An imputation-based solution to using mismeasured covariates in propensity score analysis.

Although covariate measurement error is likely the norm rather than the exception, methods for handling covariate measurement error in propensity score methods have not been widely investigated. We consider a multiple imputation-based approach that uses an external calibration sample with information on the true and mismeasured covariates, multiple imputation for external calibration, to correct for the measurement error, and investigate its performance using simulation studies. As expected, using the covariate measured with error leads to bias in the treatment effect estimate. In contrast, the multiple imputation for external calibration method can eliminate almost all the bias. We confirm that the outcome must be used in the imputation process to obtain good results, a finding related to the idea of congenial imputation and analysis in the broader multiple imputation literature. We illustrate the multiple imputation for external calibration approach using a motivating example estimating the effects of living in a disadvantaged neighborhood on mental health and substance use outcomes among adolescents. These results show that estimating the propensity score using covariates measured with error leads to biased estimates of treatment effects, but when a calibration data set is available, multiple imputation for external calibration can be used to help correct for such bias.

Coverage, compliance, acceptability and feasibility of a program to prevent pre-eclampsia and eclampsia through calcium supplementation for pregnant women: an operations research study in one district of Nepal.

BACKGROUND: Calcium supplementation during pregnancy has been shown to reduce the incidence of pre-eclampsia/eclampsia among women with low calcium intake. Universal free calcium supplementation through government antenatal care (ANC) services was piloted in the Dailekh district of Nepal. Coverage, compliance, acceptability and feasibility of the intervention were evaluated. METHODS: Antenatal care providers were trained to distribute and counsel pregnant women about calcium use, and female community health volunteers (FCHVs) were trained to reinforce calcium-related messages. A post-intervention cluster household survey was conducted among women who had given birth in the last six months. Secondary data analysis was performed using monitoring data from health facilities and FCHVs. RESULTS: One Thousand Two hundred-forty postpartum women were interviewed. Most (94.6 %) had attended at least one ANC visit; the median gestational age at first ANC visit was 4 months. All who attended ANC were counseled about calcium and received calcium tablets to take daily until delivery.79.5 % of the women reported consuming the entire quantity of calcium they received. The full course of calcium (300 tablets for 150 days) was provided to 82.3 % of the women. Consumption of the full course of calcium was reported by 67.3 % of all calcium recipients. Significant predictors of completing a full course were gestational age at first ANC visit and number of ANC visits during their most recent pregnancy (p < 0.01). Nearly all (99.2 %) reported taking the calcium as instructed with respect to dose, timing and frequency. Among women who received both calcium and iron (n = 1,157), 98.0 % reported taking them at different times of the day, as instructed. Over 97 % reported willingness to recommend calcium to others, and said they would like to use it during a subsequent pregnancy. There were no stock-outs of calcium. CONCLUSIONS: Calcium distribution through ANC was feasible and effective, achieving 94.6 % calcium coverage of pregnant women in the district. Most women (over 80 %) attended ANC early enough in pregnancy to receive the full course of calcium supplements and benefit from the intervention. High coverage, compliance, acceptability among pregnant women and feasibility were reported, suggesting that this intervention can be scaled up in other areas of Nepal.

Associations between safety culture and employee engagement over time: a retrospective analysis.

With the growth of the patient safety movement and development of methods to measure workforce health and success have come multiple modes of assessing healthcare worker opinions and attitudes about work and the workplace. Safety culture, a group-level measure of patient safety-related norms and behaviours, has been proposed to influence a variety of patient safety outcomes. Employee engagement, conceptualised as a positive, work-related mindset including feelings of vigour, dedication and absorption in one's work, has also demonstrated an association with a number of important worker outcomes in healthcare. To date, the relationship between responses to these two commonly used measures has been poorly characterised. Our study used secondary data analysis to assess the relationship between safety culture and employee engagement over time in a sample of >50 inpatient hospital units in a large US academic health system. With >2000 respondents in each of three time periods assessed, we found moderate to strong positive correlations (r=0.43-0.69) between employee engagement and four Safety Attitudes Questionnaire domains. Independent collection of these two assessments may have limited our analysis in that minimally different inclusion criteria resulted in some differences in the total respondents to the two instruments. Our findings, nevertheless, suggest a key area in which healthcare quality improvement efforts might be streamlined.

