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Allogeneic islet transplant offers a minimally invasive option for β cell replacement in the treatment of type 1 diabetes (T1D). The CIT consortium trial of purified human pancreatic islets (PHPI) in patients with T1D after kidney transplant (CIT06), a National Institutes of Health-sponsored phase 3, prospective, open-label, single-arm pivotal trial of PHPI, was conducted in 24 patients with impaired awareness of hypoglycemia while receiving intensive insulin therapy. PHPI were manufactured using standardized processes. PHPI transplantation was effective with 62.5% of patients achieving the primary endpoint of freedom from severe hypoglycemic events and HbA1c ≤ 6.5% or reduced by ≥ 1 percentage point at 1 year posttransplant. Median HbA1c declined from 8.1% before to 6.0% at 1 year and 6.3% at 2 and 3 years following transplant (P

Objective To determine the cost of achieving a live birth after first transfer using highly purified human menotropin (HP-hMG) or recombinant follicle-stimulating hormone (FSH) for controlled ovarian stimulation in predicted high-responder patients in the Menopur in Gonadotropin-releasing hormone Antagonist Single Embryo Transfer–High Responder (MEGASET-HR) trial. Design Cost minimization analysis of trial results. Setting Thirty-one fertility centers. Patient(s) Six hundred and nineteen women with serum antimullerian hormone ≥5 ng/mL. Intervention(s) Controlled ovarian stimulation with HP-hMG or recombinant FSH in a gonadotropin-releasing hormone (GnRH) antagonist assisted reproduction cycle where fresh transfer of a single blastocyst was performed unless ovarian response was excessive whereupon all embryos were cryopreserved and patients could undergo subsequent frozen blastocyst transfer within 6 months of randomization. Main Outcome Measure(s) Mean cost of achieving live birth after first transfer (fresh or frozen). Result(s) First-transfer efficacy, defined as live birth after first fresh or frozen transfer, was 54.5% for HP-hMG and 48.0% for recombinant FSH (difference 6.5%). Average cost to achieve a live birth after first transfer (fresh or frozen) was lower with HP-hMG compared with recombinant FSH. For fresh transfers, the cost was lower with HP-hMG compared with recombinant FSH. The average cost to achieve a live birth after first frozen transfer was also lower in patients treated with HP-hMG compared with recombinant FSH. Conclusion(s) Treatment of predicted high-responders with HP-hMG was associated with lower cost to achieve a live birth after first transfer compared with recombinant FSH. Clinical Trial Registration Number NCT02554279.

Background A direct antidepressant effect has been reported for certain dopaminergic medications used in the treatment of Parkinson's disease (PD). Objective To examine whether dopaminergic medications may exert differential effects on mood in early PD. Methods We analyzed prospectively-collected 5-year data on 405 early, drug-naive (at baseline) PD patients enrolled in the Parkinson's Progression Markers Initiative (PPMI) cohort study, initiated on levodopa, dopamine agonists (DAs), or monoamine-oxidase type B inhibitors (iMAO-B) under naturalistic conditions. The outcome for depressive symptoms was the 15-item Geriatric Depression Scale (GDS-15) score. Potential motor and cognitive confounders were measured using the Unified Parkinson's disease Rating Scale (MDS-UPDRS-III) and the Montreal Cognitive Assessment (MoCA). Three statistical models were used to determine medication effects on GDS-15 scores: unadjusted, adjusted, and a marginal structural model. Results One-third of patients in this cohort met GDS-15 threshold for clinically-significant depressive symptoms (GDS-15 ≥ 5). There was a marginal positive effect on GDS-15 scores after iMAO-B treatment initiation (−0.35 95%; CI: −0.73, 0.04; p = 0.08). There were no significant interactions between any of the three medication groups, but robust interactions between MoCA scores and both DAs (p = 0.005) and iMAO-B (p = 0.03) use on GDS-15 scores. Specifically, as MoCA scores worsened, DAs yielded a steeper worsening of GDS-15 scores while iMAO-B a moderating effect on GDS-15. Conclusion Dopaminergic medications have no direct effect on mood in early, unselected PD patients.

ObjectivesWe examined whether a home-based, adaptive cognitive training (CT) program would lead to cognitive performance changes on a neuropsychological test battery in cognitively normal older adults.MethodSixty-eight older adults (age = 70.0, SD = 3.74) were randomly assigned to either CT or an active control group (AC, casual computer games). Participants were instructed to train on their assigned programs for 42 min per day, 5 days per week, over 10 weeks (35 hr of total program usage). Participants completed tests of processing speed, working memory, and executive control before and after 10 weeks of training.ResultsTraining groups did not differ in performance before training. After training, CT participants out-performed AC participants in the overall cognitive composite score, driven by processing speed and working memory domains.DiscussionOur results show that a limited dose of home-based CT can drive cognitive improvements as measured with neuropsychological test battery, suggesting potential cognitive health maintenance implications for cognitively normal older adults.

OBJECTIVE Attaining glycemic targets without severe hypoglycemic events (SHEs) is a challenging treatment goal for patients with type 1 diabetes complicated by impaired awareness of hypoglycemia (IAH). The CIT Consortium Protocol 07 (CIT-07) trial showed islet transplantation to be an effective treatment for subjects with IAH and intractable SHEs. We evaluated health-related quality of life (HRQOL), functional health status, and health utility before and after pancreatic islet transplantation in CIT-07 trial participants. RESEARCH DESIGN AND METHODS Four surveys, the Diabetes Distress Scale (DDS), the Hypoglycemic Fear Survey (HFS), the Short Form 36 Health Survey (SF-36), and the EuroQoL 5 Dimensions (EQ-5D), were administered repeatedly before and after islet transplantation. Summary statistics and longitudinal modeling were used to describe changes in survey scores from baseline and to characterize change in relation to a minimally important difference (MID) threshold of half an SD. RESULTS Improvements in condition-specific HRQOL met the MID threshold. Reductions from baseline in the DDS total score and its four DDS subscales (all P ≤ 0.0013) and in the HFS total score and its two subscales (all P < 0.0001) were observed across all time points. Improvements were observed after both 1 and 2 years for the EQ-5D visual analog scale (both P < 0.0001). CONCLUSIONS In CIT-07, 87.5% of the subjects achieved the primary end point of freedom from SHE along with glycemic control (HbA1c

