Underestimation of Standard Errors in Multi-Site Time Series Studies

Multi-site time series studies of air pollution and mortality and morbidity have figured prominently in the literature as comprehensive approaches for estimating acute effects of air pollution on health. Hierarchical models are generally used to combine site-specific information and estimate pooled air pollution effects taking into account both within-site statistical uncertainty, and across-site heterogeneity. Within a site, characteristics of time series data of air pollution and health (small pollution effects, missing data, highly correlated predictors, non linear confounding etc.) make modelling all sources of uncertainty challenging. One potential consequence is underestimation of the statistical variance of the site-specific effects to be combined. In this paper we investigate the impact of variance underestimation on the pooled relative rate estimate. We focus on two-stage normal-normal hierarchical models and on under- estimation of the statistical variance at the first stage. By mathematical considerations and simulation studies, we found that variance underestimation does not affect the pooled estimate substantially. However, some sensitivity of the pooled estimate to variance underestimation is observed when the number of sites is small and underestimation is severe. These simulation results are applicable to any two-stage normal-normal hierarchical model for combining information of site-specific results, and they can be easily extended to more general hierarchical formulations. We also examined the impact of variance underestimation on the national average relative rate estimate from the National Morbidity Mortality Air Pollution Study and we found that variance underestimation as much as 40% has little effect on the national average.

Kernel Estimation of Rate Function for Recurrent Event Data

Recurrent event data are largely characterized by the rate function but smoothing techniques for estimating the rate function have never been rigorously developed or studied in statistical literature. This paper considers the moment and least squares methods for estimating the rate function from recurrent event data. With an independent censoring assumption on the recurrent event process, we study statistical properties of the proposed estimators and propose bootstrap procedures for the bandwidth selection and for the approximation of confidence intervals in the estimation of the occurrence rate function. It is identified that the moment method without resmoothing via a smaller bandwidth will produce curve with nicks occurring at the censoring times, whereas there is no such problem with the least squares method. Furthermore, the asymptotic variance of the least squares estimator is shown to be smaller under regularity conditions. However, in the implementation of the bootstrap procedures, the moment method is computationally more efficient than the least squares method because the former approach uses condensed bootstrap data. The performance of the proposed procedures is studied through Monte Carlo simulations and an epidemiological example on intravenous drug users.

Chlorhexidine and preservation of sound tooth structure in older adults. A placebo-controlled trial

The Trial to Enhance Elderly Teeth Health (TEETH) was designed to test the impact of regular rinsing with a 0.12% chlorhexidine (CHX) solution on tooth loss, and the causes of tooth loss (caries, periodontal disease and trauma) were also investigated. This paper reports on the effectiveness of a 0.12% CHX solution for controlling caries using a tooth surface (coronal and root) survival analysis. A total of 1,101 low income elders in Seattle (United States) and Vancouver (Canada), aged 60-75 years, were recruited for a double-blind clinical trial and assigned to either a CHX (n = 550) or a placebo (n = 551) mouth rinse. Subjects alternated between daily rinsing for 1 month, followed by weekly rinsing for 5 months. All sound coronal and root surfaces at baseline were followed annually for up to 5 years. At each follow-up examination, those tooth surfaces with caries, restored, or extracted were scored as 'carious'. The hazard ratio associated with CHX for a sound surface to become filled, decayed, or extracted was 0.87 for coronal surfaces (95% confidence interval: 0.71-1.14, p = 0.20) and 0.91 for root surfaces (95% confidence interval: 0.73-1.14, p = 0.41). These findings suggest that regular rinsing with CHX does not have a substantial effect on the preservation of sound tooth structure in older adults.

