent baseline factors associated with the occurrence of all-cause stroke. After adjustment for baseline factors, the rates of ischemic stroke and all-cause stroke remained lower in patients treated with ticagrelor as compared with those receiving clopidogrel. There was no significant difference in the incidence of hemorrhagic stroke or TIA between the 2 treatment groups. Conclusions- In patients with symptomatic PAD, ischemic stroke and TIA occur frequently over time. Comorbidities such as age, prior stroke, prior atrial fibrillation/flutter, diabetes mellitus, higher blood pressure, prior amputation, lower ankle-brachial index, and geographic region were each independently associated with the occurrence of all-cause stroke. Use of ticagrelor, as compared with clopidogrel, was associated with a lower adjusted rate of ischemic and all-cause stroke. Further study is needed to optimize medical management and risk reduction of all-cause stroke in patients with PAD. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT01732822.

Malnutrition in Kidney Allograft Recipients Treated with Mycophenolate Mofetil is Associated with IMPDH1 rs2278294 Polymorphism

Introduction The exposure to mycophenolic acid (MPA) and drug effects might be due to inosine 5'-monophosphate dehydrogenase (IMPDH1) polymorphisms. Formation of lipid bodies in adipocytes associates with IMPDH translocation into those structures. In the mouse model of diet-induced obesity, MMF induced loss of body weight and fat content. Our study aims to evaluate whether IMPDH1 polymorphism rs2278294 correlates with malnutrition in kidney recipients treated with mycophenolate mofetil (MMF). Patients and Methods – 240 kidney recipients engrafted 1996-2009, longitudinal observation lasting at least five post-implantation years, treated with mycophenolate mofetil and either tacrolimus (n=100; 42%) or cyclosporine A (n=139; 58%). – BMI was calculated at 3,6,12, 24 and 60th post-transplant months. – Minimal BMI within three post-transplant months was regarded as baseline value. – SNP genetic variants of IMPDH1 (rs2278294) were genotyped by PCR-RFLP method. – Mixed models for repeated measurements after adjustment for baseline factors were used to test relation between rs2278294 polymorphism of IMPDH1 and BMI in 5 years follow-up (MIXED Procedure of SAS System). Results Genotypes frequencies for rs2278294 polymorphism of IMPDH1 were as follow: 27(11%) of AA homozygotes, 91(38%) GA heterozygotes and 122(51%) GG homozygotes In the subset of recipients with initially normal or diminished BMI(≤25kg/m2) there was a substantial increase of BMI at 6,12, 24 and 60 th post-tx months. Moreover, BMI increase was correlated with rs2278294 polymorphism of IMPDH1. Among allele G carriers (GG or GA) BMI gain was significantly slower than in AA homozygotes (p<0.0025; interaction effect). Mean values of BMI(kg/m2) at 3,6,12, 24 and 60 th months were as follow: 22.0 vs 22.5; 22.6 vs 23.6; 23.1vs 24.5; 23.6 vs 24.9 and 24,1 vs 24.8 kg/m2 in (GG or GA) and AA carriers, respectively. In cosequence, among G allele carriers 5% experienced seriously diminished BMI fulfilling malnutrition criteria (18.2, 18.2, 18.8 and 18.8, 19 kg/m2 at 3,6,12 24 and 60 th post-transplant months). In G allele carriers mycophenolate mofetil dimunition or withdrawal resulted solely in preserving the subset of patients prone to malnutrition. Conclusions Since the effect of rs2278294 on BMI was found at transplantation and persisted until 5th post-implantation year, we hypothesize that the variant of interest influences fat-tissue formation in humans.

Hypotension Risk Based on Vasoactive Agent Discontinuation Order in Patients in the Recovery Phase of Septic Shock.

Patients with septic shock often require vasoactive agents for hemodynamic support; however, the optimal approach to discontinuing these agents once patients reach the recovery phase is currently unknown. The objective of this evaluation was to compare the incidence of hypotension within 24 hours based on the discontinuation order of norepinephrine (NE) and vasopressin (AVP) in patients in the recovery phase of septic shock. Retrospective cohort study. The medical, surgical, and neurosciences intensive care units (ICUs) at a large tertiary care academic medical center. A total of 585 adults in the recovery phase of septic shock who received fixed-dose AVP for at least 6 hours as an adjunct to NE between September 2011 and August 2015 were included. Of these patients, 155 had AVP discontinued first, and 430 had NE discontinued first. Hypotension was evaluated during the 24-hour period after discontinuation of the first vasoactive agent and was defined as mean arterial pressure less than 60 mm Hg with one or more of the following interventions: increased remaining vasoactive agent dose by 25%, reinstitution of the discontinued agent, or administration of at least 1 L of fluid bolus. Time to hypotension was evaluated with survival analysis, and risk of hypotension was evaluated with multivariable Cox proportional hazards regression. No significant difference between groups was noted in the incidence of hypotension within 24 hours (55% in the AVP discontinued first group vs 50% in the NE discontinued first group, p=0.28) or ICU mortality (45.2% vs 40.0%, p=0.26). After adjustment for baseline factors with multivariable Cox proportional hazards regression, having AVP discontinued first was independently associated with an increased risk of hypotension with a time-varying effect that decreased over time (HR(t) = e[1.16-0.08*t] , p<0.001). In patients recovering from septic shock treated with concomitant AVP and NE, no significant difference was noted in the incidence of hypotension based on discontinuation order of these agents.

