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CONTEXT The Advisory Committee on Immunization Practices (ACIP) publishes annual recommendations for the prevention and control of seasonal influenza. Between 2011 and 2013, the ACIP recommended 2 approaches that providers could use to determine how many influenza vaccine doses children aged 6 months through 8 years should receive. One did not consider doses received prior to the 2010-2011 season; the other considered complete influenza immunization history, such as that available in immunization information system (IIS). OBJECTIVES To use Michigan's IIS, the Michigan Care Improvement Registry (MCIR), to compare the number of children recommended to receive 2 doses of influenza vaccine under each ACIP approach, and to determine the potential for overimmunization of Michigan children with influenza vaccine if providers do not use the data in MCIR. DESIGN Cross-sectional analysis in the 2011-2012 to 2013-2014 influenza seasons. SETTING We used the seasonal influenza and 2009 H1N1 monovalent vaccine doses in MCIR to determine the number of influenza vaccine doses children should receive using both ACIP approaches each season. PARTICIPANTS We analyzed data for more than 900 000 children aged 6 months through 8 years in each influenza season. MAIN OUTCOME MEASURE Number of children recommended 2 doses of influenza vaccine using each ACIP approach in each influenza season. RESULTS Our evaluation showed that using MCIR could prevent the overimmunization with a second influenza vaccine dose for 70 323 children during the 2011-2012 influenza season, 126 076 children during the 2012-2013 season, and 81 635 children during the 2013-2014 season. CONCLUSIONS This is the first study to use an IIS to quantify the difference between ACIP's approaches for 2-dose influenza vaccine recommendations. The immunization history and 2-dose forecasting algorithm available through MCIR minimizes overimmunization and has potential cost-saving implications. Our study illustrates the value of a centralized repository provided by IISs to immunization providers, public health, and caregivers.

The role of indulgences in pre-Reformation English religion remains incompletely studied. Centred on material contained in the Lincoln episcopal registers dating from c. 1290 to c. 1340, granting indulgences for prayers for the souls of named people and often specifying their burial locations, this article argues that their place in medieval spirituality and charitable activity has been under- appreciated. Examining the mechanisms and implications of the Lincoln records, it suggests that under-recording of actions considered normal and routine, rather than lack of popularity, lies behind the failure to give indulgences their due place in assessment of English medieval religious life.

L'A. veut etudier ici la liturgie dans son contexte social pour mieux comprendre la vie spirituelle et religieuse anglaise medievale. Ainsi, il considere evenements et experiences dans l'Angleterre de la fin du Moyen Age, a partir du XIVe siecle. Il propose des lignes d'approche, plutot que des analyses detaillees, considerant la repartition et la pratique de la liturgie textualisee ; l'existence d'une «culture liturgique» plus large ; les problemes de controle et d'amplification et celui du contexte.

Objective:To quantify the association of initial ED serum cardiac markers with the risk for life-threatening events (LEs) or need for lifesaving interventions (Lis) or administration of IV nitroglycerin. Methods: A prospective, observational study was performed using a cohort of hemodynamically stable, hospitalized patients (age > 25 years) presenting with nontraumatic chest discomfort. Patients with ST-segment elevation on their initial ECGs were excluded. Presenting serum samples were assayed for serum myoglobin and creatine kinase-MB isomer (CK-MB) using the Opus and Stratus systems. Target cases were defined as patients having LEs (e.g., cardiogenic shock, ventricular fibrillation, cardiac arrest), requiring Lis (e.g., intubation, cardioversion, pacing, reperfusion therapy), or needing IV nitroglycerin within 48 hours. Manufacturer's thresholds defined abnormal marker levels. Abnormal ECGs were defined using the Brush criteria. Results: Of the 178 eligible patients, 44 (25%) were target cases. Most (55%) target cases had blood drawn for assays within four hours of chest discomfort onset. The relative risk and sensitivity of the serum markers and the ECG for target cases follow: Of the seven patients with an LE/LI, six had blood drawn four hours or less after symptom onset; two LE/LI patients had abnormal myoglobin levels' no LE/LI patient had an abnormal CK-MB level. Conclusions: Isolated serum myoglobin and CK-MB levels obtained at patient ED presentation were not strongly associated with the 48-hour risk for LEs, Lis, or the use of IV nitroglycerin. Future studies of risk stratification should address the merits of serial serum marker measurements that extend up to 12 hours beyond patient symptom onset.