Bacillus Calmette-Guérin Failure in Patients with Non-Muscle-invasive Urothelial Carcinoma of the Bladder May Be Due to the Urologist's Failure to Detect Urothelial Carcinoma of the Upper Urinary Tract and Urethra

BACKGROUND: Various reasons exist for so-called bacillus Calmette-Guérin (BCG) failure in patients with non-muscle-invasive urothelial bladder carcinoma (NMIBC). OBJECTIVE: To explore whether urothelial carcinoma of the upper urinary tract (UUT) and/or prostatic urethra may be a cause for BCG failure. DESIGN, SETTING, AND PARTICIPANTS: Retrospective analysis of 110 patients with high-risk NMIBC repeatedly treated with intravesical BCG, diagnosed with disease recurrence, and followed for a median time of 9.1 yr. INTERVENTION: Two or more intravesical BCG induction courses without maintenance. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary outcome was pattern of disease recurrence (BCG failure) within the urinary tract categorised into UUT and/or urethral carcinoma (with or without intravesical recurrence), and intravesical recurrence alone. Secondary outcome was survival. Predictors of UUT and/or urethral carcinoma and the effect of pattern of disease recurrence on cancer-specific survival were assessed with multivariable Cox regression analysis adjusting for multiple clinical and tumour characteristics. RESULTS AND LIMITATIONS: Of the 110 patients, 57 (52%) had UUT and/or urethral carcinoma (with or without intravesical recurrence), and 53 (48%) had intravesical recurrence alone. In patients with UUT and/or urethral carcinoma, bladder carcinoma in situ (Tis) before the first and second BCG course was present in 42 of 57 (74%) and 47 of 57 (82%) patients, respectively. On multivariable analysis, bladder Tis before the first and/or second BCG course was the only independent predictor of UUT and/or urethral carcinoma. Of the 110 patients, 69 (63%) were alive at last follow-up visit, 18 (16%) had died due to metastatic urothelial carcinoma, and 23 (21%) had died of other causes. Pattern of disease recurrence within the urinary tract was not an independent predictor of cancer-specific survival. Main study limitations were retrospective design and limited power for survival analysis. CONCLUSIONS: In our patients with high-risk NMIBC failing after two or more courses of intravesical BCG, UUT and/or urethral carcinoma was detected in >50% of the cases during follow-up. The vast majority of these patients had bladder Tis before the first and/or second BCG course. In patients experiencing the so-called BCG failure, a diagnostic work-up of UUT and prostatic urethra should always be performed to exclude urothelial carcinoma before additional intravesical therapy or even a radical cystectomy is considered.

High myeloperoxidase positive cell infiltration in colorectal cancer is an independent favorable prognostic factor

BACKGROUND Colorectal cancer (CRC) infiltration by adaptive immune system cells correlates with favorable prognosis. The role of the innate immune system is still debated. Here we addressed the prognostic impact of CRC infiltration by neutrophil granulocytes (NG). METHODS A TMA including healthy mucosa and clinically annotated CRC specimens (n = 1491) was stained with MPO and CD15 specific antibodies. MPO+ and CD15+ positive immune cells were counted by three independent observers. Phenotypic profiles of CRC infiltrating MPO+ and CD15+ cells were validated by flow cytometry on cell suspensions derived from enzymatically digested surgical specimens. Survival analysis was performed by splitting randomized data in training and validation subsets. RESULTS MPO+ and CD15+ cell infiltration were significantly correlated (p<0.0001; r = 0.76). However, only high density of MPO+ cell infiltration was associated with significantly improved survival in training (P = 0.038) and validation (P = 0.002) sets. In multivariate analysis including T and N stage, vascular invasion, tumor border configuration and microsatellite instability status, MPO+ cell infiltration proved an independent prognostic marker overall (P = 0.004; HR = 0.65; CI:±0.15) and in both training (P = 0.048) and validation (P = 0.036) sets. Flow-cytometry analysis of CRC cell suspensions derived from clinical specimens showed that while MPO+ cells were largely CD15+/CD66b+, sizeable percentages of CD15+ and CD66b+ cells were MPO-. CONCLUSIONS High density MPO+ cell infiltration is a novel independent favorable prognostic factor in CRC.

