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Source Citation: Lambrakis K, Papendick C, French JK, et al. Late outcomes of the RAPID-TnT randomized controlled trial: 0/1-hour high-sensitivity troponin T protocol in suspected ACS. Circulation. 2021;144:113-25. 33998255.

We present the case of a 20-year-old man with a background of transposition of the great arteries presenting with fever of unknown origin, who developed a shock like syndrome with respiratory failure necessitating intubation. After extensive investigation, a diagnosis of adult-onset Kawasaki disease was made, and he was successfully treated with IVIg and corticosteroids. We present the clinical findings clinicians should be aware of, and review the literature on managing this rare presentation in adult, highlighting the importance of early diagnosis in improving outcomes. Both children and adults with Kawasaki disease require long-term follow-up, as they remain at increased risk of both coronary artery aneurysms and early acute coronary syndrome., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

In the 12,000 years preceding the Industrial Revolution, human activities led to significant changes in land cover, plant and animal distributions, surface hydrology, and biochemical cycles. Earth system models suggest that this anthropogenic land cover change influenced regional and global climate. However, the representation of past land use in earth system models is currently oversimplified. As a result, there are large uncertainties in the current understanding of the past and current state of the earth system. In order to improve representation of the variety and scale of impacts that past land use had on the earth system, a global effort is underway to aggregate and synthesize archaeological and historical evidence of land use systems. Here we present a simple, hierarchical classification of land use systems designed to be used with archaeological and historical data at a global scale and a schema of codes that identify land use practices common to a range of systems, both implemented in a geospatial database. The classification scheme and database resulted from an extensive process of consultation with researchers worldwide. Our scheme is designed to deliver consistent, empirically robust data for the improvement of land use models, while simultaneously allowing for a comparative, detailed mapping of land use relevant to the needs of historical scholars. To illustrate the benefits of the classification scheme and methods for mapping historical land use, we apply it to Mesopotamia and Arabia at 6 kya (c. 4000 BCE). The scheme will be used to describe land use by the Past Global Changes (PAGES) LandCover6k working group, an international project comprised of archaeologists, historians, geographers, paleoecologists, and modelers. Beyond this, the scheme has a wide utility for creating a common language between research and policy communities, linking archaeologists with climate modelers, biodiversity conservation workers and initiatives., Competing Interests: The authors have declared that no competing interests exist.

Introduction: The coronavirus disease of 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 is a global pandemic that expresses itself with a wide variety of presenting symptoms in patients. There is a paucity of literature describing the dermatologic manifestations of the virus, particularly in the United States., Case Report: Here we present a case of COVID-19 that manifested with a purpuric rash on the lower extremities and a maculopapular eruption on the abdomen in a patient in acute diabetic ketoacidosis and normal platelet count., Discussion: The reported presenting symptoms of patients with COVID-19 vary greatly. This is the first documented case of COVID-19 presenting with mixed cutaneous manifestations of a purpuric as well as maculopapular rash., Conclusion: The cutaneous lesions associated with the COVID-19 infection may mimic or appear similar to other well-known conditions. We illustrate a case of COVID-19 infection presenting with purpuric rash on the lower extremities and a maculopapular rash on the abdomen.

Background and Objectives: Residents as teachers (RAT) and medical students as teachers (MSAT) programs are important for the development of future physicians. In 2010, Northwestern University Feinberg School of Medicine (NUFSM) aligned RAT and MSAT programs, which created experiential learning opportunities in teaching and feedback across the graduate and undergraduate medical education continuum. The purpose of this study was to provide a curricular overview of the aligned program and to evaluate early outcomes through analysis of narrative feedback quality and participant satisfaction., Methods: Program evaluation occurred through analysis of written feedback quality provided within the aligned program and postparticipation satisfaction surveys. A total of 445 resident feedback narratives were collected from 2013 to 2016. We developed a quality coding scheme using an operational definition of feedback. After independent coding of feedback quality, an expert panel established coding consensus. We evaluated program satisfaction and perceived importance through posttraining surveys in residents and fourth-year medical students (M4s)., Results: Seventy-nine residents participated in the aligned program and provided high-quality feedback with a relative quality rating of 2.71 (scale 0-3). Consistently high-quality written feedback was provided over the duration of the program and regardless of years of resident participation. Posttraining surveys demonstrated high levels of satisfaction and perceived importance of the program to both residents and M4s., Conclusions: The aligned RAT and MSAT program across the medical education continuum provided experiential learning opportunities for future physician educators with evidence of high-quality written feedback to learners and program satisfaction.