Haemophilus haemolyticus and nontypeable Haemophilus influenzae (NTHi) are closely related upper airway commensal bacteria that are difficult to distinguish phenotypically. NTHi causes upper and lower airway tract infections in individuals with compromised airways, while H. haemolyticus rarely causes such infections. The lipooligosaccharide (LOS) is an outer membrane component of both species and plays a role in NTHi pathogenesis. In this study, comparative analyses of the LOS structures and corresponding biosynthesis genes were performed. Mass spectrometric and immunochemical analyses showed that NTHi LOS contained terminal sialic acid more frequently and to a higher extent than H. haemolyticus LOS did. Genomic analyses of 10 strains demonstrated that H. haemolyticus lacked the sialyltransferase genes lic3A and lic3B (9/10) and siaA (10/10), but all strains contained the sialic acid uptake genes siaP and siaT (10/10). However, isothermal titration calorimetry analyses of SiaP from two H. haemolyticus strains showed a 3.4- to 7.3-fold lower affinity for sialic acid compared to that of NTHi SiaP. Additionally, mass spectrometric and immunochemical analyses showed that the LOS from H. haemolyticus contained phosphorylcholine (ChoP) less frequently than the LOS from NTHi strains. These differences observed in the levels of sialic acid and ChoP incorporation in the LOS structures from H. haemolyticus and NTHi may explain some of the differences in their propensities to cause disease.

Importance One major advantage of developing large, federally funded networks for clinical research in neurology is the ability to have a trial-ready network that can efficiently conduct scientifically rigorous projects to improve the health of people with neurologic disorders. Observations National Institute of Neurological Disorders and Stroke Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) was established in 2011 and renewed in 2018 with the goal of being an efficient network to test between 5 and 7 promising new agents in phase II clinical trials. A clinical coordinating center, data coordinating center, and 25 sites were competitively chosen. Common infrastructure was developed to accelerate timelines for clinical trials, including central institutional review board (a first for the National Institute of Neurological Disorders and Stroke), master clinical trial agreements, the use of common data elements, and experienced research sites and coordination centers. During the first 7 years, the network exceeded the goal of conducting 5 to 7 studies, with 9 funded. High interest was evident by receipt of 148 initial applications for potential studies in various neurologic disorders. Across the first 8 studies (the ninth study was funded at end of initial funding period), the central institutional review board approved the initial protocol in a mean (SD) of 59 (21) days, and additional sites were added a mean (SD) of 22 (18) days after submission. The median time from central institutional review board approval to first site activation was 47.5 days (mean, 102.1; range, 1-282) and from first site activation to first participant consent was 27 days (mean, 37.5; range, 0-96). The median time for database readiness was 3.5 months (mean, 4.0; range, 0-8) from funding receipt. In the 4 completed studies, enrollment met or exceeded expectations with 96% overall data accuracy across all sites. Nine peer-reviewed manuscripts were published, and 22 oral presentations or posters and 9 invited presentations were given at regional, national, and international meetings. Conclusions and Relevance NeuroNEXT initiated 8 studies, successfully enrolled participants at or ahead of schedule, collected high-quality data, published primary results in high-impact journals, and provided mentorship, expert statistical, and trial management support to several new investigators. Partnerships were successfully created between government, academia, industry, foundations, and patient advocacy groups. Clinical trial consortia can efficiently and successfully address a range of important neurologic research and therapeutic questions.

Introduction Cluster randomized trials (CRTs) are now the gold standard in health services research, including pharmacy-based interventions. Studies of behaviour, epidemiology, lifestyle modifications, educational programs, and health care models are utilizing the strengths of cluster randomized analyses. Methodology The key property of CRTs is the unit of randomization (clusters), which may be different from the unit of analysis (individual). Subject sample size and, ideally, the number of clusters is determined by the relationship of between-cluster and within-cluster variability. The correlation among participants recruited from the same cluster is known as the intraclass correlation coefficient (ICC). Generally, having more clusters with smaller ICC values will lead to smaller sample sizes. When selecting clusters, stratification before randomization may be useful in decreasing imbalances between study arms. Participant recruitment methods can differ from other types of randomized trials, as blinding a behavioural intervention cannot always be done. When to use CRTs can yield results that are relevant for making "real world" decisions. CRTs are often used in non-therapeutic intervention studies (e.g. change in practice guidelines). The advantages of CRT design in pharmacy research have been avoiding contamination and the generalizability of the results. A large CRT that studied physician-pharmacist collaborative management of hypertension is used in this manuscript as a CRT example. The trial, entitled Collaboration Among Pharmacists and physicians To Improve Outcomes Now (CAPTION), was implemented in primary care offices in the United States for hypertensive patients. Limitations CRT design limitations include the need for a large number of clusters, high costs, increased training, increased monitoring, and statistical complexity.

Background This study reports the baseline characteristics of diffusion tensor imaging data in Parkinson's disease (PD) patients and healthy control subjects from the Parkinson's Progression Markers Initiative. The main goals were to replicate previous findings of abnormal diffusion imaging values from the substantia nigra. in a large multicenter cohort and determine whether nigral diffusion alterations are associated with dopamine deficits. Methods Two hundred twenty subjects (PD = 153; control = 67) from 10 imaging sites were included. All subjects had a full neurological exam, a (123I)ioflupane dopamine transporter (DAT) single-photon emission computer tomography scan, and diffusion tensor imaging. Fractional anisotropy as well as radial and axial diffusivity was computed within multiple regions across the substantia nigra. Results A repeated-measures analysis of variance found a marginally nonsignificant interaction between regional fractional anisotropy of the substantia nigra and disease status (P = 0.08), conflicting with an earlier study. However, a linear mixed model that included control regions in addition to the nigral regions revealed a significant interaction between regions and disease status (P = 0.002), implying a characteristic distribution of reduced fractional anisotropy across the substantia nigra in PD. Reduced fractional anisotropy in PD was also associated with diminished DAT binding ratios. Both axial and radial diffusivity were also abnormal in PD. Conclusions Although routine nigral measurements of fractional anisotropy are clinically not helpful, the findings in this study suggest that more-sophisticated diffusion imaging protocols should be used when exploring the clinical utility of this imaging modality. © 2015 International Parkinson and Movement Disorder Society