Hypoglycemia is associated with increased mortality in patients with acute decompensated liver cirrhosis

PRINCIPALS The liver plays an important role in glucose metabolism, in terms of glucolysis and gluconeogenesis. Several studies have shown that hyperglycemia in patients with liver cirrhosis is associated with progression of the liver disease and increased mortality. However, no study has ever targeted the influence of hypoglycemia. The aim of this study was to assess the association of glucose disturbances with outcome in patients presenting to the emergency department with acute decompensated liver cirrhosis. METHODS Our retrospective data analysis comprised adult (≥16 years) patients admitted to our emergency department between January 1, 2002, and December 31, 2012, with the primary diagnosis of decompensated liver cirrhosis. RESULTS A total of 312 patients were eligible for study inclusion. Two hundred thirty-one (74.0%) patients were male; 81 (26.0%) were female. The median age was 57 years (range, 51-65 years). Overall, 89 (28.5%) of our patients had acute glucose disturbances; 49 (15.7%) of our patients were hypoglycemic and 40 (12.8%) were hyperglycemic. Patients with hypoglycemia were significantly more often admitted to the intensive care unit than hyperglycemic patients (20.4% vs 10.8%, P < .015) or than normoglycemic patients (20.4% vs 10.3%, P < .011), and they significantly more often died in the hospital (28.6% hypoglycemic vs 7.5% hyperglycemic, P < .024; 28.6% hypoglycemic vs 10.3% normoglycemic P < .049). Survival analysis showed a significantly lower estimated survival for hypoglycemic patients (36 days) than for normoglycemic patients (54 days) or hyperglycemic patients (45 days; hypoglycemic vs hyperglycemic, P < .019; hypoglycemic vs normoglycemic, P < .007; hyperglycemic vs normoglycemic, P < .477). CONCLUSION Hypoglycemia is associated with increased mortality in patients with acute decompensated liver cirrhosis. It is not yet clear whether hypoglycemia is jointly responsible for the increased short-term mortality of patients with acute decompensated liver cirrhosis or is only a consequence of the severity of the disease or the complications.

Contribution of the collagen adhesin Acm to pathogenesis of Enterococcus faecium in experimental endocarditis.

Enterococcus faecium is a multidrug-resistant opportunist causing difficult-to-treat nosocomial infections, including endocarditis, but there are no reports experimentally demonstrating E. faecium virulence determinants. Our previous studies showed that some clinical E. faecium isolates produce a cell wall-anchored collagen adhesin, Acm, and that an isogenic acm deletion mutant of the endocarditis-derived strain TX0082 lost collagen adherence. In this study, we show with a rat endocarditis model that TX0082 Deltaacm::cat is highly attenuated versus wild-type TX0082, both in established (72 h) vegetations (P < 0.0001) and for valve colonization 1 and 3 hours after infection (P or=50-fold reduction relative to an Acm producer) were found in three of these five nonadherent isolates, including the sequenced strain TX0016, by quantitative reverse transcription-PCR, indicating that acm transcription is downregulated in vitro in these isolates. However, examination of TX0016 cells obtained directly from infected rat vegetations by flow cytometry showed that Acm was present on 40% of cells grown during infection. Finally, we demonstrated a significant reduction in E. faecium collagen adherence by affinity-purified anti-Acm antibodies from E. faecium endocarditis patient sera, suggesting that Acm may be a potential immunotarget for strategies to control this emerging pathogen.

Congenital diaphragmatic hernia in the preterm infant.

BACKGROUND: Congenital diaphragmatic hernia (CDH) remains a significant cause of death in newborns. With advances in neonatal critical care and ventilation strategies, survival in the term infant now exceeds 80% in some centers. Although prematurity is a significant risk factor for morbidity and mortality in most neonatal diseases, its associated risk with infants with CDH has been described poorly. We sought to determine the impact of prematurity on survival using data from the Congenital Diaphragmatic Hernia Registry (CDHR). METHODS: Prospectively collected data from live-born infants with CDH were analyzed from the CDHR from January 1995 to July 2009. Preterm infants were defined as <37 weeks estimated gestational age at birth. Univariate and multivariate logistic regression analysis were>performed. RESULTS: During the study period, 5,069 infants with CDH were entered in the registry. Of the 5,022 infants with gestational age data, there were 3,895 term infants (77.6%) and 1,127 preterm infants (22.4%). Overall survival was 68.7%. A higher percentage of term infants were treated with extracorporeal membrane oxygenation (ECMO) (33% term vs 25.6% preterm). Preterm infants had a greater percentage of chromosomal abnormalities (4% term vs 8.1% preterm) and major cardiac anomalies (6.1% term vs 11.8% preterm). Also, a significantly higher percentage of term infants had repair of the hernia (86.3% term vs 69.4% preterm). Survival for infants that underwent repair was high in both groups (84.6% term vs 77.2% preterm). Survival decreased with decreasing gestational age (73.1% term vs 53.5% preterm). The odds ratio (OR) for death among preterm infants adjusted for patch repair, ECMO, chromosomal abnormalities, and major cardiac anomalies was OR 1.68 (95% confidence interval [CI], 1.34-2.11). CONCLUSION: Although outcomes for preterm infants are clearly worse than in the term infant, more than 50% of preterm infants still survived. Preterm infants with CDH remain a high-risk group. Although ECMO may be of limited value in the extremely premature infant with CDH, most preterm infants that live to undergo repair will survive. Prematurity should not be an independent factor in the treatment strategies of infants with CDH.