Background: The accountability for reasonableness (A4R) framework defines 4 conditions for legitimate healthcare coverage decision processes: Relevance, Publicity, Appeals, and Enforcement. The aim of this study was to reflect on how the diverse features of decision-making processes can be aligned with A4R conditions to guide decision-making towards legitimacy. Rare disease and regenerative therapies (RDRTs) pose special decision-making challenges and offer therefore a useful case study., Methods: Features operationalizing each A4R condition as well as three different approaches to address these features (cost-per-QALY-focused and multicriteria-based) were defined and organized into a matrix. Seven experts explored these features during a panel run under the Chatham House Rule and provided general and RDRT-specific recommendations. Responses were analyzed to identify converging and diverging recommendations., Results: Regarding Relevance, recommendations included supporting deliberation, stakeholder participation and grounding coverage decision criteria in normative and societal objectives. Thirteen of 17 proposed decision criteria were recommended by a majority of panelists. The usefulness of universal cost-effectiveness thresholds to inform allocative efficiency was challenged, particularly in the RDRT context. RDRTs raise specific issues that need to be considered; however, rarity should be viewed in relation to other aspects, such as disease severity and budget impact. Regarding Publicity, panelists recommended transparency about the values underlying a decision and value judgements used in selecting evidence. For Appeals, recommendations included a life-cycle approach with clear provisions for re-evaluations. For Enforcement, external quality reviews of decisions were recommended., Conclusion: Moving coverage decision-making processes towards enhanced legitimacy in general and in the RDRT context involves designing and refining approaches to support participation and deliberation, enhancing transparency, and allowing explicit consideration of multiple decision criteria that reflect normative and societal objectives., (© 2019 The Author(s); Published by Kerman University of Medical Sciences. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.)

Background/aims: Few studies have modeled individual Neuropsychiatric Inventory (NPI) symptom scores for Alzheimer disease (AD) patients and assessed the value of therapeutic interventions that can potentially impact them. The main objective of this study was to evaluate the impact of new AD symptomatic treatments on relevant health economic outcomes via their potential effects on cognition and neuropsychiatric symptoms such as depression, irritability, anxiety, and sleep disorder., Methods: We enhanced the previously published AHEAD model (Assessment of Health Economics in Alzheimer's Disease) by including new variables and functional relations to capture the NPI's individual neuropsychiatric symptoms in addition to the total NPI score. This update allowed us to study the longitudinal effect of improvements in specific NPI subscale scores and the downstream impact on outcomes such as psychiatric medication use, survival, and institutional placement., Results: The model base-case results showed that a hypothetical treatment with symptomatic effects on anxiety, depression, and irritability NPI subscales was not cost-effective; however, the treatment's cost-effectiveness was improved once a direct link between NPI subscales and mortality was explored or under relatively stronger treatment effects., Conclusion: Treatments that influence specific symptoms within the overall NPI have the potential to improve patient outcomes in a cost-effective way. This model is a useful tool for evaluating target product profiles of drugs with effect on NPI symptoms in early stages of development.

Do human societies from around the world exhibit similarities in the way that they are structured, and show commonalities in the ways that they have evolved? These are long-standing questions that have proven difficult to answer. To test between competing hypotheses, we constructed a massive repository of historical and archaeological information known as "Seshat: Global History Databank." We systematically coded data on 414 societies from 30 regions around the world spanning the last 10,000 years. We were able to capture information on 51 variables reflecting nine characteristics of human societies, such as social scale, economy, features of governance, and information systems. Our analyses revealed that these different characteristics show strong relationships with each other and that a single principal component captures around three-quarters of the observed variation. Furthermore, we found that different characteristics of social complexity are highly predictable across different world regions. These results suggest that key aspects of social organization are functionally related and do indeed coevolve in predictable ways. Our findings highlight the power of the sciences and humanities working together to rigorously test hypotheses about general rules that may have shaped human history., Competing Interests: The authors declare no conflict of interest., (Copyright © 2018 the Author(s). Published by PNAS.)

The nature and timing of rice domestication and the development of rice cultivation in South Asia is much debated. In northern South Asia there is presently a significant gap ( c .4200 years) between earliest evidence for the exploitation of wild rice (Lahuradewa c .6000 BCE) and earliest dated evidence for the utilisation of fully domesticated rice (Mahagara c .1800 BCE). The Indus Civilisation ( c. 3000-1500 BCE) developed and declined during the intervening period, and there has been debate about whether rice was adopted and exploited by Indus populations during this 'gap'. This paper presents new analysis of spikelet bases and weeds collected from three Indus Civilisation settlements in north-west India, which provide insight into the way that rice was exploited. This analysis suggests that starting in the period before the Indus urban phase (Early Harappan) and continuing through the urban (Mature Harappan/Harappan), post-urban (Late Harappan) and on into the post-Indus Painted Grey Ware (PGW) period, there was a progressive increase in the proportion of domesticated-type spikelet bases and a decrease in wild-types. This pattern fits with a model of the slow development of rice exploitation from wild foraging to agriculture involving full cultivation. Importantly, the accompanying weeds show no increased proportions of wetland species during this period. Instead a mix of wetland and dryland species was identified, and although these data are preliminary, they suggest that the development of an independent rice tradition may have been intertwined with the practices of the eastern most Indus peoples. These data also suggest that when fully domesticated Oryza sativa ssp. japonica was introduced around 2000 BCE, it arrived in an area that was already familiar with domesticated rice cultivation and a range of cultivation techniques., (© 2016 The Authors.)