Objective: To demonstrate that creatine kinase-MB fraction (CK-MB) elevations within three hours of presentation in the emergency department (ED) are associated with subsequent ischemic events in clinically stable chest pain patients. Methods: Prospective cohort study at two university-affiliated teaching hospitals. Participants were consenting ED chest pain patients 25 years old or older without evidence of rhythm or hemodynamic instability (n = 449). Exclusions included ST-segment elevation ≥0.1 mV in ≥2 electrocardiogram leads, chest wall trauma, abnormal x-ray studies, and incomplete data collection. Measurements included presenting and three-hour CK-MB levels, presenting ECG, initial clinical impression of coronary care unit need, and clinical follow up. Monitored adverse events included myocardial ischemia necessitating coronary angioplasty or cardiac bypass surgery, recurrent in-hospital myocardial infarction, bradycardia requiring pacing, emergent cardioversion, cardiogenic shock, ventricular fibrillation, and death. Results: Overall, nine (2%) of 449 patients experienced an ischemic event within the first 48 hours. All nine patients required either coronary angioplasty or bypass surgery. Four (44%) of the nine patients with 48-hour ischemic events had elevated CK-MB levels. Of 23 patients who had complications within one week of ED presentation, seven (30%) had elevated ED CK-MB levels. An elevated CK-MB level was associated with an ischemic event both within 48 hours (risk ratio 9.5; 95% CI 2.7–33.7) and within one week (risk ratio 5.2; 95% CI 2.3–11.7). Conclusions: An elevated CK-MB level within three hours of ED presentation is associated with a subsequent ischemic event in the clinically stable chest pain patient without ST-segment elevation. However, the ED CK-MB identifies only a minority of otherwise low-risk patients who develop ischemic events; other markers for diagnosing myocardial ischemia in the ED are needed.

Postpollination nonrandom mating among compatible mates is a widespread phenomenon in plants and is genetically undefined. In this study, we used the recombinant inbred line (RIL) population between Landsberg erecta and Columbia (Col) accessions of Arabidopsis (Arabidopsis thaliana) to define the genetic architecture underlying both female- and male-mediated nonrandom mating traits. To map the genetic loci responsible for male-mediated nonrandom mating, we performed mixed pollinations with Col and RIL pollen on Col pistils. To map the genetic loci responsible for female-mediated nonrandom mating, we performed mixed pollinations with Col and Landsberg erecta pollen on RIL pistils. With these data, we performed composite interval mapping to identify two quantitative trait loci (QTLs) that control male-mediated nonrandom mating. We detected epistatic interactions between these two loci. We also explored female- and male-mediated traits involved in seed yield in mixed pollinations. We detected three female QTLs and one male QTL involved in directing seed number per fruit. To our knowledge, the results of these experiments represent the first time the female and male components of seed yield and nonrandom mating have been separately mapped.

Systematic optimisation of a poorly soluble lead series of isoxazole-3-carboxamides was conducted. Substitution of the 4-position with specific polar functionality afforded the requisite balance of potency, solubility and physicochemical properties. Compound 21a was found to be efficacious in the rat Capsaicin Hargreaves assay following oral administration.

Optimisation of a screening hit incorporating both TRPV1 activity and solubility was conducted. Substitution of the isoxazole-3-carboxamide with the bespoke 1S, 3R-3-aminocyclohexanol motif afforded the requisite balance of potency and solubility. Compounds 32 and 40 were found to have antihyperalgesic effects in the rat CFA Hg assay and induce a mechanism based hyperthermia.