A randomized, double-blind, placebo-controlled pilot study of naltrexone in outpatients with bipolar disorder and alcohol dependence.

BACKGROUND: Alcohol dependence is extremely common in patients with bipolar disorder and is associated with unfavorable outcomes including treatment nonadherence, violence, increased hospitalization, and decreased quality of life. While naltrexone is a standard treatment for alcohol dependence, no controlled trials have examined its use in patients with co-morbid bipolar disorder and alcohol dependence. In this pilot study, the efficacy of naltrexone in reducing alcohol use and on mood symptoms was assessed in bipolar disorder and alcohol dependence. METHODS: Fifty adult outpatients with bipolar I or II disorders and current alcohol dependence with active alcohol use were randomized to 12 weeks of naltrexone (50 mg/d) add-on therapy or placebo. Both groups received manual-driven cognitive behavioral therapy designed for patients with bipolar disorder and substance-use disorders. Drinking days and heavy drinking days, alcohol craving, liver enzymes, and manic and depressed mood symptoms were assessed. RESULTS: The 2 groups were similar in baseline and demographic characteristics. Naltrexone showed trends (p < 0.10) toward a greater decrease in drinking days (binary outcome), alcohol craving, and some liver enzyme levels than placebo. Side effects were similar in the 2 groups. Response to naltrexone was significantly related to medication adherence. CONCLUSIONS: Results suggest the potential value and acceptable tolerability of naltrexone for alcohol dependence in bipolar disorder patients. A larger trial is needed to establish efficacy.

Outcomes of truncal vascular injuries in children.

BACKGROUND: Pediatric truncal vascular injuries occur infrequently and have a reported mortality rate of 30% to 50%. This report examines the demographics, mechanisms of injury, associated trauma, and outcome of patients presenting for the past 10 years at a single institution with truncal vascular injuries. METHODS: A retrospective review (1997-2006) of a pediatric trauma registry at a single institution was undertaken. RESULTS: Seventy-five truncal vascular injuries occurred in 57 patients (age, 12 +/- 3 years); the injury mechanisms were penetrating in 37%. Concomitant injuries occurred with 76%, 62%, and 43% of abdominal, thoracic, and neck vascular injuries, respectively. Nonvascular complications occurred more frequently in patients with abdominal vascular injuries who were hemodynamically unstable on presentation. All patients with thoracic vascular injuries presenting with hemodynamic instability died. In patients with neck vascular injuries, 1 of 2 patients who were hemodynamically unstable died, compared to 1 of 12 patients who died in those who presented hemodynamically stable. Overall survival was 75%. CONCLUSIONS: Survival and complications of pediatric truncal vascular injury are related to hemodynamic status at the time of presentation. Associated injuries are higher with trauma involving the abdomen.

Aortic valve replacement and concomitant procedures with the Perceval valve: results of European trials.