The transition period for new junior doctors is a daunting and challenging time, as vast amounts of information specific to each hospital, ward, and job must be learnt while maintaining patient care standards.[1] In NHS Tayside, Scotland, tips and guidance for each job are informally handed over from previous junior doctors to the next, resulting in an unreliable and unsustainable handover of information. Time must then be spent by new doctors learning the intricacies and practicalities of their new job, rather than spending time focusing on patient care. Our aim was to improve this transition period for new junior doctors to NHS Tayside through the creation and implementation of a junior doctors' handbook, which would provide information and practical advice on day to day life as a junior doctor. We hoped to implement this project by August 2015 to coincide with the arrival of these new doctors to NHS Tayside. Through repeat PDSA cycles we created a sustainable and reliable junior doctors' handbook, containing a centralised hub of information for doctors that was accessible through our health board's website. The junior doctors' handbook has been a highly beneficial resource that has been praised for its detailed information on all aspects of day to day life for doctors in NHS Tayside. Feedback also demonstrated that doctors felt the junior doctors' handbook had improved their efficiency. Our hope is that this project can continue to be developed within our hospital, but also to be used as an idea outside our health board to improve the transition period for new doctors on a wider scale.

Background: HIV-1 is a lifelong disease, often without serious symptoms for years after infection, and thus many infected persons go undetected for a long time. This makes it difficult to track incidence, and thus epidemics may go through dramatic changes largely unnoticed, only to be detected years later. Because direct measurement of incidence is expensive and difficult, several biomarker-based tests and algorithms have been developed to distinguish between recent and long-term infections. However, current methods have been criticized and demands for novel methods have been raised., Methods: We developed and applied a biomarker-based incidence model, joining a time-continuous model of immunoglobulin G (IgG) growth (measured by the IgG-capture BED-enzyme immunoassay) with statistical corrections for both sample size and unobserved diagnoses. Our method uses measurements of IgG concentration in newly diagnosed people to calculate the posterior distribution of infection times. Time from infection to diagnosis is modelled for all individuals in a given period and is used to calculate a sample weight to correct for undiagnosed individuals. We then used a bootstrapping method to reconstruct point estimates and credible intervals of the incidence of HIV-1 in Sweden based on a sample of newly diagnosed people., Results: We found evidence for: (i) a slowly but steadily increasing trend in both the incidence and incidence rate in Sweden; and (ii) an increasing but well-controlled epidemic in gay men in Stockholm. Sensitivity analyses showed that our method was robust to realistic levels (up to 15%) of BED misclassification of non-recently infected persons as early infections., Conclusions: We developed a novel incidence estimator based on previously published theoretical work that has the potential to provide rapid, up-to-date estimates of HIV-1 incidence in populations where BED test data are available., (Published by Oxford University Press on behalf of the International Epidemiological Association 2015. This work is written by US Government employees and is in the public domain in the US.)

Background: Troponin testing in acute medicine is routine. The introduction of a high sensitivity assay (hs Tn T) has created uncertainty regarding the clinical significance of 'abnormal' troponin T levels. The previous assay could not detect troponin levels <30 ng/l., Aims and Methods: To characterize those with a hs Tn T ≥14 ng/l. Prospective cohort study of consecutive admissions to an acute medical unit., Results: Troponin was measured in 564 consecutive patients (∼50% of all admissions) over 1 month; was ≥14 ng/l in 224 (40%) of which 220 patients had demographic data for this analysis. Median (inter-quartile range) peak troponin was 47.5 ng/l (24-130) and 36% had a Tn T between 14 and 30 ng/l. Mean [standard deviation (SD)] age was 72 (12) years and 57% were male. Only 44 patients (20%) had an acute myocardial infarction, reflecting the increased sensitivity but reduced specificity of the assay. Prognosis was poor with 31% mortality at 1 year. Over a mean (SD) follow-up of 648 (61) days, there were 87 deaths (40%). Those with a primary non-cardiac diagnosis (n = 126) had poorer survival than those with a primary cardiac diagnosis (n = 94). Troponin elevation related to sepsis conferred a very poor prognosis with 24 deaths (70%) over the follow-up period., Conclusion: Elevated hs Tn T is very common in acute medicine, but myocardial infarction as an explanation is uncommon. Overall, the prognosis is poor with a tendency to worse outcomes in those with a primary 'non-cardiac' diagnosis.

Here we confirm that intranasal (IN) dry powder anthrax vaccine formulations are able to protect rabbits against aerosol challenge 9 weeks after a single immunization. The optimum dose of rPA in our dry powder anthrax vaccine formulation in rabbits was experimentally determined to be 150microg and therefore was chosen as the target dose for all subsequent experiments. Rabbits received a single dose of either 150microg rPA, 150microg rPA+150microg of a conjugated 10-mer peptide representing the Bacillus anthracis capsule (conj), or 150microg of conj alone. All dry powder formulations contained MPL and chitosan (ChiSys). Significant anti-rPA titers and anthrax lethal toxin neutralizing antibody (TNA) levels were seen with both rPA containing vaccines, although rPA-specific IgG and TNA levels were reduced in rabbits immunized with rPA plus conj. Nine weeks after immunization, rabbits were exposed to a mean aerosol challenge dose of 278 LD50 of Ames spores. Groups immunized with rPA or with rPA+conj had significant increases in survivor proportions compared to the negative control group by Logrank test (p=0.0001 and 0.003, respectively), and survival was not statistically different for the rPA and rPA+conj immunized groups (p=0.63). These data demonstrate that a single immunization with our dry powder anthrax vaccine can protect against a lethal aerosol spore challenge 9 weeks later.