Continuing or ceasing bevacizumab beyond progression in recurrent glioblastoma: an exploratory randomized phase II trial.

In patients with recurrent glioblastoma, the benefit of bevacizumab beyond progression remains uncertain. We prospectively evaluated continuing or ceasing bevacizumab in patients who progressed while on bevacizumab. CABARET, a phase II study, initially randomized patients to bevacizumab with or without carboplatin (Part 1). At progression, eligible patients underwent a second randomization to continue or cease bevacizumab (Part 2). They could also receive additional chemotherapy regimens (carboplatin, temozolomide, or etoposide) or supportive care. Of 120 patients treated in Part 1, 48 (80% of the anticipated 60-patient sample size) continued to Part 2. Despite randomization, there were some imbalances in patient characteristics. The best response was stable disease in 7 (30%) patients who continued bevacizumab and 2 (8%) patients who stopped receiving bevacizumab. There were no radiological responses. Median progression-free survival was 1.8 vs 2.0 months (bevacizumab vs no bevacizumab; hazard ratio [HR], 1.08; 95% CI, .59-1.96; P = .81). Median overall survival was 3.4 vs 3.0 months (HR, .84; 95% CI, .47-1.50; P = .56 and HR .70; 95% CI .38-1.29; P = .25 after adjustment for baseline factors). Quality-of-life scores did not significantly differ between arms. While the maximum daily steroid dose was lower in the continuation arm, the difference was not statistically significant. Patients who continued bevacizumab beyond disease progression did not have clear survival improvements, although the study was not powered to detect other than very large differences. While these data provide the only randomized evidence related to continuing bevacizumab beyond progression in recurrent glioblastoma, the small sample size precludes definitive conclusions and suggests this remains an open question.

Body mass index is a risk factor for new-onset non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus

To investigate the effect of body mass index (BMI) on new-onset non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM). Subjects with T2DM were recruited from the population of individuals attending the Affiliated General Hospital of North China University for routine health examination between 2006 and 2007 and offered participation in this community-based prospective cohort study. Enrollees were categorized into groups according to weight assessed by baseline BMI (underweight, normal, overweight, and obese groups). Cumulative incidence of NAFLD was compared between each group and the effect of baseline BMI on new-onset NAFLD was assessed by Cox regression analysis. The cumulative incidence of NAFLD increased in conjunction with increases in weight (low weight: 69%, normal weight: 73%, overweight: 90%, obese: 97%; P<0.01). Subjects in the overweight and obese groups showed an increased risk of NAFLD (relative risk (RR)=2.00, 95% CI: 1.76-2.29 and =2.87, 95% CI: 2.42-3.40; P<0.01), compared to those in the normal weight group. Moreover, after adjustment for baseline factors (e.g.age, sex) risk of NAFLD remained higher for the overweight and obese subjects (RR=1.73, 95% CI: 1.49-2.00 and =2.12, 95% CI: 1.73-2.60; P<0.01). Risk of NAFLD in T2DM patients increases in parallel to increase in weight assessed by BMI. BMI appeared to be an independent risk factor for NAFLD.

Impact of combination antimicrobial therapy on mortality risk for critically ill patients with carbapenem-resistant bacteremia.