To diagnose hypertension, multiple blood pressure (BP) measurements are recommended. We randomized patients into three groups: EMR–only (patients recorded BP measurements in an electronic medical record [EMR] web portal), EMR + reminders (patients were sent text message reminders to record their BP measurements in the EMR), and bi–directional text messaging (patients were sent a text message asking them to respond with their current BP). Subjects were asked to complete 14 measurements. Automated messages were sent to each patient in the bi–directional text messaging and EMR + reminder groups twice daily. Among 121 patients, those in the bi–directional text messaging group reported the full 14 measurements more often than both the EMR–only group (P

Parkinson's disease (PD) is histopa- thologically characterized by the loss of dopamine neu- rons in the substantia nigra pars compacta. The depletion of these neurons is thought to reduce the dopaminergic function of the nigrostriatal pathway, as well as the neural fibers that link the substantia nigra to the striatum (putamen and caudate), causing a dysregu- lation in striatal activity that ultimately leads to lack of movement control. Based on diffusion tensor imaging, visualizing this pathway and measuring alterations of the fiber integrity remain challenging. The objectives were to 1) develop a diffusion tensor tractography pro- tocol for reliably tracking the nigrostriatal fibers on mul- ticenter data; 2) test whether the integrities measured by diffusion tensor imaging of the nigrostriatal fibers are abnormal in PD; and 3) test whether abnormal integri- ties of the nigrostriatal fibers in PD patients are associ- ated with the severity of motor disability and putaminal dopamine binding ratios. Diffusion tensor tractography was performed on 50 drug-na€ ove PD patients and 27 healthy control subjects from the international multicen- ter Parkinson's Progression Marker Initiative. Tractogra- phy consistently detected the nigrostriatal fibers, yielding reliable diffusion measures. Fractional anisot- ropy, along with radial and axial diffusivity of the nigro- striatal tract, showed systematic abnormalities in patients. In addition, variations in fractional anisotropy and radial diffusivity of the nigrostriatal tract were asso- ciated with the degree of motor deficits in PD patients. Taken together, the findings imply that the diffusion ten- sor imaging characteristic of the nigrostriatal tract is potentially an index for detecting and staging of early PD. V C 2015 International Parkinson and Movement Dis- order Society Key W ords: Parkinson's disease; MRI; diffusion ten- sor imaging; diffusion tensor tractography; nigrostriatal pathway

This study was undertaken to determine the prevalence and correlates of cognitive impairment (CI) and neuropsychiatric symptoms (NPS) in early, untreated patients with Parkinson’s disease (PD). Background Both CI and NPS are common in PD and impact disease course and quality of life. However, limited knowledge is available about cognitive abilities and NPS.

Objectives To assess the neurobiological substrate of initial cognitive decline in Parkinson’s disease (PD) to inform patient management, clinical trial design, and development of treatments. Methods We longitudinally assessed, up to 3 years, 423 newly diagnosed patients with idiopathic PD, untreated at baseline, from 33 international movement disorder centers. Study outcomes were four determinations of cognitive impairment or decline, and biomarker predictors were baseline dopamine transporter (DAT) single photon emission computed tomography (SPECT) scan, structural magnetic resonance imaging (MRI; volume and thickness), diffusion tensor imaging (mean diffusivity and fractional anisotropy), cerebrospinal fluid (CSF; amyloid beta [Aβ], tau and alpha synuclein), and 11 single nucleotide polymorphisms (SNPs) previously associated with PD cognition. Additionally, longitudinal structural MRI and DAT scan data were included. Univariate analyses were run initially, with false discovery rate = 0.2, to select biomarker variables for inclusion in multivariable longitudinal mixed-effect models. Results By year 3, cognitive impairment was diagnosed in 15–38% participants depending on the criteria applied. Biomarkers, some longitudinal, predicting cognitive impairment in multivariable models were: (1) dopamine deficiency (decreased caudate and putamen DAT availability); (2) diffuse, cortical decreased brain volume or thickness (frontal, temporal, parietal, and occipital lobe regions); (3) co-morbid Alzheimer’s disease Aβ amyloid pathology (lower CSF Aβ 1–42); and (4) genes (COMT val/val and BDNF val/val genotypes). Conclusions Cognitive impairment in PD increases in frequency 50–200% in the first several years of disease, and is independently predicted by biomarker changes related to nigrostriatal or cortical dopaminergic deficits, global atrophy due to possible widespread effects of neurodegenerative disease, co-morbid Alzheimer’s disease plaque pathology, and genetic factors.

Background and objective Although influenza has been associated with asthma exacerbations, it is not clear the extent to which this association affects health care use in the United States. The first goal of this project was to determine whether, and to what extent, the incidence of asthma hospitalizations is associated with seasonal variation in influenza. Second, we used influenza trends (2000–2008) to help predict asthma admissions during the 2009 H1N1 influenza pandemic. Methods We identified all hospitalizations between 1998 and 2008 in the Nationwide Inpatient Sample from the Healthcare Cost and Utilization Project during which a primary diagnosis of asthma was recorded. Separately, we identified all hospitalizations during which a diagnosis of influenza was recorded. We performed time series regression analyses to investigate the association of monthly asthma admissions with influenza incidence. Finally, we applied these time series regression models using 1998–2008 data, to forecast monthly asthma admissions during the 2009 influenza pandemic. Results Based on time series regression models, a strong, significant association exists between concurrent influenza activity and incidence of asthma hospitalizations (P-value