The rational design of biomimetic structures for the regeneration of damaged or missing tissue is a fundamental principle of tissue engineering. Multiple variables must be optimized, ranging from the scaffold type to the selection and properties of implanted cell(s). In this study, the osteogenic potential of a novel stem cell was analyzed on biodegradable poly(lactic-co-glycolic acid) (PLGA) biomaterials as a step toward creating new cell-materials constructs for bony regeneration. Dura mater stem cells (DSCs), isolated from rat dura mater, were evaluated and compared to bone marrow stem cells (BMSCs) for proliferative and differentiative properties in vitro. Experiments were carried out on both tissue culture plastic (TCP) and 2D planar films of PLGA. Proliferation of DSCs on both TCP and PLGA films increased over 21 days. Positive fold inductions in all five bone marker genes were observed at days 7, 14, 21 in all experimental samples compared with day 0 controls. DSCs demonstrated greater cell coverage and enhanced matrix staining on 2D PLGA films when compared with BMSCs. These cells can be isolated and expanded in culture and can subsequently attach, proliferate, and differentiate on both TCP and PLGA films to a greater extent than BMSCs. This suggests that DSCs are promising for cell-based bone tissue engineering therapies, particularly those applications involving regeneration of cranial bones., (Copyright 2007 Wiley Periodicals, Inc.)

Myanmar is experiencing an HIV epidemic documented since the late 1980s. The National AIDS Programme national surveillance ante-natal clinics had already estimated in 1993 that 1.4% of pregnant women were HIV positive, and UNAIDS estimates that at end 2005 1.3% (range 0.7-2.0%) of the adult population was living with HIV. While a HIV surveillance system has been in place since 1992, the programmatic response to the epidemic has been slower to emerge although short- and medium-terms plans have been formulated since 1990. These early plans focused on the health sector, omitted key population groups at risk of HIV transmission and have not been adequately funded. The public health system more generally is severely under-funded.By the beginning of the new decade, a number of organisations had begun working on HIV and AIDS, though not yet in a formally coordinated manner. The Joint Programme on AIDS in Myanmar 2003-2005 was an attempt to deliver HIV services through a planned and agreed strategic framework. Donors established the Fund for HIV/AIDS in Myanmar (FHAM), providing a pooled mechanism for funding and significantly increasing the resources available in Myanmar. By 2006 substantial advances had been made in terms of scope and diversity of service delivery, including outreach to most at risk populations to HIV. More organisations provided more services to an increased number of people. Services ranged from the provision of HIV prevention messages via mass media and through peers from high-risk groups, to the provision of care, treatment and support for people living with HIV. However, the data also show that this scaling up has not been sufficient to reach the vast majority of people in need of HIV and AIDS services.The operating environment constrains activities, but does not, in general, prohibit them. The slow rate of service expansion can be attributed to the burdens imposed by administrative measures, broader constraints on research, debate and organizing, and insufficient resources. Nevertheless, evidence of recent years illustrates that increased investment leads to more services provided to people in need, helping them to obtain their right to health care. But service expansion, policy improvement and capacity building cannot occur without more resources.

Gammadelta T cells are innate immune cells that participate in host responses against many pathogens and cancers. Recently, phosphoantigen-based drugs, capable of expanding gammadelta T cells in vivo, entered clinical trials with the goal of enhancing innate immune system functions. Potential shortcomings of these drugs include the induction of nonresponsiveness upon repeated use and the expansion of only the Vdelta2 subset of human gammadelta T cells. Vdelta1 T cells, the major tissue subset, are unaffected by phosphoantigen agonists. Using FACS-based assays, we screened primary bovine cells for novel gammadelta T cell agonists with activities not encompassed by the current treatments in an effort to realize the full therapeutic potential of gammadelta T cells. We identified gammadelta T cell agonists derived from the condensed tannin fractions of Uncaria tomentosa (Cat's Claw) and Malus domestica (apple). Based on superior potency, the apple extract was selected for detailed analyses on human cells. The apple extract was a potent agonist for both human Vdelta1 and Vdelta2 T cells and NK cells. Additionally, the extract greatly enhanced phosphoantigen-induced gammadelta T cell expansion. Our analyses suggest that a tannin-based drug may complement the phosphoantigen-based drugs, thereby enhancing the therapeutic potential of gammadelta T cells.

Purpose: The objectives of this investigation were to evaluate the effect of disinfection on surface quality and dimensional stability of more recent, reformulated vinylpolysiloxane (VPS) and polyether (PE) materials., Methods: Using ANSI/American Dental Association (ADA) specification 19 protocols, 50 impressions of stainless steel dies were made with each material. Ten impressions of each material were randomly assigned to a treatment group: (1) no disinfectant; (2) 10-minute dual phenol immersion; (3) 1-hour dual phenol; (4) 10-minute sodium hypochlorite (NaOCl); and (5) 1-hour NaOCl. Impression surface quality immediately after disinfection was categorized as smooth/shiny, matte, or wrinkled/sticky. Dimensional stability was evaluated by measuring dimensional accuracy according to specification 19 after 24-hour, 1-week, and 2-week storage at ambient laboratory conditions., Results: The PE material surface quality was significantly affected (Pearson Chi-square, p