There are limited treatment options for carbapenem-resistant Gram-negative infections. Currently, there are suggestions in the literature that combination therapy should be used, which frequently includes antibiotics to which the causative pathogen demonstrates in vitro resistance. This case-control study evaluated risk factors associated with all-cause mortality rates for critically ill patients with carbapenem-resistant Gram-negative bacteremia. Adult patients who were admitted to an intensive care unit with sepsis and a blood culture positive for Gram-negative bacteria resistant to a carbapenem were included. Patients with polymicrobial, recurrent, or breakthrough infections were excluded. Included patients were classified as survivors (controls) or nonsurvivors (cases) at 30 days after the positive blood culture. Of 302 patients screened, 168 patients were included, of whom 90 patients died (53.6% [cases]) and 78 survived (46.4% [controls]) at 30 days. More survivors received appropriate antibiotics (antibiotics with in vitro activity) than did nonsurvivors (93.6% versus 53.3%; P < 0.01). Combination therapy, defined as multiple appropriate agents given for 48 h or more, was more common among survivors than nonsurvivors (32.1% versus 7.8%; P < 0.01); however, there was no difference in multiple-agent use when in vitro activity was not considered (including combinations with carbapenems) (87.2% versus 80%; P = 0.21). After adjustment for baseline factors with multivariable logistic regression, combination therapy was independently associated with decreased risk of death (odds ratio, 0.19 [95% confidence interval, 0.06 to 0.56]; P < 0.01). These data suggest that combination therapy with multiple agents with in vitro activity is associated with improved survival rates for critically ill patients with carbapenem-resistant Gram-negative bacteremia. However, that association is lost if in vitro activity is not considered.

On-site programmatic attendance to cardiac rehabilitation and the healthy-adherer effect.

On-site attendance to prescheduled cardiac rehabilitation visits has been shown to be associated with improved outcomes following cardiac rehabilitation. The extent to which on-site programmatic attendance represents a healthy-adherer effect remains unknown. This retrospective cohort study consisted of 17,000 consecutively referred patients to a cardiac rehabilitation program in Ontario, Canada. On-site attendance at prescheduled visits was our primary exposure variable. The primary outcome was all-cause death or hospitalization at two years following the expected program completion date, irrespective of drop-out. Secondary outcomes included adherence to statins, health-seeking preventative health visits, and changes in clinical risk-profiles. Cox proportional hazards adjusted for baseline sociodemographic, clinical and comorbid characteristics. Among the 12,440 patients who attended at least one prescheduled on-site visit, on-site attendance was inversely correlated with baseline smoking rates and body mass index at program entry. After adjustment for baseline factors, the risk of death or hospitalization progressively fell with incremental increases in on-site attendance (adjusted hazard ratio for each 10% increase in on-site attendance: 0.96; 95% confidence interval: 0.93-0.99, p = 0.007). Such associations were driven predominantly by differences in non-cardiovascular hospitalizations. Incremental increases in on-site attendance were associated with improvements in cardiopulmonary fitness and body mass index (both p < 0.001), better attendance of preventative care physician visits (p < 0.001) and higher medication adherence to statins (p = 0.007). Associations between on-site attendance at cardiac rehabilitation and outcomes may represent a healthy-adherer effect. Future research must evaluate the clinical utility of on-site attendance as a behavioral health-adherence metric for cardiac rehabilitation monitoring and surveillance.

The effect of white matter lesions on cognition after carotid revascularization

BackgroundCerebral white matter lesions (WML) are associated with cognitive impairment, and carotid revascularization with cognitive worsening or improvement. We assessed the relation between WML severity and changes in cognition after carotid endarterectomy or stenting. MethodsPatients with symptomatic carotid artery stenosis, enrolled in the International Carotid Stenting Study (ISRCTN25337470), underwent detailed neuropsychological examinations (NPEs) before and after 6months. Cognitive results were standardized into z-scores, from which a sum score was calculated. The primary outcome was the mean difference (MD) in sum score between baseline and follow-up. Changes in sum score were related to WML severity with the ‘age-related white matter changes’ score, assessed on baseline MRI-FLAIR. Three groups were formed based on this score. ResultsEighty-nine patients had both baseline MRI and NPE, of these 77 had a calculable cognitive difference score. The cognitive sum score at six months was worse than at baseline: MD, −0.21; 95% CI, −0.32 to −0.09. The change in sum score did not depend on WML load: MD for no-to-mild WML, −0.15; 95% CI, −0.39 to 0.09, for moderate WML, −0.27; 95% CI, −0.48 to −0.06; and for severe WML, −0.21; 95% CI, −0.40 to −0.04. This did not change essentially after adjustment for baseline factors. ConclusionCognitive functioning deteriorated after carotid revascularization, regardless of baseline WML burden.

Protease inhibitors and cardiac autonomic function in HIV-infected patients: a cross-sectional analysis from the Strategies for Management of Antiretroviral Therapy (SMART) Trial

ObjectiveTo compare cardiac autonomic function as measured by heart rate variability for HIV-infected participants taking protease inhibitors (PIs) with those taking a non-nucleoside reverse transcriptase inhibitor without a PI (NNRTI-no...

Effect of using reporting guidelines during peer review on quality of final manuscripts submitted to a biomedical journal: masked randomised trial

Objective To investigate the effect of an additional review based on reporting guidelines such as STROBE and CONSORT on quality of manuscripts.Design Masked randomised trial.Population Original research manuscripts submitted to...