The discovery, synthesis and preliminary structure-activity relationships (SARs) of a novel class of CB1 antagonists is described. Initial optimization of benzimidazole-based screening hit 4 led to the identification of 'inverted' indole-based lead compound 18c with improved properties versus compound 4 including reduced AlogP, improved microsomal stability and improved aqueous solubility. Compound 18c demonstrates in vivo CB1 antagonist efficacy (CB1 agonist induced hypothermia model) and is orally bioavailable in rat.

G protein-coupled receptors represent one of the largest families of drug targets. Time and cost may be saved if GPCR modulators are assessed in terms of signaling pathway selectivity, species selectivity, and selectivity against closely-related family members early in the drug discovery process, perhaps even at the stage of high-throughput screening. Examples are given of how these kinds of selectivity have been addressed during screening.

It may be debated how far the liturgy of the medieval Church (in particular the Mass) can be considered as ‘drama’, but its theatrical impact and organization are undeniable. Staged within a distinct space, the principal act of the Church’s worship had its own text and directions, which through contemplation and allegory summarized Christ’s terrestrial experiences and various aspects of the Christian faith. The Mass and other liturgical celebrations were events to be visualized, both externally and internally. It has been said of medieval plays that their fundamentally visual nature… so apparent to [a] medieval audience, often escapes the attention of modern scholars. The lines drawn between disciplines hinder easy access to methods that would enable readers to pass from a text to a visual reconstruction of it. Nonetheless the readers of dramatic texts need to visualize stage properties, costumes, and sets, and, when appropriate, to see beyond their literal meaning to their symbolic import. Further, readers must see gesture, placement, and interrelationship of actors, and understand how these visual elements contribute to the content.

We isolated lap3-1 and lap3-2 mutants in a screen for pollen that displays abnormal stigma binding. Unlike wild-type pollen, lap3-1 and lap3-2 pollen exine is thinner, weaker, and is missing some connections between their roof-like tectum structures. We describe the mapping and identification of LAP3 as a novel gene that contains a repetitive motif found in b-propeller enzymes. Insertion mutations in LAP3 lead to male sterility. To investigate possible roles for LAP3 in pollen development, we assayed the metabolite profile of anther tissues containing devel- oping pollen grains and found that the lap3-2 defect leads to a broad range of metabolic changes. The largest changes were seen in levels of a straight-chain hydrocarbon non- acosane and in naringenin chalcone, an obligate compound in the flavonoid biosynthesis pathway.

Study objective: To analyze the effect of creatine kinase isoenzyme (CKMB) results on decision making in the evaluation of emergency department patients with chest pain. Design: Prospective, controlled observational study of clinical decision making. Setting: EDs of two teaching hospitals, a Veterans Affairs medical center, and a medical school university hospital. Type of participants: Patients more than 30 years old complaining of chest discomfort warranting an ECG. Excluded were hemodynamically unstable patients and patients with ECG evidence of an acute myocardial infarction (AMI). Interventions: After the initial assessment including ECG but not CKMB data, physicians answered questions regarding estimated probability of AMI and disposition plans. CK-MB levels were drawn every hour for as long as three hours (from one to four CK-MBs) with results readily available. Physicians could admit their patients into the hospital at any time. At disposition after reviewing a second ECG and all available CK-MB data, the physicians answered the same questions and rank ordered the contribution to disposition of the following six factors: initial and serial clinical evaluations, initial and serial ECGs, and initial and serial CK-MB enzymes, respectively. The absolute log likelihood ratio test measured the contribution of CK-MB to decision certainty. Measurements and main results: Three hundred seventy-six patients were studied: 29 (7.7%) with AMI and 347 without AMI (nonAMI). Physicians indicated that CK-MB levels were useful for more than one third of study patients. When considered useful, CK-MB results strengthened the impression of AMI in AMI patients and decreased the impression of AMI for nonAMI patients; CK-MB also correlated with the perceived need for cardiac care unit admission in AMI patients and with a reduced need to admit nonAMI patients. The use of CK-MB results did not significantly increase ED release rates. Conclusion: The rapid availability of serial CK-MB results appears to affect decision making in one third of ED patients with chest pain and nondiagnostic ECGs. CK-MB levels appear to complement clinical evaluation of the ED chest pain patient in a manner analogous to the ECG.