An intranasal vaccine targeting the Bacillus anthracis toxin and vegetative bacterium was tested for the ability to protect immunized rabbits against aerosol B. anthracis spore exposure. Rabbits were vaccinated intranasally with PA-based vaccines formulated as dry powders with or without chitosan (ChiSys, Archimedes Development Limited), a compound that exhibits muco-adhesive properties, or as a liquid. Formulations also contained MPL adjuvant and PA. Some vaccines contained PA conjugated to a 10-mer peptide of the poly-d-glutamic acid capsule of B. anthracis. Rabbits were immunized on days 0 and 28 and aerosol challenged with an average 250LD50 Ames spores on day 85. Serum antibody was measured before and after challenge. Significant anti-PA serum IgG levels were obtained, particularly with use of ChiSys based formulations. PA-Conj induced significant anti-capsule responses, although a formulation containing free capsule peptide did not. All immunized rabbits survived the challenge, but differences in morbidity, as evidenced by anorexia, between vaccine groups were observed. Only rabbits immunized with PA+PA-Conj appeared normal throughout the post-challenge observation period (14 days), while all that received PA with the free capsule peptide appeared ill at times as evidenced by a failure to eat normally. One negative control rabbit received a lower inhaled spore dose (183LD50) and survived the challenge, although it was anorexic post-challenge. It also had a high level of anti-LF antibodies in its convalescent serum (5400 U/ml), indicating an extensive infection. In contrast, 75% of the immunized rabbits had no LF-specific antibody in their post-challenge sera, and the rest had low levels (< or = 138 U/ml), indicating that infections resulting in toxin production were avoided or greatly reduced. Thus, intranasal immunization with a chitosan-based powder vaccine combining PA and capsule epitopes provided superior protection against B. anthracis infection compared to a single antigen (PA) vaccine, as evidenced by a reduction in morbidity and prevention of death.

Purpose: The most frequent cause of clinical failure of resin-bonded fixed partial dentures is a debonding at the metal-cement interface. The purpose of this in vitro study was to compare the tensile bond strengths of 3 different alloy-surface treatments when cemented to human enamel with a resin cement., Materials and Methods: Cylinders of a nickel-chromium-beryllium (Ni-Cr-Be) and a gold-palladium (Au-Pd) alloy were fabricated and assigned to different surface treatment groups as follows: Group 1: Ni-Cr-Be, chemically etched; Group 2: Au-Pd, airborne particle-abraded and tin-plated; and Group 3: Au-Pd, airborne particle-abraded and treated with the Alloy Primer (Kuraray Co, LTD, Osaka, Japan). The cylinders were bonded to the enamel surfaces of extracted, human third molars and stored in normal saline at 37 degrees C for 48 hours. The tensile bond strength of 21 specimens from each group was measured on a Universal Testing Machine (Instron, Canton, MA). Three failed specimens of each group were evaluated using scanning electron microscopy and energy dispersive spectroscopy., Results: Statistically significant differences (p <.05) were found between all 3 treatment groups. The mean tensile bond strengths (+/- the standard error of mean) recorded as follows: Group 1: 10.6 MPa (+/-1.3), Group 2: 0.9 MPa (+/-0.2), and Group 3: 13.4 MPa (+/-1.0). Specimens from groups 1 and 3 revealed a trend towards mixture of cohesive, within the resin cement, and adhesive failures at the metal-cement interface. Group 2 specimens exhibited primarily adhesive failures at the metal-cement interface., Conclusions: The tensile bond strength of Au-Pd alloy specimens was significantly increased with the Alloy Primer., (Copyright 2001 by The American College of Prosthodontists.)

A total of 1282 inguinal hernia repairs were performed between September 1989 and June 1994 using polypropylene mesh inserted in the preperitoneal space to reinforce a two-layer transversalis fascia technique. There was a recurrence rate of 0.4 per cent with a minimal follow-up of 14 months. All the operations were performed as outpatient surgery, under local anesthesia or general anesthesia, with immediate ambulating home and early return to normal activities and work. Complications were minimal, with no mortality.

The purpose of this study was to examine the interactive effects of alcohol and salience of social cues (personality traits) on allocation of attention in the intoxicated male social drinker. It was expected that inebriated subjects would preferentially attend to high threat relative to low threat information contingent on the information's personal relevance. Seventy-six participants received either alcohol or a placebo, or were in a control condition, and were given the opportunity to attend to personally salient or nonsalient positive, negative, and neutral information. Intoxicated participants viewed negative traits longer than did nonintoxicated subjects and attended to these traits longer in the salient than in the nonsalient condition. Findings are compared to the attention allocation model, and their implications for alcohol-mediated cognitive processes are discussed.

This is a retrospective case control study of the relationship between work pace of selectors at a food distribution center and the subsequent incidence of compensable back injuries. Subject employment records for 1 month were evaluated for degree of variation of actual-from-scheduled performance of weekly work pace as selectors, defined in terms of absolute values (either above or below criterion). Subjects were divided among those with no compensable claims for back injury (n=14) and those with multiple compensable claims (n=12) over a 2-year period of employment. Other dependent measures included percentage of tasks that each group completed by or before the scheduled criterion and the percentage of time working that employees engaged in selector activities. The groups differed in age, averaging 38 vs. 31 years for the no claims and multiple claims groups, respectively. The groups did not differ in terms of educational background or length of service at the food distribution center. The major finding was that there was a group difference in the actual-from-scheduled, absolute mean performance values. As expected, the multiple claims group had significantly more variability in their work pace than the no claims group. The no claims group also worked significantly more often at or faster than criterion and spent, on average, a higher percentage of their day performing selector duties. These preliminary results suggest an association between work patterns and occupational injury that warrant further research, such as a clinical trial manipulating the scheduled work criterion.