A multi-omic analysis of human naïve CD4+ T cells.

BACKGROUND: Cellular function and diversity are orchestrated by complex interactions of fundamental biomolecules including DNA, RNA and proteins. Technological advances in genomics, epigenomics, transcriptomics and proteomics have enabled massively parallel and unbiased measurements. Such high-throughput technologies have been extensively used to carry out broad, unbiased studies, particularly in the context of human diseases. Nevertheless, a unified analysis of the genome, epigenome, transcriptome and proteome of a single human cell type to obtain a coherent view of the complex interplay between various biomolecules has not yet been undertaken. Here, we report the first multi-omic analysis of human primary naïve CD4+ T cells isolated from a single individual. RESULTS: Integrating multi-omics datasets allowed us to investigate genome-wide methylation and its effect on mRNA/protein expression patterns, extent of RNA editing under normal physiological conditions and allele specific expression in naïve CD4+ T cells. In addition, we carried out a multi-omic comparative analysis of naïve with primary resting memory CD4+ T cells to identify molecular changes underlying T cell differentiation. This analysis provided mechanistic insights into how several molecules involved in T cell receptor signaling are regulated at the DNA, RNA and protein levels. Phosphoproteomics revealed downstream signaling events that regulate these two cellular states. Availability of multi-omics data from an identical genetic background also allowed us to employ novel proteogenomics approaches to identify individual-specific variants and putative novel protein coding regions in the human genome. CONCLUSIONS: We utilized multiple high-throughput technologies to derive a comprehensive profile of two primary human cell types, naïve CD4+ T cells and memory CD4+ T cells, from a single donor. Through vertical as well as horizontal integration of whole genome sequencing, methylation arrays, RNA-Seq, miRNA-Seq, proteomics, and phosphoproteomics, we derived an integrated and comparative map of these two closely related immune cells and identified potential molecular effectors of immune cell differentiation following antigen encounter.

Pars plana vitrectomy and iris suture fixation of posteriorly dislocated intraocular lenses.

PURPOSE: To describe the outcomes of combined pars plana vitrectomy (PPV) and iris suture fixation of posteriorly dislocated intraocular lenses (IOLs). SETTING: Tertiary academic referral center. DESIGN: Retrospective noncomparative consecutive case series. METHODS: The included eyes had posteriorly dislocated IOLs and had combined PPV and iris suture fixation. The IOL dislocations amenable to surgical repair with an anterior approach were excluded. Outcome measures included improvement in corrected distance visual acuity (CDVA), induction of astigmatism, and complications. RESULTS: This study consisted of 27 consecutive cases. The mean follow-up was 6.61 months ± 8.1 (SD). The median postoperative CDVA was 20/30, and 16 of 27 eyes had stable or improved CDVA compared with baseline; 8 of the others had a shift from aphakic to pseudophakic correction. Overall, a significant myopic shift in spherical equivalent occurred after surgery, from 7.62 ± 4.38 diopters (D) to -1.33 ± 1.45 D (P < .001). Surgically induced astigmatism (SIA) assessed by comparing the difference in preoperative keratometry readings with the difference in postoperative manifest refraction cylinder adjusted to the corneal plane gave the following: 1.89 ± 1.09 D versus 1.13 ± 0.86 D, respectively (P < .001). All IOLs were stable and centered at the last follow-up; however, 1 was mildly tilted. One eye had a recurrent subluxation, and the IOL was resutured before the end of the study. No cases of endophthalmitis or retinal detachment occurred. CONCLUSION: Combined PPV and iris suture fixation of posteriorly dislocated IOLs led to stable fixation of the IOLs. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned.

Outcomes Associated With Concurrent Iris-Sutured Intraocular Lens Placement and Subluxated Crystalline Lens Extraction.

