Update of the Preventive Antibiotics in Stroke Study (PASS): Statistical analysis plan

Background: Infections occur in 30% of stroke patients and are associated with unfavorable outcomes. Preventive antibiotic therapy lowers the infection rate after stroke, but the effect of preventive antibiotic treatment on functional outcome in patients with stroke is unknown. The PASS is a multicenter, prospective, phase three, randomized, open-label, blinded end-point (PROBE) trial of preventive antibiotic therapy in acute stroke. Patients are randomly assigned to either ceftriaxone at a dose of 2 g, given every 24 h intravenously for 4 days, in addition to standard stroke-unit care, or standard stroke-unit care without preventive antibiotic therapy. The aim of this study is to assess whether preventive antibiotic treatment improves functional outcome at 3 months by preventing infections. This paper presents in detail the statistical analysis plan (SAP) of the Preventive Antibiotics in Stroke Study (PASS) and was submitted while the investigators were st

Has the Rate of CD4 Cell Count Decline before Initiation of Antiretroviral Therapy Changed over the Course of the Dutch HIV Epidemic among MSM?

Introduction:Studies suggest that the HIV-1 epidemic in the Netherlands may have become more virulent, leading to faster disease progression if untreated. Analysis of CD4 cell count decline before antiretroviral therapy (ART) initiation, a surrogate marker for disease progression, may be hampered by informative censoring as ART initiation is more likely with a steeper CD4 cell count decline.Methods:Development of CD4 cell count from 9 to 48 months after seroconversion was analyzed using a mixed-effects model and 2 models that jointly modeled CD4 cell counts and time to censoring event (start ART

Sub-optimal adherence to combination anti-retroviral therapy and its associated factors according to self-report, clinician-recorded and pharmacy-refill assessment methods among HIV-infected adults in Addis Ababa

Adherence to combination antiretroviral therapy (cART) is generally high in most resource-limited settings. However, sub-optimal adherence occurs in a sizable proportion of patients, and is independently predictive of detectable viremia. We investigated sub-optimal adherence according to self-report, clinician-recorded, and pharmacy-refill assessment methods, and their associated factors among HIV-infected adults receiving cART in Addis Ababa, Ethiopia. Eight-hundred seventy patients who initiated cART between May 2009 and April 2012 were randomly selected, and 664 patients who were alive, had remained in clinical care and were receiving cART for at least six-months were included. Sub-optimal adherence was defined as patients’ response of less than “all-of the time” to the self-report adherence question, or any clinician-recorded poor adherence during the six most recent clinic visits, or a pharmacy-refill of <95% medication possession ratio (MPR). Logistic regression models were fitted to identify factors associated with sub-optimal adherence. The average adherence level to cART, expressed as MPR, was nearly 97%. However, sub-optimal adherence occurred in 12%, 4%, and 27% of patients according to self-report, clinician-recorded, and pharmacy-refill measures, respectively. More satisfaction with social support was significantly associated with less sub-optimal adherence according to self-report and clinician-record. Younger age, lower educational level, and lower CD4 cell count at cART initiation were significantly associated with sub-optimal refill-based adherence. Findings from our large multi-center study suggest that sub-optimal adherence was present in up to a quarter of the patients, despite a high degree of average adherence to cART. Interventions aimed at preventing sub-optimal adherence should focus on improving social support, on younger patients, on patients with lower educational level, and on those who started cART at a lower CD4 cell count

Prediction of Glaucomatous Visual Field Progression Using Baseline Clinical Data

Purpose: To develop a prediction model for glaucomatous visual field progression using easily accessible baseline clinical data. Patients and Methods: We collected baseline data of 613 consecutive patients with open-angle glaucoma from 2001 to 2003. The rate of visual field progression was calculated using the Visual Field Index (VFI) of routine follow-up examinations until 2010. Baseline data of 333 patients from 3 hospitals were used to develop a model to predict the rate of VFI progression using a linear regression analysis and univariate preselection (P <0.1) of 8 candidate predictors. The performance of the model was investigated using R-2, the area under the receiver-operating characteristic curve, and calibration plots. The prediction model was internally validated using bootstrapping and externally validated in 280 patients from 2 other hospitals. Results: After a mean follow-up period of 5.8 years of all 613 eyes, the mean rate of VFI progression was -1.6% per year. The final model contained the following predictors: age, baseline intraocular pressure, and baseline visual field status. During model development, 10.3% of the observed variation in VFI rates was explained by the model. The area under the receiver-operating characteristic curve was 0.76 when the prediction model was used to detect a VFI rate of -3% per year or worse, which decreased to 0.71 at external validation. Conclusions: Although our prediction model could explain only a small amount of the variance in visual field progression, it may offer the possibility to identify subgroups of treated patients with high rates of visual field progression, thereby providing an opportunity to select those patients for more intensive treatment