A new controlled-pore glass (CPG) support is described that allows for the direct synthesis of oligonucleotides bearing a 3'-aminohexyl tail. This solid support (AH-CPG) exhibits superior performance as compared to a commercially available 3'-amine CPG. The AH-CPG is prepared from 6-aminohexan-1-ol with a unique protecting group for the amine that also functions as the site of attachment to the CPG. A 3'-amine-tailed oligodeoxynucleotide (ODN) was prepared from this support using standard phosphoramidite coupling and deprotection conditions. The 3'-amine-tailed ODN was subsequently modified with an acridinylpropionic acid tetrafluorophenyl ester. Facile synthesis of the AH-CPG and the stability of the deprotected product makes this functionalized solid support especially useful for preparation of oligonucleotides bearing 3'-amine tails and other modifications.

A novel dATP analogue, 3-[5-[(N-biotinyl-6- amiocaproyl)amino]pentyl]-1-(2-deoxy-beta-D-erythro-pentofuranosyl )-1H-pyrazolo[3,4-d]pyrimidin-4-amine 5'-triphosphate (9, bio-13-dAPPTP), which is modified at the 3-position with a flexible linker arm bearing a terminal biotin moiety, has been synthesized. This nucleotide is readily incorporated into DNA probes by nick translation. These probes hybridize to complementary targets as well as probes labeled with bio-dUTP, as judged by slot blot. When incorporated into oligonucleotides, they do not cause the loss of hybridization efficiency that an N-6-substituted adenine nucleotide does when incorporated into the same sites in the oligonucleotide.

A pentadecanucleotide was prepared from 1-alpha-arabinofuranosylthymine. This novel oligonucleotide was found to hybridize to oligodeoxyadenylate, although not a s strongly as pentadecathymidylate. It formed duplex hybrids with both DNA and RNA complements, and triplex structures with a duplex containing a (dT)15-(dA)15 tract within a more complex strand. The Tm of the duplex with polyadenylate was almost the same as that of (dT)15 and polyadenylate, while its Tm with (dA)15 was substantially lower than that of the natural counterpart. A selective benzoylation of the 2'-O of a 5'-blocked alpha-ara-thymine was developed to greatly simplify the preparation of suitable blocked material for use in preparation of oligonucleotides on the automated DNA synthesizer.

A procedure for immobilization of well-defined quantities of oligodeoxyribonucleotides (ODNs) to a versatile nylon support is described. The solid support, a nylon-6/6 bead, is covalently coated with poly(ethyleneimine) to provide a reactive spacer-arm for attachment of ODNs. 5'-Aminohexyl-tailed ODNs are selectively activated using 2,4,6-trichloro-1,3,5-triazine (cyanuric chloride) and then covalently attached to the bead via the triazine moiety. The modified nylon support has a low level of binding of nonspecific nucleic acid and efficiently captures both RNA and DNA targets.

In L1210 leukemia cells, 6-deoxy-6-fluoro-D-galactose specifically inhibited the incorporation of [3H]-D-galactose, while that of other precursors of glycoconjugate biosynthesis, including mannose and glucosamine, was unaffected. The activation of [6-3H]-6-deoxy-6-fluoro-D-galactose to a nucleotide sugar was similar to that found for [3H]-D-galactose. The incorporation of either sugar after 1 hr was visualized by electron microscopic autoradiography to be in the Golgi region. Treatment of L1210 cells with 6-deoxy-6-fluoro-D-galactose in vitro or in vivo resulted in a specific, dose- and time-dependent decrease in the activity of cell surface sialyltransferase (ectosialyltransferase) but not of 5'-nucleotidase, a plasma membrane marker enzyme. The decrease in ectosialyltransferase activity appeared to be selective and is suggested to be due to structural modification of the cell surface galactoprotein acceptors for this enzyme. The data indicate that 6-deoxy-6-fluoro-D-galactose is an effective modifier of cellular glycoconjugate in that its incorporation into certain cell surface components results in a modification of plasma membrane structure and function.

The total synthesis of clitocine [6-amino-5-nitro-4-(beta-D-ribofuranosylamino)pyrimidine] (1), a nucleoside recently isolated from the mushroom Clitocybe inversa, has been accomplished. Glycosylation of 4,6-diamino-5-nitropyrimidine (4) with 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose afforded the protected nucleoside 6-amino-5-nitro-4-[(2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl) amino]pyrimidine (5) in good yield exclusively as the beta-anomer. Deprotection of 5 with NaOMe/MeOH gave 1 as an 11.5:1 mixture of the beta- and alpha-anomers, respectively. Recrystallization from MeOH, followed by chromatography, afforded 1 containing less than 1% of its alpha-anomer. X-ray crystal data revealed a planar aglycon moiety in clitocine with each oxygen atom of the nitro group intramolecularly hydrogen bonded to the hydrogen atoms of the two adjacent amino functions. Clitocine inhibited L1210 cells in vitro with an ID50 of 3 X 10(-8) M. Clitocine was also found to be a substrate and inhibitor of adenosine kinase with a Ki value of 3 X 10(-6) M.