Although influenza has been associated with chronic obstructive pulmonary disease (COPD) exacerbations, it is not clear the extent to which this association affects healthcare use in the United States. The first goal of this project was to determine to what extent the incidence of COPD hospitalizations is associated with seasonal influenza. Second, as a natural experiment, we used influenza activity to help predict COPD admissions during the 2009 H1N1 influenza pandemic. To do this, we identified all hospitalizations between 1998 and 2010 in the Nationwide Inpatient Sample from the Healthcare Cost and Utilization Project (HCUP) during which a primary diagnosis of COPD was recorded. Separately, we identified all hospitalizations during which a diagnosis of influenza was recorded. We formulated time series regression models to investigate the association of monthly COPD admissions with influenza incidence. Finally, we applied these models, fit using 1998-2008 data, to forecast monthly COPD admissions during the 2009 pandemic. Based on time series regression models, a strong, significant association exists between concurrent influenza activity and incidence of COPD hospitalizations (p-value < 0.0001). The association is especially strong among older patients requiring mechanical ventilation. Use of influenza data to predict COPD admissions during the 2009 H1N1 pandemic reduced the mean-squared prediction error by 29.9%. We conclude that influenza activity is significantly associated with COPD hospitalizations in the United States and influenza activity can be exploited to more accurately forecast COPD admissions. Our results suggest that improvements in influenza surveillance, prevention, and treatment may decrease hospitalizations of patients diagnosed with COPD.

SUMMARYThe incidence of myocardial infarctions and influenza follow similar seasonal patterns. To determine if acute myocardial infarctions (AMIs) and ischaemic strokes are associated with influenza activity, we built time-series models using data from the Nationwide Inpatient Sample. In these models, we used influenza activity to predict the incidence of AMI and ischaemic stroke. We fitted national models as well as models based on four geographical regions and five age groups. Across all models, we found consistent significant associations between AMIs and influenza activity, but not between ischaemic strokes and influenza. Associations between influenza and AMI increased with age, were greatest in those aged >80 years, and were present in all geographical regions. In addition, the natural experiment provided by the second wave of the influenza pandemic in 2009 provided further evidence of the relationship between influenza and AMI, because both series peaked in the same non-winter month.

This study aimed to identify the utility of diffusion tensor imaging (DTI) in measuring the regional distribution of abnormal microstructural progression in patients with Parkinson's disease who were enrolled in the Parkinson's progression marker initiative (PPMI). One hundred and twenty two de-novo PD patients (age = 60.5±9) and 50 healthy controls (age = 60.6±11) had DTI scans at baseline and 12.6±1 months later. Automated image processing included an intra-subject registration of all time points and an inter-subjects registration to a brain atlas. Annualized rates of DTI variations including fractional anisotropy (FA), radial (rD) and axial (aD) diffusivity were estimated in a total of 118 white matter and subcortical regions of interest. A mixed effects model framework was used to determine the degree to which DTI changes differed in PD relative to changes in healthy subjects. Significant DTI changes were also tested for correlations with changes in clinical measures, dopaminergic imaging and CSF biomarkers in PD patients. Compared to normal aging, PD was associated with higher rates of FA reduction, rD and aD increases predominantly in the substantia nigra, midbrain and thalamus. The highest rates of FA reduction involved the substantia nigra (3.6±1.4%/year from baseline, whereas the highest rates of increased diffusivity involved the thalamus (rD: 8.0±2.9%/year, aD: 4.0±1.5%/year). In PD patients, high DTI changes in the substantia nigra correlated with increasing dopaminergic deficits as well as with declining α-synuclein and total tau protein concentrations in cerebrospinal fluid. Increased DTI rates in the thalamus correlated with progressive decline in global cognition in PD. The results suggest that higher rates of regional microstructural degeneration are potential markers of PD progression.

Diverse stresses including starvation and muscle disuse cause skeletal muscle atrophy. However, the molecular mechanisms of muscle atrophy are complex and not well understood. Here, we demonstrate that growth arrest and DNA damage-inducible 45a protein (Gadd45a) is a critical mediator of muscle atrophy. We identified Gadd45a through an unbiased search for potential downstream mediators of the stress-inducible, pro-atrophy transcription factor ATF4. We show that Gadd45a is required for skeletal muscle atrophy induced by three distinct skeletal muscle stresses: fasting, muscle immobilization, and muscle denervation. Conversely, forced expression of Gadd45a in muscle or cultured myotubes induces atrophy in the absence of upstream stress. We show that muscle-specific ATF4 knock-out mice have a reduced capacity to induce Gadd45a mRNA in response to stress, and as a result, they undergo less atrophy in response to fasting or muscle immobilization. Interestingly, Gadd45a is a myonuclear protein that induces myonuclear remodeling and a comprehensive program for muscle atrophy. Gadd45a represses genes involved in anabolic signaling and energy production, and it induces pro-atrophy genes. As a result, Gadd45a reduces multiple barriers to muscle atrophy (including PGC-1α, Akt activity, and protein synthesis) and stimulates pro-atrophy mechanisms (including autophagy and caspase-mediated proteolysis). These results elucidate a critical stress-induced pathway that reprograms muscle gene expression to cause atrophy.

Nontypeable Haemophilus influenzae (NTHI) forms biofilms in the middle ear during human infection. The biofilm matrix of NTHI contains extracellular DNA. We show that NTHI possesses a potent nuclease, which is a homolog of the thermonuclease of Staphylococcus aureus . Using a biofilm dispersal assay, studies showed a biofilm dispersal pattern in the parent strain, no evidence of dispersal in the nuclease mutant, and a partial return of dispersion in the complemented mutant. Quantitative PCR of mRNA from biofilms from a 24-h continuous flow system demonstrated a significantly increased expression of the nuclease from planktonic organisms compared to those in the biofilm phase of growth ( P < 0.042). Microscopic analysis of biofilms grown in vitro showed that in the nuclease mutant the nucleic acid matrix was increased compared to the wild-type and complemented strains. Organisms were typically found in large aggregates, unlike the wild-type and complement biofilms in which the organisms were evenly dispersed throughout the biofilm. At 48 h, the majority of the organisms in the mutant biofilm were dead. The nuclease mutant formed a biofilm in the chinchilla model of otitis media and demonstrated a propensity to also form similar large aggregates of organisms. These studies indicate that NTHI nuclease is involved in biofilm remodeling and organism dispersal.