MRI of carotid atherosclerosis to identify TIA and stroke patients who are at risk of a recurrence

PURPOSE: To evaluate the potential of carotid plaque MRI to predict transient ischemic attack (TIA) and stroke recurrence in previously symptomatic patients. MATERIALS AND METHODS: One hundred twenty-six TIA/stroke patients with ipsilateral 30-69% carotid stenosis underwent multisequence carotid plaque MRI. The presence of a lipid-rich necrotic core (LRNC), fibrous cap (FC) status, and intraplaque hemorrhage (IPH) were assessed. Patients were followed to determine the recurrence of ipsilateral TIA and/or stroke within 1 year after inclusion. RESULTS: Thirteen patients suffered from recurrent ipsilateral clinical ischemic events (10 TIAs and 3 strokes). Carotid stenosis grade was not associated with recurrent events (hazard ratio [HR] for 50-69% versus 30-49% stenosis = 1.198; 95% confidence interval [CI], 0.383 to 3.749; P = 0.756). The presence of an LRNC (HR = 3.2001; 95% CI, 1.078 to 9.504; P = 0.036), a thin and/or ruptured FC (HR = 5.756; 95% CI, 1.913 to 17.324; P = 0.002), and IPH (HR = 3.542; 95% CI, 1.058 to 11.856; P = 0.040) were associated with recurrence. CONCLUSION: The presence of MRI-depicted LRNC, a thin and/or ruptured FC, and IPH are associated with the recurrence of clinical cerebrovascular ischemic events in TIA and stroke patients with carotid atherosclerosis. J. Magn. Reson. Imaging 2013;

The MicroRNA-371 Family as Plasma Biomarkers for Monitoring Undifferentiated and Potentially Malignant Human Pluripotent Stem Cells in Teratoma Assays

Summary: Predicting developmental potency and risk of posttransplantation tumor formation by human pluripotent stem cells (hPSCs) and their derivatives largely rely on classical histological analysis of teratomas. Here, we investigated whether an assay based on microRNAs (miRNA) in blood plasma is able to detect potentially malignant elements. Several hPSCs and human malignant germ cell tumor (hGCT) lines were investigated in vitro and in vivo after mouse xenografting. The multiple conventional hPSC lines generated mature teratomas, while xenografts from induced hPSCs (hiPSCs) with reactivated reprogramming transgenes and hGCT lines contained undifferentiated and potentially malignant components. The presence of these elements was reflected in the mRNA and miRNA profiles of the xenografts with OCT3/4 mRNA and the miR-371 and miR-302 families readily detectable. miR-371 family members were also identified in mouse plasma faithfully reporting undifferentiated elements in the xenografts. This study demonstrated that undifferentiated and potentially malignant cells could be detected in vivo. : Salvatori et al. showed histological, mRNA, microRNA similarities between human germ cell tumors and xenografts derived from human pluripotent stem cells (hPSCs). miR-371, -302, and C19MC families were present in the blood plasma of mice after injection of hPSCs (teratoma assay) and were indicative of undifferentiated and potentially malignant cells in the growing xenograft. Keywords: teratoma, human pluripotent stem cells, malignant elements, embryonal carcinoma, human germ cell tumors, microRN

Implementation and evaluation of an antimicrobial stewardship programme in companion animal clinics : A stepped-wedge design intervention study