A number of 3,4-disubstituted pyrazolo[3,4-d]pyrimidine ribonucleosides were synthesized and tested for their biological activity. Glycosylation of persilylated as well as nonsilylated 3-bromoallopurinol with 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose (4) provided the key intermediate 3-bromo-1-(2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl)-pyrazolo[3,4-d] pyrimidin-4(5H)-one (5a). Similar glycosylations of 3-cyanoallopurinol and 3-(methylthio)allopurinol furnished the corresponding protected N-1 glycosyl derivatives (5b and 5c). Debenzoylation of these nucleosides (5a-c) gave the corresponding 3-bromo-, 3-cyano-, and 3-(methylthio)allopurinol nucleosides (6a-c). The site of glycosylation and anomeric configuration of 6a and 6c were assigned on the basis of spectral studies as well as conversion to allopurinol ribonucleoside, whereas the structural assignment of 6b was made by single-crystal X-ray analysis. Conventional functional group transformation of 5a and 5b provided a number of novel 3-substituted allopurinol nucleosides, which included 10a and 18a-d. Glycosylation of 4-amino-3-bromopyrazolo[3,4-d]pyrimidine (14) with 4 and subsequent debenzoylation gave 3-bromo-4-aminopyrazolo[3,4-d]pyrimidine ribonucleoside (13a) from which 3,4-diamino-1-beta-D-ribofuranosylpyrazolo[3,4-d]pyrimidine (13b) was obtained by amination. Thiation of 5b, followed by deblocking, gave 3-cyanothiopurinol ribonucleoside (20). All of these compounds were tested in vitro against certain viruses, tumor cells, and the parasite Leishmania tropica. Among the 3-substituted allopurinol nucleosides, 18b and 18c showed significant activity against Para 3 virus and were found to be potent inhibitors of growth of L1210 and P388 leukemia. Compound 20 exhibited the most significant broad-spectrum in vitro antiviral and antitumor activity. 3-Bromoallopurinol ribonucleoside (6a) was found to be more active than allopurinol ribonucleoside against Leishmania tropica within human macrophages in vitro.

Magnesium and manganese ions bind strongly to the unusual transfer RNA anticodon loop nucleotides, N-[(9-beta-D-ribofuranosyl-9H-purin-6-yl)carbamoyl]-L-threonine 5'-monophosphate (pt6A) and uridine-5-oxyacetic acid 5'-monophosphate (pV). Potentiometric measurements have shown that the delta G for metal ion-pt6A complex formation is 2-3-times more exothermic than for AMP. Electron-nuclear longitudinal dipolar relaxation data yielded manganese-ligand atom distances which permit a three-dimensional construct of the complex in which metal is coordinated to the phosphate, carboxylate of the threonine side-chain (with the nucleotide in the anti glycosidic conformation) and N7 of the adenine ring. Similarly, manganese binds strongly to pV, involving phosphate and carboxylate functions. It is possible that a facet of the functional role of these unusual residues is to chelate magnesium ions and in so doing permit optimum anticodon loop conformational stability and stability of tRNA-mRNA-ribosome complexes.

Methyl 5-acetamido-3,5-dideoxy-2-O-methyl-D-glycero-D-galacto-2-nonulopyrano sate was converted into the 9-O-trityl derivative and the remaining hydroxyl groups were protected as benzyl ethers. Removal of the trityl group, followed by treatment with diethylaminosulfur trifluoride gave the 9-deoxy-9-fluoro derivative, and deprotection N-acetyl-9-deoxy-9-fluoroneuraminic acid (8). In another procedure, coupling of 2-acetamido-2,6-dideoxy-6-fluoro-D-glucopyranose with potassium di(tert-butyl) oxaloacetate, followed by hydrolysis and decarboxylation gave 8. Some of the derivatives were active as inhibitors of growth of mouse mammary adenocarcinoma (TA3) and L1210 cells in culture.