IMPORTANCE: We have developed a novel surgical technique, to our knowledge, for the management of subluxated crystalline lenses involving preplacement of an iris-sutured posterior chamber intraocular lens (PCIOL) before pars plana vitrectomy and lensectomy. OBJECTIVE: To investigate the outcomes of eyes with subluxated crystalline lenses, predominantly a result of Marfan syndrome (14 eyes [58%]) or trauma (5 eyes [21%]), that underwent pars plana vitrectomy and lensectomy with placement of an iris-sutured PCIOL. DESIGN, SETTING, AND PARTICIPANTS: We performed a retrospective, noncomparative case series of 24 eyes from 17 consecutive adult patients with surgically treated subluxated crystalline lenses presenting to the Wilmer Eye Institute at Johns Hopkins Hospital from October 6, 2006, through May 1, 2013. The mean (SD) postoperative follow-up was 24.4 (20.5) months for eyes with at least 6 months of follow-up (last date, October 13, 2014). We performed the analysis from January 21, 2014, through January 3, 2015. MAIN OUTCOMES AND MEASURES: Improvement in best-corrected visual acuity using an automated Snellen chart and induction of astigmatism for eyes with at least 6 months of follow-up (n = 18) and IOL stability during follow-up for all eyes (n = 24). RESULTS: The mean (SD) age at surgery was 49.4 (10.7 [range, 29-67]) years. We found an improvement in mean (SD [95% CI]) best-corrected visual acuity from 0.66 (0.71 [0.30-1.02]) logMAR preoperatively (Snellen equivalent, approximately 20/90; range, 20/30 to hand motions) to 0.07 (0.11 [95% CI, 0.01-0.12]) logMAR postoperatively (Snellen equivalent, approximately 20/23; range, 20/15 to 20/50). We found little change in astigmatism postoperatively (mean change, -0.1 [95% CI, -0.5 to 0.13] diopters). Postoperative complications included retinal detachment (1 eye [4%]), retained cortical fragment (1 [4%]), cystoid macular edema (2 [8%]), and IOL subluxation (3 [13%]) owing to haptic slippage within 3 months of the procedure. The overall probability of successfully achieving placement of a centered iris-sutured PCIOL in patients with follow-up of longer than 6 months (n = 18) was 100% (95% CI, 81.5%-100%). CONCLUSIONS AND RELEVANCE: Placement of iris-sutured PCIOLs at the time of subluxated lens extraction with a pars plana surgical approach yields favorable results in terms of postoperative visual outcomes and surgical complications. This technique offers an effective procedure for surgeons to use when treating clinically significant subluxated crystalline lenses.

Iris suture fixation of subluxated intraocular lenses.

PURPOSE: To assess the results of iris suture fixation of subluxated intraocular lenses. DESIGN: Retrospective study. METHODS: This was a nonrandomized chart review of eyes with subluxated intraocular lenses that underwent iris suture fixation at an academic institutional care center. Seventy-two eyes of 67 consecutive patients were included. The following cases were excluded: posterior dislocations necessitating pars plana vitrectomy; secondary implantations for aphakia; and iris suture fixation at primary cataract extraction. Main outcome measures included visual acuity improvement, surgically induced astigmatism, and postsurgical complications. RESULTS: The mean follow-up duration was 16.64 ± 24.37 months (median = 4.03 months). All patients had preoperative monocular diplopia or unstable vision attributable to the subluxated intraocular lenses, and 40.3% of them required aphakic correction. There was an overall improvement in best-corrected visual acuity from a mean preoperative logMAR 0.35 ± 0.32 (Snellen equivalent∼20/45) to logMAR 0.21 ± 0.25 (20/32, P = .001). There was no significant change in astigmatism secondary to the surgery. The mean difference in preoperative keratometry readings was 1.6 ± 1.07 diopter (D), whereas the mean postoperative manifest refraction astigmatic error (vertexed to the corneal surface) was 1.29 ± 0.92 D (P < .02). Re-subluxations occurred in 7 eyes during follow-up; the majority of these eyes underwent repeat fixation. Most (93.55%) intraocular lenses were stable and centered at the final follow-up. Glaucoma developed in 2 eyes postoperatively. CONCLUSIONS: Iris suture fixation of subluxated intraocular lenses was efficacious for the eyes included in this study, and it led to long-term stability of the intraocular lenses in 93.55% of cases.