Background To curb increasing resistance rates, responsible antimicrobial use (AMU) is needed, both in human and veterinary medicine. In human healthcare, antimicrobial stewardship programmes (ASPs) have been implemented worldwide to improve appropriate AMU. No ASPs have been developed for and implemented in companion animal clinics yet. Objectives The objective of the present study was to implement and evaluate the effectiveness of an ASP in 44 Dutch companion animal clinics. The objectives of the ASP were to increase awareness on AMU, to decrease total AMU whenever possible and to shift AMU towards 1st choice antimicrobials, according to Dutch guidelines on veterinary AMU. Methods The study was designed as a prospective, stepped-wedge, intervention study, which was performed from March 2016 until March 2018. The multifaceted intervention was developed using previous qualitative and quantitative research on current prescribing behaviour in Dutch companion animal clinics. The number of Defined Daily Doses for Animal (DDDAs) per clinic (total, 1st, 2nd and 3rd choice AMU) was used to quantify systemic AMU. Monthly AMU data were described using a mixed effect time series model with auto-regression. The effect of the ASP was modelled using a step function and a change in the (linear) time trend. Results A statistically significant decrease of 15% (7%-22%) in total AMU, 15% (5%-24%) in 1st choice AMU and 26% (17%-34%) in 2nd choice AMU was attributed to participation in the ASP, on top of the already ongoing time trends. Use of 3rd choice AMs did not significantly decrease by participation in the ASP. The change in total AMU became more prominent over time, with a 16% (4%-26%) decrease in (linear) time trend per year. Conclusions This study shows that, although AMU in Dutch companion animal clinics was already decreasing and changing, AMU could be further optimised by participation in an antimicrobial stewardship programme

Appropriateness of empirical treatment and outcome in bacteremia caused by extended-spectrum-β-lactamase-producing bacteria

We studied clinical characteristics, appropriateness of initial antibiotic treatment, and other factors associated with day 30 mortality in patients with bacteremia caused by extended-spectrum-β-lactamase (ESBL)-producing bacteria in eight Dutch hospitals. Retrospectively, information was collected from 232 consecutive patients with ESBL bacteremia (due to Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae) between 2008 and 2010. In this cohort (median age of 65 years; 24 patients were <18 years of age), many had comorbidities, such as malignancy (34%) or recurrent urinary tract infection (UTI) (15%). One hundred forty episodes (60%) were nosocomial, 54 (23%) were otherwise health care associated, and 38 (16%) were community acquired. The most frequent sources of infection were UTI (42%) and intra-abdominal infection (28%). Appropriate therapy within 24 h after bacteremia onset was prescribed to 37% of all patients and to 54% of known ESBL carriers. The day 30 mortality rate was 20%. In a multivariable analysis, a Charlson comorbidity index of ≥3, an age of ≥75 years, intensive care unit (ICU) stay at bacteremia onset, a non-UTI bacteremia source, and presentation with severe sepsis, but not inappropriate therapy within <24 h (adjusted odds ratio [OR], 1.53; 95% confidence interval [CI], 0.68 to 3.45), were associated with day 30 mortality. Further assessment of confounding and a stratified analysis for patients with UTI and non-UTI origins of infection did not reveal a statistically significant effect of inappropriate therapy on day 30 mortality, and these results were insensitive to the possible misclassification of patients who had received β-lactam-β-lactamase inhibitor combinations or ceftazidime as initial treatment. In conclusion, ESBL bacteremia occurs mostly in patients with comorbidities requiring frequent hospitalization, and 84% of episodes were health care associated. Factors other than inappropriate therapy within <24 h determined day 30 mortality. Copyrigh

Lactobacilli vs antibiotics to prevent urinary tract infections: A randomized, double-blind, noninferiority trial in postmenopausal women

Background: Growing antibiotic resistance warrants studying nonantibiotic prophylaxis for recurrent urinary tract infections (UTIs). Use of lactobacilli appears to be promising. Methods: Between January 2005 and August 2007, we randomized 252 postmenopausal women with recurrent UTIs taking part in a double-blind noninferiority trial to receive 12 months of prophylaxis with trimethoprimsulfamethoxazole, 480 mg, once daily or oral capsules containing 09 colony-forming units of Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 twice daily. Primary end points were the mean number of symptomatic UTIs, proportion of participants with at least 1 UTI during 12 months, time to first UTI, and development of antibiotic resistance by Escherichia coli. Results: The mean number of symptomatic UTIs in the year preceding randomization was 7.0 in the trimethoprimsulfamethoxazole group and 6.8 in the lactobacilli group. In the intention-to-treat analysis, after 12 months of prophylaxis, these numbers were 2.9 and 3.3, respectively. The betw

Supplementary Data FS3 from Therapeutic Vaccination against Human Papillomavirus Type 16 for the Treatment of High-Grade Anal Intraepithelial Neoplasia in HIV⁺ Men

Supplementary Figure S3: Type of T cells responding to HPV16 oncoproteins.</p