BACKGROUND The Perceval (Sorin Group, Milan, Italy) is a self-anchoring sutureless aortic valve prosthesis. We report the short- to midterm results of combined aortic valve replacement (AVR) with concomitant procedures in elderly patients undergoing operation as part of 3 consecutive prospective multicenter European studies. METHODS From April 2007 to February 2013, 243 patients (mean age, 79.7 ± 5.1 years; female patients, 61%; median EuroSCORE, 9%) underwent AVR with concomitant procedures. The concomitant procedures were coronary artery bypass grafting (CABG) (182 cases), septal myectomy (21 cases), CABG + other procedures (18 cases), and 22 other procedures. Primary and secondary end points included implant feasibility and safety (for mortality and morbidity) and efficacy (New York Heart Association [NYHA] class improvement and hemodynamic results) of the prosthesis at the different follow-up periods. Data were expressed as mean ± standard deviation. Kaplan-Meier analysis was performed for survival analysis. RESULTS Mean aortic cross-clamp and extracorporeal circulation (ECC) times were 50.7 ± 22.8 minutes and 78.9 ± 32.3 minutes, respectively. Thirty-day mortality was 2.1%. Mean postoperative gradient and effective orifice area were 10.1 ± 4.7 mm Hg and 1.5 ± 0.4 cm(2) and 8.9 ± 5.6 mm Hg and 1.6 ± 0.4 cm(2), respectively, at 1 year. There were early explantations, 4 of which resulted from paravalvular leaks. One additional valve explantation resulted from aortic root bleeding, probably caused by excessively extensive decalcification. In the late period, there was 1 mild paravalvular leak and no intravalvular insufficiency. No migration, dislodgement, or degeneration of the valve occurred during follow-up. Median follow-up was 444 days. CONCLUSIONS These trials confirm the safety and efficacy of the Perceval sutureless aortic valve, especially in elderly patients requiring AVR + concomitant procedures. In this patient group, sutureless valves may be advantageous compared to transcatheter valve implantations as concomitant procedures other than percutaneous coronary artery angioplasty are not always possible in the latter.

Time relevance, citation of reporting guidelines, and breadth of literature search in systematic reviews in orthodontics

INTRODUCTION As the importance of systematic review (SR) conclusions relies upon the scientific rigor of methods and the currency of evidence, we aimed to investigate the currency of orthodontic SRs using as proxy the time from the initial search to publication. Additionally, SR information regarding reporting guidelines, registration, and literature searches were recorded when available. MATERIALS AND METHODS A systematic PubMed search was carried out using the Clinical Queries page to identify orthodontic SRs cited between 1 January 2008 and 7 November 2013. Data related to reporting guidelines, review registration, dates of review processing, literature search, and abstract reporting were retrieved and classified by journal type. Survival analysis was used to assess the time to reach predefined manuscript stages for orthodontic and non-orthodontic journals. RESULTS One hundred twenty seven of the originally identified 585 SRs were considered eligible. The median interval from search until publication was 13.2 months (interquartile range: IQR = 9.7 months) irrespective of the journal type. There was evidence (P = 0.05) that SRs published by non-orthodontic journals appeared in PubMed faster than in orthodontic journals (non-orthodontic: median = 6.5 months; IQR = 5.7 months; orthodontic: median = 10.2 months; IQR = 5.6 months) from submission to publication and from acceptance to publication (non-orthodontic: median = 1.5 months; IQR = 2.4 months; orthodontic: median = 6.0 months; IQR = 6.2 months; P < 0.001). More than half of these SRs did not cite adherence to any reporting guidelines, whereas all but five studies were not prospectively registered. Search of unpublished research was undertaken in approximately 21 per cent and 29 per cent of the SRs published in non-orthodontic and orthodontic periodicals, respectively. CONCLUSIONS This study indicates that SR users should be aware that median time for orthodontic SRs from search to publication is 13.2 months. SRs published in non-orthodontic journals are likely to be more current in terms of submission until time to publication and acceptance until time to publication compared with those published in orthodontic journals.

Workshop: ASSIP - Attempted Suicide Short Intervention Program. Theory, Practice, and 24 Months Follow-up RCT.