A single institution's 26-year experience with nonfunctional pancreatic neuroendocrine tumors: a validation of current staging systems and a new prognostic nomogram.

OBJECTIVE: To validate the 2010 American Joint Committee on Cancer (AJCC) and 2006 European Neuroendocrine Tumor Society (ENETS) tumor staging systems for pancreatic neuroendocrine tumors (PanNETs) using the largest, single-institution series of surgically resected patients in the literature. BACKGROUND: The natural history and prognosis of PanNETs have been poorly defined because of the rarity and heterogeneity of these neoplasms. Currently, there are 2 main staging systems for PanNETs, which can complicate comparisons of reports in the literature and thereby hinder progress against this disease. METHODS: Univariate and multivariate analyses were conducted on the prognostic factors of survival using 326 sporadic, nonfunctional, surgically resected PanNET patients who were cared for at our institution between 1984 and 2011. Current and proposed models were tested for survival prognostication validity as measured by discrimination (Harrel's c-index, HCI) and calibration. RESULTS: Five-year overall-survival rates for AJCC stages I, II, and IV are 93% (88%-99%), 74% (65%-83%), and 56% (42%-73%), respectively, whereas ENETS stages I, II, III, and IV are 97% (92%-100%), 87% (80%-95%), 73% (63%-84%), and 56% (42%-73%), respectively. Each model has an HCI of 0.68, and they are no different in their ability to predict survival. We developed a simple prognostic tool just using grade, as measured by continuous Ki-67 labeling, sex, and binary age that has an HCI of 0.74. CONCLUSIONS: Both the AJCC and ENETS staging systems are valid and indistinguishable in their survival prognostication. A new, simpler prognostic tool can be used to predict survival and decrease interinstitutional mistakes and uncertainties regarding these neoplasms.

Dexmedetomidine preserves attention/calculation when used for cooperative and short-term intensive care unit sedation.

PURPOSE: Differential effects on cognition were recently demonstrated between dexmedetomidine (DEX) and propofol (PRO) when used for cooperative sedation. Propofol was found to reduce cognition, whereas DEX improved cognition. To further discriminate these effects, we evaluated the effect of PRO vs DEX in selected areas of cognition. METHODS: This is a post hoc analysis of the Acute Neurologic Intensive Care Unit Sedation Trial and an investigator-initiated, prospective, randomized, double-blinded, crossover study, comparing the effect of PRO and DEX on cognition measure by the Johns Hopkins Adapted Cognitive Exam (ACE). A linear model analysis accounting for within-patient correlation of measures was used to estimate differences in ACE subscales between drugs. RESULTS: Propofol diminished adjusted scores on all ACE subscales (P < .05), whereas DEX improved adjusted scores selectively for attention/calculation (3.55; 95% confidence interval, 1.49-5.61; P < .01). The positive and significant difference in ACE scores between agents was present across subscales. CONCLUSIONS: Our findings indicate that DEX improved ACE attention/calculation subscale in awake patients receiving cooperative sedation. This is in contrast to the deterioration in all mean ACE subscale scores observed using PRO, suggesting DEX preserved cognitive function with specific preservation of focus and attention and allows for greater cognition compared with PRO across all cognitive domains.

Improving immunization delivery using an electronic health record: the ImmProve project.