This study reports the baseline characteristics of diffusion tensor imaging data in Parkinson's disease (PD) patients and healthy control subjects from the Parkinson's Progression Markers Initiative. The main goals were to replicate previous findings of abnormal diffusion imaging values from the substantia nigra. in a large multicenter cohort and determine whether nigral diffusion alterations are associated with dopamine deficits.Two hundred twenty subjects (PD = 153; control = 67) from 10 imaging sites were included. All subjects had a full neurological exam, a ((123) I)ioflupane dopamine transporter (DAT) single-photon emission computer tomography scan, and diffusion tensor imaging. Fractional anisotropy as well as radial and axial diffusivity was computed within multiple regions across the substantia nigra.A repeated-measures analysis of variance found a marginally nonsignificant interaction between regional fractional anisotropy of the substantia nigra and disease status (P = 0.08), conflicting with an earlier study. However, a linear mixed model that included control regions in addition to the nigral regions revealed a significant interaction between regions and disease status (P = 0.002), implying a characteristic distribution of reduced fractional anisotropy across the substantia nigra in PD. Reduced fractional anisotropy in PD was also associated with diminished DAT binding ratios. Both axial and radial diffusivity were also abnormal in PD.Although routine nigral measurements of fractional anisotropy are clinically not helpful, the findings in this study suggest that more-sophisticated diffusion imaging protocols should be used when exploring the clinical utility of this imaging modality.

Objectives To show the effect of clinical, angio and demographic traits on late survival of Coronary Artery Surgery Study (CASS) patients following coronary artery bypass grafting (CABG) and introduce Hazard Function analysis to CASS survival data. Methods Patients were reached by mail survey with 94% response. By National Death Index, vital status was obtained in 99.7% (n = 8221) with a mean follow up of 15 years. Cox proportional hazard and Blackstone Hazard Function regressions were used to assess effects of preoperative traits. Results Ninety percent of patients were alive at 5, 74% at 10 and 56% at 15 years. Of those age 65 and age 75 at operation, 74% and 59% were living at 10 years and 54% and 33% at 15 years (now age 90), survival exceeding the matched U.S. population. Hazard Function falls rapidly after CABG to 9 to 12 months, then rises, doubling by 15 years. Young patients, below age 35, had lower late survival. The time-segmented Cox model (divided at time suggested by the Hazard Function) identified traits showing predictive power early, throughout and late. Female sex, small body surface, ischemic symptoms and emergency status affected survival early. Heavier weight, infarct(s), diuretics, diabetes, smoking, left main and LAD stenosis and use of vein grafts only increased hazard late only. Conclusions There are still lessons from the CASS database. CABG in the elderly is supported by the survival pattern of our patients age 75 at operation. Time-segmented Cox analysis and Hazard Function analysis separate baseline variables into those that predict early mortality and those that predict long survival.

Objective: Patients with lower extremity arterial disease (LEAD) are at an increased risk of having coronary artery disease (CAD). Diabetics are at especially high risk for having LEAD with concomitant CAD. This study was undertaken (1) to define the clinical and arteriographic features associated with CAD among diabetics and nondiabetics with LEAD and (2) to determine the long-term survival and predictors of mortality of diabetics and nondiabetics with LEAD and CAD. Research Design and Methods: Two hundred sixty-three diabetics and 1137 nondiabetics from the Coronary Artery Surgery Study who had evidence of LEAD, who were 50 years and older, and who had arteriographically proven CAD were monitored for a mean of 12.8 years. Results: Among all the subjects with LEAD there was a high prevalence of current and past smoking, history of previous myocardial infarction, systemic hypertension, congestive heart failure, high degrees of angina pectoris and unstable angina pectoris, and use of β-blockers. On arteriographic evaluation a high prevalence of three-vessel epicardial coronary disease and involvement of multiple coronary segments with ≥50% diameter narrowing was found. Multivariate analysis showed the number of coronary segments with ≥50% occlusion, the presence of cerebrovascular disease, the use of digitalis, and elevated systolic blood pressure were independently associated with diabetes. On follow-up diabetics had a significantly higher mortality rate (mostly cardiac) than nondiabetics: median survival, 8.1 years and 12.7 years, respectively. At 15 years the mortality rates were 77.1% and 62.0%, respectively. On multivariate analysis, age, number of coronary occlusions, number of significantly narrowed epicardial arteries, diminished myocardial contractility, hypertension, and smoking were significant predictors of mortality in the total group and in each subgroup. Coronary artery bypass grafting surgery was protective. The presence of diabetes was an independent risk factor for mortality. Conclusions: The presence of LEAD is associated with multivessel epicardial and multiple coronary segment occlusion. On long-term follow-up there is a high mortality rate. In patients with LEAD and diabetes, CAD is especially severe and prognosis is poor. (Am Heart J 1998;135:1055-62.)

Background The influence of prior coronary artery bypass surgery (CABG) versus medical therapy for reducing the risk of postoperative cardiac complications after noncardiac surgery continues to be debated. To further clarify this controversy we studied 24 959 participants in the Coronary Artery Surgery Study (CASS) database with suspected coronary disease by identifying those who required noncardiac surgery during more than 10 years of follow-up. Methods and Results CASS registry enrollees were either treated with CABG or medical therapy after initial entry. During follow-up, patients who required noncardiac operations were evaluated for hospital death or out-of-hospital death within 30 days of noncardiac surgery and nonfatal postoperative myocardial infarction (MI). At a mean follow-up of 4.1 years, 3368 patients underwent noncardiac surgery, with abdominal (36%), urologic (21%), orthopedic (15%), and vascular being most common. Abdominal, vascular, thoracic, and head and neck surgery each had a combined MI/death rate among patients with nonrevascularized coronary disease >4%. Among 1961 patients undergoing higher-risk surgery, prior CABG was associated with fewer postoperative deaths (1.7% versus 3.3%, P =.03) and MIs (0.8% versus 2.7%, P =.002) compared with medically managed coronary disease. Contrariwise, 1297 patients undergoing urologic, orthopedic, breast, and skin operations had mortality of Conclusions In patients with known coronary artery disease, noncardiac surgeries involving the thorax, abdomen, vasculature, and head and neck are associated with the highest cardiac risk, which is reduced among patients with prior CABG.