Several 3,4,6-trisubstituted pyrazolo[3,4-d]pyrimidine ribonucleosides were prepared and tested for their biological activity. High-temperature glycosylation of 3,6-dibromoallopurinol with 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose in the presence of BF3 X OEt2, followed by ammonolysis, provided 6-amino-3-bromo-1-beta-D-ribofuranosylpyrazolo-[3,4-d]pyrimidin-4(5H)-on e. Similar glycosylation of either 3-bromo-4(5H)-oxopyrazolo [3,4-d]pyrimidin-6-yl methyl sulfoxide or 6-amino-3-bromopyrazolo [3,4-d]pyrimidin-4(5H)-one, and subsequent ammonolysis, also gave 7a. The structural assignment of 7a was on the basis of spectral studies, as well as its conversion to the reported guanosine analogue 1d. Application of this glycosylation procedure to 6-(methylthio)-4(5H)-oxopyrazolo[3,4-d]pyrimidine-3-carboxamide gave the corresponding N-1 glycosyl derivative. Dethiation and debenzoylation of 16a provided an alternate route to the recently reported 3-carbamoylallopurinol ribonucleoside thus confirming the structural assignment of 16a and the nucleosides derived therefrom. Oxidation of 16a and subsequent ammonolysis afforded 6-amino-1-beta-D-ribofuranosyl-4(5H)-oxopyrazolo[3, 4-d]pyrimidine-3-carboxamide. Alkaline treatment of 15a gave 6-azacadeguomycin. Acetylation of 15a, followed by dehydration with phosgene, provided the versatile intermediate 6-amino-1-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)-4(5H)-oxopyrazolo [3, 4-d]pyrimidine-3-carbonitrile. Deacetylation of 19 gave 6-amino-1-beta-D-ribofuranosyl-4(5H)-oxopyrazolo[3, 4-d]pyrimidine-3-carbonitrile. Reaction of 19 with H2S gave 6-amino-1-beta-D-ribofuranosyl-4(5H)-oxopyrazolo[3, 4-d]pyrimidine-3-thiocarboxamide. All of these compounds were tested in vitro against certain viruses and tumor cells. Among these compounds, the guanosine analogues 7a and 20a showed significant activity against measles in vitro and were found to exhibit moderate antitumor activity in vitro against L1210 and P388 leukemia. 6-Azacadeguomycin and all other compounds were inactive against the viruses and tumor cells tested in vitro.

An HPLC method has been developed for the assay of cytidine monophosphate-sialic acid synthetase (EC 2.7.7.43) using ion-pair chromatography and gradient elution. This procedure permits the assay of alternative substrates and inhibitors of the enzyme and is not subject to the limitation of the colorimetric method. The newly synthesized N-acetyl-9-deoxy-9-fluoro-D-neuraminic acid was found to be a good substrate of the enzyme with a Km of 6.35 mM as compared to 1.84 mM for N-acetylneuraminic acid.

The first synthesis of 2,5-anhydro-5-thio-D-allononitrile starting with L-lyxose, via a trifluoromethanesulfonic ester intermediate, has been accomplished. Methods have been developed to achieve a large-scale synthesis of 3,4,5,7-tetra-O-acetyl-2,6-anhydro-D-glycero-D-talo-heptononitrile (5). An improved procedure has been developed to synthesize 2,5-anhydro-3,4,6-tri-O-benzoyl-D-gulononitrile (9). The structures of 5 and the thioamide derivative from 9, 2,5-anhydro-3,4,6-tri-O-benzoyl-D-gulonothioamide, were confirmed by X-ray crystallographic analysis.

A number of nucleoside and nucleotide derivatives of 4-hydroxy-3-beta-D-ribofuranosylpyrazole-5-carboxamide (pyrazofurin, 1) were prepared and tested for their antiviral and cytostatic activity in cell culture. Treatment of 1 with benzyl bromide gave 4-O-benzylpyrazofurin (4). Methylation of 4 with CH2N2 and subsequent removal of the benzyl group by catalytic hydrogenation provided 1-methylpyrazofurin (8). Direct methylation of 1 with CH3I furnished 4-O-methylpyrazofurin (6). Dehydration of the pentaacetylpyrazofurin (9) with phosgene furnished 4-acetoxy-3-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)-1-acetylpyrazol e-5-carbonitrile (10). A similar dehydration of the precursor tetraacetyl derivative of 4 gave the corresponding carbonitrile, which on deprotection and subsequent treatment with hydroxylamine furnished 4- (benzyloxy)-3-beta-D-ribofuranosylpyrazole-5-carboxamidoxime (13). Treatment of the tetraacetyl derivative of 4 with Lawesson's reagent and subsequent deacetylation furnished a mixture of 4- (benzyloxy)-3-beta-D-ribofuranosylpyrazole-5-thiocarboxamide (15) and the corresponding nitrile derivative (16). Phosphorylation of unprotected 4 with POCl3 and subsequent debenzylation of the intermediate 17 gave pyrazofurin 5'-phosphate (18), which provided the first chemical synthesis of 18. Similar phosphorylation of 4 with POCl3 and quenching the reaction mixture with either EtOH or MeOH, followed by debenzylation, furnished the 5'-O-(ethyl phosphate) (19b) and 5'-O-(dimethyl phosphate) (20b) derivatives of pyrazofurin. DCC-mediated cyclization of 17, followed by debenzylation, gave pyrazofurin 3',5'-(cyclic)phosphate (21b). The NAD analogue 23b was also prepared by the treatment of 17 with an activated form of AMP in the presence of AgNO3. The structural assignment of 7,8, and 20a were made by single-crystal X-ray analysis, and along with pyrazofurin, their intramolecular hydrogen bond characteristics have been studied. All of these compounds were tested in Vero cell cultures against a spectrum of viruses. Compounds 18 and 23b were active at concentrations very similar to pyrazofurin but are less toxic to the cells than pyrazofurin. Compounds 19b, 20b, and the 3',5'-(cyclic)phosphate 21b are less active than 1. Compounds 18, 19b, 20b, and 23b also exhibited significant inhibitory effects on the growth of L1210 and P388 leukemias and Lewis lung carcinoma cells in vitro, whereas B16 melanoma cells were less sensitive to growth inhibition by these compounds. Pyrazofurin derivatives modified at the 1-, 4-, or 5-position showed neither antiviral nor cytostatic activity in cell culture.