OBJECTIVE: Though an essential pediatric preventive service, immunizations are challenging to deliver reliably. Our objective was to measure the impact on pediatric immunization rates of providing clinicians with electronic health record-derived immunization prompting. METHODS: Operating in a large, urban, hospital-based pediatric primary care clinic, we evaluated 2 interventions to improve immunization delivery to children ages 2, 6, and 13 years: point-of-care, patient-specific electronic clinical decision support (CDS) when children overdue for immunizations presented for care, and provider-specific bulletins listing children overdue for immunizations. RESULTS: Overall, the proportion of children up to date for a composite of recommended immunizations at ages 2, 6, and 13 years was not different in the intervention (CDS active) and historical control (CDS not active) periods; historical immunization rates were high. The proportion of children receiving 2 doses of hepatitis A immunization before their second birthday was significantly improved during the intervention period. Human papillomavirus (HPV) immunization delivery was low during both control and intervention periods and was unchanged for 13-year-olds. For 14-year-olds, however, 4 of the 5 highest quarterly rates of complete HPV immunization occurred in the final year of the intervention. Provider-specific bulletins listing children overdue for immunizations increased the likelihood of identified children receiving catch-up hepatitis A immunizations (hazard ratio 1.32; 95% confidence interval 1.12-1.56); results for HPV and the composite of recommended immunizations were of a similar magnitude but not statistically significant. CONCLUSIONS: In our patient population, with high baseline uptake of recommended immunizations, electronic health record-derived immunization prompting had a limited effect on immunization delivery. Benefit was more clearly demonstrated for newer immunizations with lower baseline uptake.

Genome-wide DNA methylation scan in major depressive disorder.

While genome-wide association studies are ongoing to identify sequence variation influencing susceptibility to major depressive disorder (MDD), epigenetic marks, such as DNA methylation, which can be influenced by environment, might also play a role. Here we present the first genome-wide DNA methylation (DNAm) scan in MDD. We compared 39 postmortem frontal cortex MDD samples to 26 controls. DNA was hybridized to our Comprehensive High-throughput Arrays for Relative Methylation (CHARM) platform, covering 3.5 million CpGs. CHARM identified 224 candidate regions with DNAm differences >10%. These regions are highly enriched for neuronal growth and development genes. Ten of 17 regions for which validation was attempted showed true DNAm differences; the greatest were in PRIMA1, with 12-15% increased DNAm in MDD (p = 0.0002-0.0003), and a concomitant decrease in gene expression. These results must be considered pilot data, however, as we could only test replication in a small number of additional brain samples (n = 16), which showed no significant difference in PRIMA1. Because PRIMA1 anchors acetylcholinesterase in neuronal membranes, decreased expression could result in decreased enzyme function and increased cholinergic transmission, consistent with a role in MDD. We observed decreased immunoreactivity for acetylcholinesterase in MDD brain with increased PRIMA1 DNAm, non-significant at p = 0.08.While we cannot draw firm conclusions about PRIMA1 DNAm in MDD, the involvement of neuronal development genes across the set showing differential methylation suggests a role for epigenetics in the illness. Further studies using limbic system brain regions might shed additional light on this role.

Bump hunting to identify differentially methylated regions in epigenetic epidemiology studies.

BACKGROUND: During the past 5 years, high-throughput technologies have been successfully used by epidemiology studies, but almost all have focused on sequence variation through genome-wide association studies (GWAS). Today, the study of other genomic events is becoming more common in large-scale epidemiological studies. Many of these, unlike the single-nucleotide polymorphism studied in GWAS, are continuous measures. In this context, the exercise of searching for regions of interest for disease is akin to the problems described in the statistical 'bump hunting' literature. METHODS: New statistical challenges arise when the measurements are continuous rather than categorical, when they are measured with uncertainty, and when both biological signal, and measurement errors are characterized by spatial correlation along the genome. Perhaps the most challenging complication is that continuous genomic data from large studies are measured throughout long periods, making them susceptible to 'batch effects'. An example that combines all three characteristics is genome-wide DNA methylation measurements. Here, we present a data analysis pipeline that effectively models measurement error, removes batch effects, detects regions of interest and attaches statistical uncertainty to identified regions. RESULTS: We illustrate the usefulness of our approach by detecting genomic regions of DNA methylation associated with a continuous trait in a well-characterized population of newborns. Additionally, we show that addressing unexplained heterogeneity like batch effects reduces the number of false-positive regions. CONCLUSIONS: Our framework offers a comprehensive yet flexible approach for identifying genomic regions of biological interest in large epidemiological studies using quantitative high-throughput methods.