(See the editorial commentary by Inzana on pages 713–6.) Phase variation is described as a random process by which a clonal population of microbes can present heterogeneous phenotypes as a result of a reversible genetic event [1, 2]. The process can involve several mechanisms, including slipped-strand mispairing (SSM), site-specific recombination, and epigenetic regulation mediated by DNA methylation [2]. SSM is a mechanism found in human pathogens, including pathogenic Neisseria, Bordetella pertussis, Haemophilus influenzae, and Helicobacter pylori. The resulting frame shift causes on-off changes in gene expression [3]. The process can occur at rates as high as 2–3 × 10−4 colony forming units [3]. Nontypeable H. influenzae (NTHi), which colonizes human mucosal surfaces and can cause disease, has genes with long tandem repeats that undergo high rates of phase variation [3]. In 1989, Weiser et al identified a tetranucleotide repeat region (5′-CAAT-3′) in licA that was responsible for phase-variable expression of that gene in H. influenzae type b [4]. Subsequent work showed that a number of genes in the H. influenzae chromosome had similar characteristics and underwent phase variation. These genes are associated with iron regulation, membrane protein expression, and lipooligosaccharide (LOS) biosynthesis [5–9]. The opportunity to directly study the effect of experimental human colonization on changes in the phase-on, phase-off status of NTHi phase-varying genes was presented to us. This article describes the results of that study.

Respiratory quotient, the ratio of CO2 production to oxygen consumption (VO2), is principally affected by the fuel source used for aerobic metabolism. Since the respiratory quotient, VO2, and CO2 production cannot be directly measured easily, indirect calorimetry is commonly used to determine the value of these variables at the airway level (i.e., airway respiratory quotient, airway VO2, and airway CO2 production). However, under nonsteady-state conditions, a variety of phenomena can alter the relationship between true metabolic activity and measurements determined by indirect calorimetry. During exercise, for example, airway respiratory quotient increases as anaerobic threshold is reached because of the disproportionate increase in airway CO2 production that results from the CO2 liberated through the buffering of excess hydrogen ions by bicarbonate. We hypothesized that hemorrhage and reinfusion might change airway respiratory quotient in a consistent manner as shock is produced and reversed.Prospective laboratory study.University animal laboratory.Eight pigs (25 +/- 2 [SD] kg), anesthetized with fentanyl and relaxed with pancuronium bromide, and mechanically ventilated on room air.The animals were sequentially hemorrhaged and then autotransfused while metabolic and hemodynamic measurements were obtained, using continuous indirect calorimetry and continuous applications of the Fick principle. Hemoglobin, arterial lactate concentration, and blood gases for calibration were measured serially. Analysis of variance was used to compare various periods in time.Between baseline and peak hemorrhage, and between peak hemorrhage and postreinfusion, all of the following variables changed significantly (p.05): airway VO2 (baseline 6.4 +/- 0.9 mL/min/kg, peak hemorrhage 3.9 +/- 0.6 mL/min/kg, postreinfusion 7.0 +/- 1.4 mL/min/kg); airway CO2 production (baseline 5.5 +/- 0.9 mL/min/kg, peak hemorrhage 4.5 +/- 0.9 mL/min/kg, postreinfusion 6.0 +/- 1.4 mL/min/kg); airway respiratory quotient (baseline 0.87 +/- 0.07, peak hemorrhage 1.16 +/- 0.07, postreinfusion 0.87 +/- 0.05); lactate concentration (baseline 2.4 +/- 1.2 mmol/L, peak hemorrhage 6.7 +/- 1.9 mmol/L, postreinfusion 5.1 +/- 2.0 mmol/L); and delta PCO2 (venous PCO2-PaCO2) (baseline 4.5 +/- 3.6 torr [0.6 +/- 0.5 kPa], peak hemorrhage 12.1 +/- 5.3 torr [1.6 +/- 0.7 kPa], postreinfusion 2.7 +/- 2.7 torr [0.4 +/- 0.4 kPa]).Airway respiratory quotient increases in hemorrhagic shock and decreases again as shock is reversed during reinfusion. This phenomenon appears related to the buffering of excess of hydrogen ion during hemorrhagic shock.

We compared the observations of nearly 1,400 hand-hygiene-related events recorded by an automated system and by human observers. Observation details differed for 38% of these events. Two likely explanations for these inconsistencies were the distance between the observer and the event and the busyness of the clinic.

A cohort of 317 diabetic patients, aged ≥ 65 years, with angiographically proven coronary artery disease, was analyzed and followed for a mean of 12.8 years. Compared with 1,843 age-matched nondiabetic patients, diabetic patients were more likely to (1) have a higher number of coronary occlusions, (2) not be current smokers, (3) have higher systolic but lower diastolic blood pressures, (4) have evidence of peripheral vascular disease, and (5) be women. They did not differ significantly with respect to total cholesterol, family history of coronary artery disease, history of hypertension, or left ventricular hypertrophy. In the total elderly cohort, diabetes was found to be an independent predictor of mortality, conferring a 57.0% increased risk of death. Survival analysis showed that diabetic subjects consistently had higher mortality than nondiabetics. However, the relative survival benefit of coronary artery bypass graft surgery versus medical therapy was comparable in diabetic and nondiabetic patients. Surgical therapy conferred a reduction in mortality of 44%.

Objectives. The purpose of this study was to determine the importance of peripheral arterial disease in predicting long-term survival in patients with clinically evident coronary artery disease. Background. Patients in the Coronary Artery Surgery Study (CASS) Registry were followed up for >10 years. Methods. Survival in 2,296 patients with peripheral arterial disease was compared with that of 13,953 patients without peripheral arterial disease using Kaplan-Meier survival curves. All patients had known stable coronary artery disease. Clinical, electrocardiographic (ECG), chest X-ray film and catheterizalion variables of the two groups were compared using the chi-square statistic or the two-sample t test. The independent effect of peripheral arterial disease (as well as other variables) on mortality was determined utilizing a Cox proportional hazards model. Results. Patients with peripheral vascular disease were more likely to have hypertension, diabetes, family history of coronary artery disease, previous angina or myocardial infarction, previous coronary bypass surgery or to have smoked. They also had a higher incidence of congestive heart failure, ECG abnormality and modestly increased frequency of three-vessel disease. Independent correlates of long-term mortality for the entire cohort included age, smoking, diabetes, number of diseased coronary vessels, left ventricular function, hypertension, pulmonary disease, anginal class, previous myocardial infarction and peripheral vascular disease (all p < 0.061). At any point in time, patients with peripheral vascular disease had a 25% greater likelihood of mortality than patients without peripheral vascular disease (multivariate chi-square 25.83, hazard ratio 1.25, 95% confidence interval 1.15 to 1.36, p < 0.0001). Conclusions. Peripheral vascular disease is a strong, independent predictor of long-term mortality in patients with stable coronary artery disease. Aggressive attempts at secondary disease prevention are warranted in this high risk group.