Background Callose (β-1,3 glucan) separates developing pollen grains, preventing their underlying walls (exine) from fusing. The pollen tubes that transport sperm to female gametes also contain callose, both in their walls as well as in the plugs that segment growing tubes. Mutations in CalS5, one of several Arabidopsis β-1,3 glucan synthases, were previously shown to disrupt callose formation around developing microspores, causing aberrations in exine patterning, degeneration of developing microspores, and pollen sterility. Results Here, we describe three additional cals5 alleles that similarly alter exine patterns, but instead produce fertile pollen. Moreover, one of these alleles (cals5-3) resulted in the formation of pollen tubes that lacked callose walls and plugs. In self-pollinated plants, these tubes led to successful fertilization, but they were at a slight disadvantage when competing with wild type. Conclusion Contrary to a previous report, these results demonstrate that a structured exine layer is not required for pollen development, viability or fertility. In addition, despite the presence of callose-enriched walls and callose plugs in pollen tubes, the results presented here indicate that callose is not required for pollen tube functions.

This project examined which child health data would be appropriate and useful to integrate with an existing real-time Michigan Department of Community Health (MDCH) application, such as the Michigan Childhood Immunization Registry. A consultant was secured to conduct data gathering analysis activities. An advisory committee of MDCH Administrators convened to guide the project. Interviews were conducted with MDCH administrators, program managers and representatives from the public and private health care provider community. These interviews focused on answering three main questions: (1) What MDCH data resources do you currently use? (2) How do you use and access these data? and (3) What is your vision for expanding, enhancing, and linking these data to meet Michigan's future health goals? Acceptance of the Michigan Childhood Immunization Registry by the pediatric and family practice community demonstrates the utility of providing more information electronically to the medical community in Michigan. The MDCH has completed a stakeholders analysis and is moving forward with requirements gathering sessions in order to create an integrated child health data system. The integrated child health data system will include data from immunizations, newborn screening, newborn hearing, lead, the Women, Infants, and Children program, and Medicaid.

▪ Abstract For pollination to succeed, pollen must carry sperm through a variety of different floral tissues to access the ovules within the pistil. The pistil provides everything the pollen requires for success in this endeavor including distinct guidance cues and essential nutrients that allow the pollen tube to traverse enormous distances along a complex path to the unfertilized ovule. Although the pistil is a great facilitator of pollen function, it can also be viewed as an elaborate barrier that shields ovules from access from inappropriate pollen, such as pollen from other species. Each discrete step taken by pollen tubes en route to the ovules is a potential barrier point to ovule access and waste by inappropriate mates. In this review, we survey the current molecular understanding of how pollination proceeds, and ask to what extent is each step important for mate discrimination. As this field progresses, this synthesis of functional biology and evolutionary studies will provide insight into the molecular basis of the species barriers that maintain the enormous diversity seen in flowering plants.

An investigation into the structure–activity relationship of a lead compound, prolyl-5-aminopentanoic acid 4 , led to the identification of a novel series of 4-piperidinylacetic acid, 1-piperazinylacetic acid, and 4-aminobenzoic acid derivatives as potent VLA-4 antagonists with low nanomolar IC 50 values. A representative compound morpholinyl-4-piperidinylacetic acid derivative ( 13d : IC 50 = 4.4 nM) showed efficacy in the Ascaris -antigen sensitized murine airway inflammation model by oral administration.

A screen of a GPCR against Pharmacopeia's combinatorial libraries was performed using 1,536-well plates in a 1.5-microl assay volume with an LSI that was specially modified to enable detection at these volumes. The screen encompassed approximately 4 x 10(6) compounds. The assay uses a CHO cell line that expresses human CXCR1. The plate format chosen was the Corning 1536 low-profile wafer plate. The performance of the screen is evaluated, and the necessity to obtain cytotoxicity data from the same well is described.

The ornate surfaces of male and female reproductive cells in flowering plants have long attracted attention for their variety and evolutionary significance. These structures, and the molecules involved in sexual interactions, remain among the most rapidly evolving and diverse characteristics known.