Adaptation of the CHARM DNA methylation platform for the rat genome reveals novel brain region-specific differences.

Comprehensive High-throughput Arrays for Relative Methylation (CHARM) was recently developed as an experimental platform and analytic approach to assess DNA methylation (DNAm) at a genome-wide level. Its initial implementation was for human and mouse. We adapted it for rat and sought to examine DNAm differences across tissues and brain regions in this model organism. We extracted DNA from liver, spleen, and three brain regions: cortex, hippocampus, and hypothalamus from adult Sprague Dawley rats. DNA was digested with McrBC, and the resulting methyl-depleted fraction was hybridized to the rat CHARM array along with a mock-treated fraction. Differentially methylated regions (DMRs) between tissue types were detected using normalized methylation log-ratios. In validating 24 of the most significant DMRs by bisulfite pyrosequencing, we detected large mean differences in DNAm, ranging from 33-59%, among the most significant DMRs in the across-tissue comparisons. The comparable figures for the hippocampus vs. hypothalamus DMRs were 14-40%, for the cortex vs. hippocampus DMRs, 12-29%, and for the cortex vs. hypothalamus DMRs, 5-35%, with a correlation of r(2) = 0.92 between the methylation differences in 24 DMRs predicted by CHARM and those validated by bisulfite pyrosequencing. Our adaptation of the CHARM array for the rat genome yielded highly robust results that demonstrate the value of this method in detecting substantial DNAm differences between tissues and across different brain regions. This platform should prove valuable in future studies aimed at examining DNAm differences in particular brain regions of rats exposed to environmental stimuli with potential epigenetic consequences.

Evaluation of an algorithm for detecting visual field defects due to chiasmal and postchiasmal lesions: the neurological hemifield test.

PURPOSE: To develop an automated neurologic hemifield test (NHT) to detect visual field loss caused by chiasmal or postchiasmal lesions. METHODS: Visual field locations from 24-2 pattern automated visual fields were grouped into two symmetric regions with 16 points on either side of the vertical meridian. A scoring system similar to the Glaucoma Hemifield Test (GHT) was used to calculate point scores using the pattern deviation values from the right and left regions. The cross-vertical difference in the sum of these values was the NHT score. The NHT was evaluated using visual fields from subjects with known neurologic disease, subjects with glaucoma, and glaucoma suspects (92 pairs of eyes each). The NHT score was calculated for each eye. Four masked reviewers scored all pairs of visual fields with regard to the likelihood of neurologic and glaucomatous optic neuropathy. Both NHT score and expert field ratings were compared with clinical diagnosis by receiver operating characteristic (ROC) analysis. RESULTS: The NHT effectively discriminated neurologic fields from those of glaucoma patients and glaucoma suspects (area under the ROC curve [AUC] = 0.90; 95% confidence interval [CI], 0.86-0.94). The NHT score correlated well with clinician grading (Pearson correlation estimates, 0.74-0.78). Even when field defects were subtle, the NHT had some ability to discriminate neurologic from nonneurologic fields (AUC 0.68; 95% CI, 0.56-0.79). CONCLUSIONS: The NHT distinguished neurologic field defects from those of glaucoma and glaucoma suspects, rivaling the performance of subspecialist clinicians. Its implementation may help identify unsuspected neurologic disease.

Assessing affymetrix GeneChip microarray quality.