International Society for Disease Surveillance Annual Conference 2011(ISDS) 1220673 Changes in alcohol-related travel behavior due to an under 21 ordinance the drinking culture. Of course, since the arresting officer cannot generally detect residency prior to arrest, arrest data still represent a geographically unbiased sample of bar patrons and can be used to explore changes in the mix of patrons. We hypothesize that the changes detected in the proportion of arrests of in town and out of town patrons reflect a more homogeneous student clientele, where town-gown tensions are less likely to arise. Of course, any reduction in out of town patrons also corresponds to a reduction in the risk of DUI-related fatalities, since students walk to the bars. There are several shortcomings to this study. First, our data are incomplete as data from other enforcement agencies was not available. Second, we were unable to directly confirm the link with violence or sexual assault, as additional data would be required to do so: these are our next steps. Alcohol abuse is one of the major leading causes of preventable mortality in the United States (1). Binge drinking or excessive alcohol consumption, categorized as a pattern of drinking that brings a person’s blood alcohol concentration (BAC) to 0.08 (2), has become a major cause for concern, especially in the 18to 20 year-old population. Iowa City is home to the University of Iowa, a large public university of 30,000 students. On June 1, 2010, the city council enacted a new ordinance prohibiting persons under 21 from entering or remaining in bars (establishments after 10:00 PM whose primary purpose is the sale of alcoholic beverages) after 10:00 PM (3). Prior to the ordinance, Iowa City was the only municipality in the region where underage patrons were allowed on premises. The new ordinance was enacted largely in response to public safety concerns, Arrest records were obtained from the University of Iowa Police Department containing all alcohol-related citations from January 1, 2004 to June 26, 2011. As the University of Iowa Police Department is one of the 4 local law enforcement agencies (Iowa City Police, Coralville Police and Johnson County Sheriff), these 7002 records represent a sample of alcohol-related arrests, albeit one focused on the downtown bar area frequented by college students. Each record contains the date of the arrest as well as the age and home address of the offender, allowing us to compare ‘in town’ offenders (i.e., from within Iowa City, Coralville and transients) with ‘out of town’ offenders. Records corresponding to football Saturdays, where some 50,000 people come to Iowa City to tailgate and attend the Big10 football game, were excluded from the analysis as not representative of the usual bar culture. A total of 1490 alcohol-related Background To study alcohol-related arrests during the time surrounding the introduction of an alcohol-related ordinance in the Iowa City, IA, area.

Introduction Influenza is a major cause of mortality. In developed countries, mortality is at its highest during winter months, not only as a result of deaths from influenza and pneumonia but also as a result of deaths attributed to other diseases (e.g., cardiovascular disease). Understandably, much of the surveillance of influenza follows predefined geographic regions (e.g., census regions or state boundaries). However, the spread of influenza and its resulting mortality does not respect such boundaries.

Introduction ILI data are collected via an Influenza Sentinel Provider Surveillance Network at the state level. Because participation is voluntary, locations of the sentinel providers may not reflect optimal geographic placement. This study analyzes two different geographic placement schemes*a maximal coverage model (MCM) and a K-median model, two location-allocation models commonly used in geographic information systems (GIS) (1). The MCM chooses sites in areas with the densest population. The K-median model chooses sites, which minimize the average distance traveled by individuals to their nearest site. We have previously shown how a placement model can be used to improve population coverage for ILI surveillance in Iowa when considering the sites recruited by the Iowa Department of Public Health (IDPH) (2). We extend this work by evaluating different surveillance placement algorithms with respect to outbreak intensity and timing (i.e., being able to capture the start, peak and end of the influenza season).

Objectives. The Coronary Artery Surgery Study (CASS) required participants to undergo follow-up angiography at 5 years to identify clinical and angiographic features associated with progression of coronary artery disease. Background. The CASS randomized 780 patients at 11 participating clinical centers between an initial strategy of medical therapy versus bypass surgery. Five clinical sites accomplished follow-up angiography in >50% of their randomized subjects within a 42- to 66-month period after the entry arteriogram (n = 314). Methods. Qualified clinical site angiographers, using side by side film review, evaluated an average of 13 segments/patient on both arteriograms for initial stenosis severity, morphologic features, lesion location and occurrence of disease progression or occlusion. Progression was defined as further definite narrowing by ≥15% and occlusion as lesion progression to ≥98%. Lesions were subcategorized as to whether they were univariate and had or had not been treated with bypass surgery. Multivariate logistic regression analyses were performed. Results. For nonbypassed segments, right coronary artery and left anterior descending artery proximal and midlocations were associated with disease progression. For stenosis-containing segments, the initial severity, a non-left anterior descending artery location and increased treadmill duration predicted progression. Segment occlusion was associated with initial lesion severity, right coronary artery location and subsequent interval myocardial infarction. There were few predictors of progression or occlusion in bypassed arteries, other than initial lesion severity. Conclusions. Univariate and multivariate associations with lesion progression and occlusion included diabetes, lesion location, elevated cholesterol level, interval infarction and lesion morphology. These angiographic results, collected in a prospective trial, are consistent with known risk factors.