Background: ASSIP is a manualized brief therapy based on a model of suicide as goal-directed action, aimed at establishing a therapeutic alliance in a patient-oriented, collaborative approach. The main goals of the three-session program ASSIP are for patients to understand, from an observer’s position, patterns leading to a suicidal crisis, recognize triggers and warning signs, and to establish individual safety strategies for future suicidal crises. An ongoing therapeutic support is provided with regular letters over 24 months. Method: The study was conducted in a naturalistic setting. 120 Patients were randomly assigned to an intervention group (60 participants) treated with ASSIP combined with follow-up contact through letters, and a control group (60 participants) receiving a single session of clinical assessment. Both groups had treatment as usual. Patients completed a set of psychosocial and clinical questionnaires every six months over a period of 24 months. Results: In the ASSIP group 5 patients made a total of 5 reattempts, compared to 15 patients with 41 reattempts in the control group. The survival analysis yielded a significant difference with a Wald Chi2 of .000003. The ASSIP group had significantly lower suicidal ideation and fewer days of inpatient treatment compared to the control group. Higher scores in the Penn Helping Alliance Questionnaire were associated with lower suicidal ideation during follow-up. Conclusions: ASSIP is a highly effective brief therapy for patients with recent suicide attempts. Forming a strong therapeutic alliance is considered to be a major factor for outcome. ASSIP can be used with minimal training by experienced therapists. An English version of the manual will be published in May 2015.

VE1 immunohistochemistry predicts BRAF V600E mutation status and clinical outcome in colorectal cancer

AIM VE1 is a monoclonal antibody detecting mutant BRAFV600E protein by immunohistochemistry. Here we aim to determine the inter-observer agreement and concordance of VE1 with mutational status, investigate heterogeneity in colorectal cancers and metastases and determine the prognostic effect of VE1 in colorectal cancer patients. METHODS Concordance of VE1 with mutational status and inter-observer agreement were tested on a pilot cohort of colorectal cancers (n = 34), melanomas (n = 23) and thyroid cancers (n = 8). Two prognostic cohorts were evaluated (n = 259, Cohort 1 and n = 226, Cohort 2) by multiple-punch tissue microarrays. VE1 staining on preoperative biopsies (n = 118 patients) was compared to expression in resections. Primary tumors and metastases from 13 patients were tested for VE1 heterogeneity using a tissue microarray generated from all available blocks (n = 100 blocks). RESULTS Inter-observer agreement was 100% (kappa = 1.0). Concordance between VE1 and V600E mutation was 98.5%. Cohort 1: VE1 positivity (seen in 13.5%) was associated with older age (p = 0.0175) and MLH1 deficiency (p < 0.0001). Cohort 2: VE1 positivity (seen in 12.8%) was associated with female gender (p = 0.0016), right-sided tumor location (p < 0.0001), higher tumor grade (p < 0.0001) and mismatch repair (MMR)-deficiency (p < 0.0001). In survival analysis, MMR status and postoperative therapy were identified as possible confounding factors. Adjusting for these features, VE1 was an unfavorable prognostic factor. Preoperative biopsy staining matched resections in all cases except one. No heterogeneity was found across any primary/metastatic tumor blocks. CONCLUSION VE1 is highly concordant for V600E and homogeneously expressed suggesting staining can be analysed on resection specimens, preoperative biopsies, metastatic lesions and tissue microarrays.

A retrospective study of 1- versus 2-cm excision margins for cutaneous malignant melanomas thicker than 2 mm.

BACKGROUND Most guidelines recommend at least 2-cm excision margin for melanomas thicker than 2 mm. OBJECTIVE We evaluated whether 1- or 2-cm excision margins for melanoma (>2 mm) result in different outcomes. METHODS This is a retrospective cohort study on patients with melanomas (>2 mm) who underwent tumor excision with 1-cm (228 patients) or 2-cm (97 patients) margins to investigate presence of local recurrences, locoregional and distant metastases, and disease-free and overall survival. RESULTS In all, 325 patients with mean age of 61.84 years and Breslow thickness of 4.36 mm were considered for the study with a median follow-up of 1852 days (1995-2012). There was no significant difference in the frequency of locoregional and distant metastasis between the 2 groups (P = .311 and .571). The survival analysis showed no differences for disease-free (P = .800; hazard ratio 0.948; 95% confidence interval 0.627-1.433) and overall (P = .951; hazard ratio 1.018; 95% confidence interval 0.575-1.803) survival. LIMITATIONS The study was not prospectively randomized. CONCLUSIONS Our study did not show any significant differences in important outcome parameters such as local or distant metastases and overall survival. A prospective study testing 1- versus 2-cm excision margin is warranted.