BACKGROUND: Microarray technology has become a widely used tool in the biological sciences. Over the past decade, the number of users has grown exponentially, and with the number of applications and secondary data analyses rapidly increasing, we expect this rate to continue. Various initiatives such as the External RNA Control Consortium (ERCC) and the MicroArray Quality Control (MAQC) project have explored ways to provide standards for the technology. For microarrays to become generally accepted as a reliable technology, statistical methods for assessing quality will be an indispensable component; however, there remains a lack of consensus in both defining and measuring microarray quality. RESULTS: We begin by providing a precise definition of microarray quality and reviewing existing Affymetrix GeneChip quality metrics in light of this definition. We show that the best-performing metrics require multiple arrays to be assessed simultaneously. While such multi-array quality metrics are adequate for bench science, as microarrays begin to be used in clinical settings, single-array quality metrics will be indispensable. To this end, we define a single-array version of one of the best multi-array quality metrics and show that this metric performs as well as the best multi-array metrics. We then use this new quality metric to assess the quality of microarry data available via the Gene Expression Omnibus (GEO) using more than 22,000 Affymetrix HGU133a and HGU133plus2 arrays from 809 studies. CONCLUSIONS: We find that approximately 10 percent of these publicly available arrays are of poor quality. Moreover, the quality of microarray measurements varies greatly from hybridization to hybridization, study to study, and lab to lab, with some experiments producing unusable data. Many of the concepts described here are applicable to other high-throughput technologies.

Factors associated with pharyngoesophageal stricture in patients treated with concurrent chemotherapy and radiation therapy for oropharyngeal squamous cell carcinoma.

BACKGROUND: The purpose of this study was to elucidate factors associated with pharyngoesophageal strictures after treatment for head and neck squamous cell carcinoma (SCC). METHODS: We conducted a retrospective review of patients receiving cisplatin and 5-fluorouracil chemotherapy combined with concurrent hyperfractionated radiation therapy for oropharyngeal squamous cell carcinoma. RESULTS: Strictures developed in 13 of 67 patients (19%). Strictures were associated with tumor location (tonsil vs base of tongue; p = .03), neck dissection after completion of therapy (p = .03), and the duration of treatment-induced mucositis (weeks with mucositis grade ≥2; National Cancer Institute (NCI) Common Toxicity Criteria; p < .001). Age, sex, race, tumor stage, nodal stage, American Joint Committee on Cancer (AJCC) stage, human papillomavirus (HPV) status, smoking, radiation dose, maximum severity of mucositis, amifostine use, and pretreatment swallow dysfunction were not significantly associated with stricture. In multivariate analysis, only duration of mucositis, after controlling for age, sex, and tumor location, remained highly significant (p < .01). CONCLUSION: The duration of treatment-related mucositis is an independent risk factor for stricture formation in patients with oropharyngeal SCC treated with concurrent chemotherapy and radiation therapy.

Personalized epigenomic signatures that are stable over time and covary with body mass index.

The epigenome consists of non-sequence-based modifications, such as DNA methylation, that are heritable during cell division and that may affect normal phenotypes and predisposition to disease. Here, we have performed an unbiased genome-scale analysis of ~4 million CpG sites in 74 individuals with comprehensive array-based relative methylation (CHARM) analysis. We found 227 regions that showed extreme interindividual variability [variably methylated regions (VMRs)] across the genome, which are enriched for developmental genes based on Gene Ontology analysis. Furthermore, half of these VMRs were stable within individuals over an average of 11 years, and these VMRs defined a personalized epigenomic signature. Four of these VMRs showed covariation with body mass index consistently at two study visits and were located in or near genes previously implicated in regulating body weight or diabetes. This work suggests an epigenetic strategy for identifying patients at risk of common disease.

Comprehensive methylome map of lineage commitment from haematopoietic progenitors.

Epigenetic modifications must underlie lineage-specific differentiation as terminally differentiated cells express tissue-specific genes, but their DNA sequence is unchanged. Haematopoiesis provides a well-defined model to study epigenetic modifications during cell-fate decisions, as multipotent progenitors (MPPs) differentiate into progressively restricted myeloid or lymphoid progenitors. Although DNA methylation is critical for myeloid versus lymphoid differentiation, as demonstrated by the myeloerythroid bias in Dnmt1 hypomorphs, a comprehensive DNA methylation map of haematopoietic progenitors, or of any multipotent/oligopotent lineage, does not exist. Here we examined 4.6 million CpG sites throughout the genome for MPPs, common lymphoid progenitors (CLPs), common myeloid progenitors (CMPs), granulocyte/macrophage progenitors (GMPs), and thymocyte progenitors (DN1, DN2, DN3). Marked epigenetic plasticity accompanied both lymphoid and myeloid restriction. Myeloid commitment involved less global DNA methylation than lymphoid commitment, supported functionally by myeloid skewing of progenitors following treatment with a DNA methyltransferase inhibitor. Differential DNA methylation correlated with gene expression more strongly at CpG island shores than CpG islands. Many examples of genes and pathways not previously known to be involved in choice between lymphoid/myeloid differentiation have been identified, such as Arl4c and Jdp2. Several transcription factors, including Meis1, were methylated and silenced during differentiation, indicating a role in maintaining an undifferentiated state. Additionally, epigenetic modification of modifiers of the epigenome seems to be important in haematopoietic differentiation. Our results directly demonstrate that modulation of DNA methylation occurs during lineage-specific differentiation and defines a comprehensive map of the methylation and transcriptional changes that accompany myeloid versus lymphoid fate decisions.