The Coronary Artery Surgery Study (CASS) includes 780 patients with mild or moderate stable angina pectoris or asymptomatic survivors of a myocardial infarction who were randomized to either medical or surgical therapy and 1,319 patients who were eligible for randomization but were not randomized (randomizable patients). There were no substantial aggregate differences observed in any of the survival comparisons after 10 years of follow-up study between the randomized and randomizable patients assigned to the medical (79% versus 80%) or surgical (82% versus 81%) groups or in patient subgroups stratified according to coronary artery disease extent and left ventricular ejection fraction. Cox regression analyses were done with independent variables known to be predictors of survival, including surgical versus medical therapy and randomized versus randomizable group, to test the null hypothesis of a mortality difference between medical versus surgical assignment according to group assignment (randomized versus randomizable). In no case did the initial group category enter as a significant predictor of survival. The results in the randomizable group reinforce those in the randomized group with respect to the medical versus surgical comparison. Two subgroups are identified with a significant surgical advantage: 1) patients with proximal left anterior descending coronary artery stenosis greater than or equal to 70% and an ejection fraction less than 0.50, and 2) patients with three vessel coronary artery disease and an ejection fraction less than 0.50. In both groups, coronary bypass surgery had a statistically significant beneficial effect on survival (p less than 0.05). After a decade of follow-up, the CASS randomizable patients confirm conclusions reached on the basis of the CASS randomized trial.

(2008). Introduction to Bioinformatics. The American Statistician: Vol. 62, No. 3, pp. 268-269.

OBJECTIVE Patients who have diabetes and lower-extremity arterial disease (LEAD) are at an increased risk of dying from coronary artery disease (CAD). This study was undertaken to: 1) define the clinical and arteriographic factors associated with LEAD among diabetic patients; 2) determine the long-term survival and predictors of mortality of diabetic patients with LEAD, compared to those without LEAD; and 3) determine if the presence of LEAD is an independent risk factor for mortality among diabetic patients with CAD. RESEARCH DESIGN AND METHODS A total of 263 diabetic patients from the Coronary Artery Surgery Study (CASS) registry with LEAD, who were ≥ 50 years of age, and who had arteriographically proven CAD, were identified and followed for a mean of 12.8 years. A total of 1,349 comparably aged diabetic patients from the CASS registry with CAD and no evidence of LEAD were followed for an equivalent period of time. RESULTS Compared with diabetic patients without LEAD, diabetic patients with LEAD were characterized by the presence of cerebrovascular disease, a high rate of current smoking, elevated systolic blood pressure, high grades of angina pectoris, and digitalis use. Severity of epicardial CAD and extent of CAD were not independent predictors of the presence of LEAD. On follow-up, diabetic patients with LEAD had significantly higher mortality (mostly cardiovascular) than diabetic patients without LEAD, with a median survival of 8.1 and 10.9 years, respectively. On multivariate analysis, age, the number of significantly narrowed coronary arteries, and the presence of left ventricular dysfunction predicted mortality in both subsets of diabetic patients. Among all the diabetic patients with CAD, the presence of LEAD was an independent risk factor for mortality. CONCLUSIONS Diabetic patients with LEAD have a higher mortality rate (mostly cardiovascular) than diabetic patients without LEAD, despite no apparent anatomic differences in the severity and extent of CAD. This suggests that factors associated with the presence of LEAD, other than the anatomy of the coronary circulation, may play a role in determining survival among diabetic patients with LEAD and CAD.

Background Data from surveillance networks help epidemiologists and public health officials detect emerging diseases, conduct outbreak investigations, manage epidemics, and better understand the mechanics of a particular disease. Surveillance networks are used to determine outbreak intensity (i.e., disease burden) and outbreak timing (i.e., the start, peak, and end of the epidemic), as well as outbreak location. Networks can be tuned to preferentially perform these tasks. Given that resources are limited, careful site selection can save costs while minimizing performance loss. Methods We study three different site placement algorithms: two algorithms based on the maximal coverage model and one based on the K-median model. The maximal coverage model chooses sites that maximize the total number of people within a specified distance of a site. The K-median model minimizes the sum of the distances from each individual to the individual’s nearest site. Using a ground truth dataset consisting of two million de-identified Medicaid billing records representing eight complete influenza seasons and an evaluation function based on the Huff spatial interaction model, we empirically compare networks against the existing Iowa Department of Public Health influenza-like illness network by simulating the spread of influenza across the state of Iowa. Results We show that it is possible to design a network that achieves outbreak intensity performance identical to the status quo network using two fewer sites. We also show that if outbreak timing detection is of primary interest, it is actually possible to create a network that matches the existing network’s performance using 59% fewer sites. Conclusions By simulating the spread of influenza across the state of Iowa, we show that our methods are capable of designing networks that perform better than the status quo in terms of both outbreak intensity and timing. Additionally, our results suggest that network size may only play a minimal role in outbreak timing detection. Finally, we show that it may be possible to reduce the size of a surveillance system without affecting the quality of surveillance information produced.

Background Among patients with combined coronary artery and peripheral vascular disease, long-term benefits of surgical therapy compared with medical therapy for coronary artery disease are unknown. Methods and Results Using prospectively collected data from the Coronary Artery Surgery Study registry, we performed a retrospective cohort analysis of 1834 patients (mean age, 56 years; 20% women) with both coronary artery and peripheral vascular disease and evaluated their long-term outcomes. Of these patients, 986 received (nonrandomly) coronary artery bypass graft surgery, and 848 were treated medically. Perioperative mortality was 4.2% (2.9% in the absence of peripheral vascular disease; P =.02). In a mean follow-up period of 10.4 years, 1100 deaths occurred (80% due to cardiovascular causes). For the surgical group, 4-, 8-, 12-, and 16-year estimated probabilities of survival were 88%, 72%, 55%, and 41%, respectively, and 73%, 57%, 44%, and 34%, respectively, for the medical group ( P P =.0001; χ 2 =15.34). Subgroup analysis suggested that benefits of surgical treatment on survival were limited to patients with three-vessel coronary artery disease and were inversely related to ejection fraction. Survival free of death or myocardial infarction was also significantly better among the surgical group. Type of therapy was significantly associated with occurrence of late events ( P =.01; χ 2 =6.55). Subgroup analysis again demonstrated that beneficial effects of surgery were limited to patients with three-vessel coronary artery disease and were inversely related to ejection fraction. Conclusions Surgical treatment provides long-term benefit for certain subgroups of patients with combined coronary artery and peripheral arterial vascular disease.