Cognitive improvement during continuous sedation in critically ill, awake and responsive patients: the Acute Neurological ICU Sedation Trial (ANIST).

INTRODUCTION: Most anxiolytics and sedative regimens in the intensive care unit (ICU) impair intellectual function, reducing patient autonomy, and often add to patient morbidity. Using an ICU-validated cognitive assessment tool Adapted Cognitive Exam (ACE), we performed a comparison between dexmedetomidine (DEX) and propofol (PRO) to evaluate which sedative regimen offered the least decrement in intellectual capacity. METHODS: This was a prospective, randomized, double-blinded study of 30 awake and intubated brain-injured (BI, n = 18) and non-BI (12) ICU patients. Each patient received fentanyl/PRO and fentanyl/DEX titrated to a calm, awake state using a crossover design. Cognitive testing was performed at each study period using the validated 100-point Hopkins ACE cognitive battery. FINDINGS: Sedation with PRO diminished adjusted ACE scores (100-point exam) by a mean of -12.4 (95% CI -8.3 to -16.5, p < 0.001) while DEX, in contrast, improved ACE scores (6.8, 95% CI 1.2-12.4, p < 0.018). The difference in the change of ACE score between DEX versus PRO, our primary endpoint, was 19.2 (95% CI 12.3-26.1 p < 0.001) in favor of an improved ACE score on DEX. Patients with BI required less sedative, but effects of PRO and DEX on cognition were not changed. No serious adverse events occurred. Modest bradycardia was noted post hoc with DEX (-7.7 bpm, p < 0.01). INTERPRETATION: ICU patients may be offered sedation without necessarily compromising arousal or cognition. Alleviation of anxiety and agitation can singly and effectively improve mental engagement and performance if overt forebrain dysfunction is avoided. Higher ACE scores with DEX may be a consequence of the intellect-sparing yet calming effect of this drug.

Cytomegalovirus infection and the risk of mortality and frailty in older women: a prospective observational cohort study.

Cytomegalovirus (CMV), a prevalent pathogen, causes severe disease in immunocompromised humans. However, present understanding is limited regarding the long-term clinical effect of persistent CMV infection in immunocompetent adults. The authors conducted a prospective observational cohort study (1992-2002) of 635 community-dwelling women in Baltimore, Maryland, aged 70-79 years in the Women's Health and Aging Studies to examine the effect of CMV infection on the risk of frailty, a common geriatric syndrome, and mortality in older women. The effect of baseline serum CMV antibody (immunoglobulin G) concentration on the risk of 3-year incident frailty, defined by using a 5-component measure, and 5-year mortality was examined with Cox proportional hazards models. Compared with those who were CMV seronegative, women in the highest quartile of CMV antibody concentration had a greater incidence of frailty (hazard ratio = 3.46, 95% confidence interval: 1.45, 8.27) and mortality (hazard ratio = 3.81, 95% confidence interval: 1.64, 8.83). After adjustment for potential confounders, CMV antibody concentration in the highest quartile independently increased the risk of 5-year mortality (hazard ratio = 2.79, 95% confidence interval: 1.22, 6.40). Better understanding of the long-term clinical consequences of CMV infection in immunocompetent humans is needed to guide public health efforts for this widely prevalent infection.